Torsten Falk

Interests

Teaching

Dr. Falk mentors students from the High school to the Gradate Student level.

Research

Dr. Falk's research focuses on cellular and rodent models to test 1) novel pharmacological treatments for levodopa-induced dyskinesias, a major side effect of Parkinson’s disease treatment, 2) novel neuroprotective (growth factor mediated) gene therapy approaches to Parkinson’s disease, and 3) development of glycopeptides for the treatment of Parkinson’s disease and other neurological conditions.

Courses

Scholarly Contributions

Journals/Publications

• Jordan, G., Vishwanath, A., Holguin, G., Bartlett, M., Tapia, A., Winter, G., Sexauer, M., Stopera, C., Falk, T., & Cowen, S. (2024). Automated system for training and assessing reaching and grasping behaviors in rodents. Journal of Neuroscience Methods, 401(109990). doi:10.1016/j.jneumeth.2023.109990
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  Background: Reaching, grasping, and pulling behaviors are studied across species to investigate motor control and problem solving. String pulling is a distinct reaching and grasping behavior that is rapidly learned, requires bimanual coordination, is ethologically grounded, and has been applied across species and disease conditions. New Method: Here we describe the PANDA system (Pulling And Neural Data Analysis), a hardware and software system that integrates a continuous string loop connected to a rotary encoder, feeder, microcontroller, high-speed camera, and analysis software for the assessment and training of reaching, grasping, and pulling behaviors and synchronization with neural data. Results: We demonstrate this system in rats implanted with electrodes in motor cortex and hippocampus and show how it can be used to assess relationships between reaching, pulling, and grasping movements and single-unit and local-field activity. Furthermore, we found that automating the shaping procedure significantly improved performance over manual training, with rats pulling > 100 m during a 15-minute session. Comparison with Existing Methods: String-pulling is typically shaped by tying food reward to the string and visually scoring behavior. The system described here automates training, streamlines video assessment with deep learning, and automatically segments reaching movements into distinct reach/pull phases. No system, to our knowledge, exists for the automated shaping and assessment of this behavior. Conclusions: This system will be of general use to researchers investigating motor control, motivation, sensorimotor integration, and motor disorders such as Parkinson's disease and stroke.
• Flores, A., Bartlett, M., Seaton, B., Samtani, G., Sexauer, M., Weintraub, N., Siegenthaler, J., Lu, D., Heien, M., Porreca, F., Sherman, S., & Falk, T. (2023). Antagonism of kappa opioid receptors accelerates the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion. Brain Research, 1821(148613). doi:10.1016/j.brainres.2023.148613
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  Levels of the opioid peptide dynorphin, an endogenous ligand selective for kappa-opioid receptors (KORs), its mRNA and pro-peptide precursors are differentially dysregulated in Parkinson's disease (PD) and following the development of L-DOPA-induced dyskinesia (LID). It remains unclear whether these alterations contribute to the pathophysiological mechanisms underlying PD motor impairment and the subsequent development of LID, or whether they are part of compensatory mechanisms. We sought to investigate nor-BNI, a KOR antagonist, 1) in the dopamine (DA)-depleted PD state, 2) during the development phase of LID, and 3) via measuring of tonic levels of striatal DA. While nor-BNI (3 mg/kg; s.c.) did not lead to functional restoration in the DA-depleted state, it affected the dose-dependent development of abnormal voluntary movements (AIMs) in response to escalating doses of L-DOPA in a rat PD model with a moderate striatal 6-hydroxdopamine (6-OHDA) lesion. We tested five escalating doses of L-DOPA (6, 12, 24, 48, 72 mg/kg; i.p.), and nor-BNI significantly increased the development of AIMs at the 12 and 24 mg/kg L-DOPA doses. However, after reaching the 72 mg/kg L-DOPA, AIMs were not significantly different between control and nor-BNI groups. In summary, while blocking KORs significantly increased the rate of development of LID induced by chronic, escalating doses of L-DOPA in a moderate-lesioned rat PD model, it did not contribute further once the overall severity of LID was established. While we observed an increase of tonic DA levels in the moderately lesioned dorsolateral striatum, there was no tonic DA change following administration of nor-BNI.
• Szabó, L. Z., Tanguturi, P., Goodman, H. J., Sprőber, S., Liu, C., Al-Obeidi, F., Bartlett, M. J., Falk, T., Kumirov, V. K., Heien, M. L., Streicher, J. M., & Polt, R. (2023). Structure-Based Design of Glycosylated Oxytocin Analogues with Improved Selectivity and Antinociceptive Activity. ACS medicinal chemistry letters, 14(2), 163-170.
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  Acute and chronic pain is often treated with opioids despite the negative side effects of constipation, physical dependence, respiratory depression, and overdose. The misuse of opioid analgesics has given rise to the opioid crisis/epidemic, and alternate nonaddictive analgesics are urgently needed. Oxytocin, a pituitary hormone, is an alternative to the small molecule treatments available and has been used as an analgesic as well as for the treatment and prevention of opioid use disorder (OUD). Clinical implementation is limited by its poor pharmacokinetic profile, a result of the labile disulfide bond between two cysteine residues in the native sequence. Stable brain penetrant oxytocin analogues have been synthesized by replacement of the disulfide bond with a stable lactam and glycosidation of the C-terminus. These analogues show exquisite selectivity for the oxytocin receptor and potent antinociception in mice following peripheral (i.v.) administration, supporting further study of their clinical potential.
• Apostol, C. R., Bernard, K., Tanguturi, P., Molnar, G., Bartlett, M. J., Szabò, L., Liu, C., Ortiz, J. B., Saber, M., Giordano, K. R., Green, T. R., Melvin, J., Morrison, H. W., Madhavan, L., Rowe, R. K., Streicher, J. M., Heien, M. L., Falk, T., & Polt, R. L. (2022). Design and Synthesis of Novel Brain Penetrant Glycopeptide Analogues of PACAP with Neuroprotective Potential for Traumatic Brain Injury and Parkinsonism.. Frontiers in drug discovery, Vol. 1:(818003). doi:https://doi.org/10.3389/fddsv.2021.818003
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  There is an unmet clinical need for curative therapies to treat neurodegenerative disorders. Most mainstay treatments currently on the market only alleviate specific symptoms and do not reverse disease progression. The Pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide hormone, has been extensively studied as a potential regenerative therapeutic. PACAP is widely distributed in the central nervous system (CNS) and exerts its neuroprotective and neurotrophic effects via the related Class B GPCRs PAC1, VPAC1, and VPAC2, at which the hormone shows roughly equal activity. Vasoactive intestinal peptide (VIP) also activates these receptors, and this close analogue of PACAP has also shown to promote neuronal survival in various animal models of acute and progressive neurodegenerative diseases. However, PACAP’s poor pharmacokinetic profile (non-linear PK/PD), and more importantly its limited blood-brain barrier (BBB) permeability has hampered development of this peptide as a therapeutic. We have demonstrated that glycosylation of PACAP and related peptides promotes penetration of the BBB and improves PK properties while retaining efficacy and potency in the low nanomolar range at its target receptors. Furthermore, judicious structure-activity relationship (SAR) studies revealed key motifs that can be modulated to afford compounds with diverse selectivity profiles. Most importantly, we have demonstrated that select PACAP glycopeptide analogues (2LS80Mel and 2LS98Lac) exert potent neuroprotective effects and anti-inflammatory activity in animal models of traumatic brain injury and in a mild-toxin lesion model of Parkinson’s disease, highlighting glycosylation as a viable strategy for converting endogenous peptides into robust and efficacious drug candidates.
• Pottenger, A. E., Bartlett, M. J., Sherman, S. J., Falk, T., & Morrison, H. W. (2021). Evaluation of microglia in a rodent model of Parkinson's disease primed with L-DOPA after sub-anesthetic ketamine treatment. Neuroscience letters, 765, 136251.
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  Parkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), characterized by motor dysfunction. While PD symptoms are well treated with L-DOPA, continuous use can cause L-DOPA-induced dyskinesia (LID). We have previously demonstrated that sub-anesthetic ketamine attenuated LID development in rodents, measured by abnormal involuntary movements (AIMs), and reduced the density of maladaptive striatal dendritic mushroom spines. Microglia may play a role by phagocytosing maladaptive neuronal spines. In this exploratory study, we hypothesized that ketamine would prevent AIMs and change microglia ramified morphology - an indicator of a microglia response. Unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats were primed with daily injections of L-DOPA for 14 days, treated on days 0 and 7 for 10-hours with sub-anesthetic ketamine (i.p.), and we replicated that this attenuated LID development. We further extended our prior work by showing that while ketamine treatment did lead to an increase of striatal interleukin-6 in dyskinetic rats, indicating a modulation of an inflammatory response, it did not change microglia number or morphology in the dyskinetic striatum. Yet an increase of CD68 in the SNpc of 6-OHDA-lesioned hemispheres post-ketamine indicates increased microglia phagocytosis suggestive of a lingering microglial response to 6-OHDA injury in the SNpc pointing to possible anti-inflammatory action in the PD model in addition to anti-dyskinetic action. In conclusion, we provide further support for sub-anesthetic ketamine treatment of LID. The mechanisms of action for ketamine, specifically related to inflammation and microglia phagocytic functions, are emerging, and require further examination.
• Ye, T., Bartlett, M. J., Sherman, S. J., Falk, T., & Cowen, S. L. (2021). Spectral signatures of L-DOPA-induced dyskinesia depend on L-DOPA dose and are suppressed by ketamine.. Experimental neurology, 340, 113670. doi:10.1016/j.expneurol.2021.113670
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  L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson's disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub-anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured movement and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, 12 mg/kg L-DOPA triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed after 7 mg/kg administration despite clear evidence of LID, indicating that 80-Hz oscillations are not an exclusive signature of LID. We also found that weeks-long low-dose priming resulted in the emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L-DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 h. We found that ketamine exposure suppressed striatal broadband gamma associated with LID but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine's therapeutic effects are region specific. Our findings also have clinical implications, as we are the first to report novel oscillatory signatures of the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD. We also identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.
• Young, K. F., Gardner, R., Sariana, V. C., Whitman, S. A., Bartlett, M. J., Falk, T., & Morrison, H. W. (2021). Can quantifying morphology and TMEM119 expression distinguish between microglia and infiltrating macrophages after ischemic stroke and reperfusion in male and female mice?. Journal of neuroinflammation, 18(1), 58. doi:10.1186/s12974-021-02105-2
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  Ischemic stroke is an acquired brain injury with gender-dependent outcomes. A persistent obstacle in understanding the sex-specific neuroinflammatory contributions to ischemic brain injury is distinguishing between resident microglia and infiltrating macrophages-both phagocytes-and determining cell population-specific contributions to injury evolution and recovery processes. Our purpose was to identify microglial and macrophage populations regulated by ischemic stroke using morphology analysis and the presence of microglia transmembrane protein 119 (TMEM119). Second, we examined sex and menopause differences in microglia/macrophage cell populations after an ischemic stroke..Male and female, premenopausal and postmenopausal, mice underwent either 60 min of middle cerebral artery occlusion and 24 h of reperfusion or sham surgery. The accelerated ovarian failure model was used to model postmenopause. Brain tissue was collected to quantify the infarct area and for immunohistochemistry and western blot methods. Ionized calcium-binding adapter molecule, TMEM119, and confocal microscopy were used to analyze the microglia morphology and TMEM119 area in the ipsilateral brain regions. Western blot was used to quantify protein quantity..Post-stroke injury is increased in male and postmenopause female mice vs. premenopause female mice (p < 0.05) with differences primarily occurring in the caudal sections. After stroke, the microglia underwent a region, but not sex group, dependent transformation into less ramified cells (p < 0.0001). However, the number of phagocytic microglia was increased in distal ipsilateral regions of postmenopausal mice vs. the other sex groups (p < 0.05). The number of TMEM119-positive cells was decreased in proximity to the infarct (p < 0.0001) but without a sex group effect. Two key findings prevented distinguishing microglia from systemic macrophages. First, morphological data were not congruent with TMEM119 immunofluorescence data. Cells with severely decreased TMEM119 immunofluorescence were ramified, a distinguishing microglia characteristic. Second, whereas the TMEM119 immunofluorescence area decreased in proximity to the infarcted area, the TMEM119 protein quantity was unchanged in the ipsilateral hemisphere regions using western blot methods..Our findings suggest that TMEM119 is not a stable microglia marker in male and female mice in the context of ischemic stroke. Until TMEM119 function in the brain is elucidated, its use to distinguish between cell populations following brain injury with cell infiltration is cautioned.
• Young, K., Gardner, R., Sariana, V. C., Whitman, S. A., Barlett, M. J., Falk, T., & Morrison, H. W. (2021). Can quantifying morphology and TMEM119 expression distinguish between microglia and infiltrating macrophages after ischemic stroke and reperfusion in male and female mice?. Journal of Neuroinflammation, 18:58. doi:https://doi.org/10.1186/s12974-021-02105-2
• Bartlett, M. J., Flores, A. J., Ye, T., Smidt, S. I., Dollish, H. K., Stancati, J. A., Farrell, D. C., Parent, K. L., Besselsen, D. G., Doyle, K., Heien, M. L., Cowen, S. L., Steece-Collier, K., Sherman, S. J., & Falk, T. (2020). Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia.. Experimental Neurology, 333, 113413. doi:https://doi.org/10.1016/j.expneurol.2020.113413
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  Parkinson's disease (PD) is the second most common neurodegenerative disease. Pharmacotherapy with L-DOPA remains the gold-standard therapy for PD, but is often limited by the development of the common side effect of L-DOPA-induced dyskinesia (LID), which can become debilitating. The only effective treatment for disabling dyskinesia is surgical therapy (neuromodulation or lesioning), therefore effective pharmacological treatment of LID is a critical unmet need. Here, we show that sub-anesthetic doses of ketamine attenuate the development of LID in a rodent model, while also having acute anti-parkinsonian activity. The long-term anti-dyskinetic effect is mediated by brain-derived neurotrophic factor-release in the striatum, followed by activation of ERK1/2 and mTOR pathway signaling. This ultimately leads to morphological changes in dendritic spines on striatal medium spiny neurons that correlate with the behavioral effects, specifically a reduction in the density of mushroom spines, a dendritic spine phenotype that shows a high correlation with LID. These molecular and cellular changes match those occurring in hippocampus and cortex after effective sub-anesthetic ketamine treatment in preclinical models of depression, and point to common mechanisms underlying the therapeutic efficacy of ketamine for these two disorders. These preclinical mechanistic studies complement current ongoing clinical testing of sub-anesthetic ketamine for the treatment of LID by our group, and provide further evidence in support of repurposing ketamine to treat individuals with PD. Given its clinically proven therapeutic benefit for both treatment-resistant depression and several pain states, very common co-morbidities in PD, sub-anesthetic ketamine could provide multiple therapeutic benefits for PD in the future.
• Bartlett, M. J., Mabrouk, O. S., Szabò, L., Flores, A. J., Parent, K. L., Bidlack, J. M., Heien, M. L., Kennedy, R. T., Polt, R., Sherman, S. J., & Falk, T. (2020). The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia. International journal of molecular sciences, 22(1).
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  In previous work we evaluated an opioid glycopeptide with mixed μ/δ-opioid receptor agonism that was a congener of leu-enkephalin, MMP-2200. The glycopeptide analogue showed penetration of the blood-brain barrier (BBB) after systemic administration to rats, as well as profound central effects in models of Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesia (LID). In the present study, we tested the glycopeptide BBI-11008 with selective δ-opioid receptor agonism, an analogue of deltorphin, a peptide secreted from the skin of frogs (genus ). We tested BBI-11008 for BBB-penetration after intraperitoneal () injection and evaluated effects in LID rats. BBI-11008 (10 mg/kg) demonstrated good CNS-penetrance as shown by microdialysis and mass spectrometric analysis, with peak concentration levels of 150 pM in the striatum. While BBI-11008 at both 10 and 20 mg/kg produced no effect on levodopa-induced limb, axial and oral (LAO) abnormal involuntary movements (AIMs), it reduced the levodopa-induced locomotor AIMs by 50% after systemic injection. The -methyl-D-aspartate receptor antagonist MK-801 reduced levodopa-induced LAO AIMs, but worsened PD symptoms in this model. Co-administration of MMP-2200 had been shown prior to block the MK-801-induced pro-Parkinsonian activity. Interestingly, BBI-11008 was not able to block the pro-Parkinsonian effect of MK-801 in the LID model, further indicating that a balance of mu- and delta-opioid agonism is required for this modulation. In summary, this study illustrates another example of meaningful BBB-penetration of a glycopeptide analogue of a peptide to achieve a central behavioral effect, providing additional evidence for the glycosylation technique as a method to harness therapeutic potential of peptides.
• Bartlett, M. J., So, L. Y., Szabò, L., Skinner, D. P., Parent, K. L., Heien, M. L., Vanderah, T. W., Polt, R., Sherman, S. J., & Falk, T. (2020). Highly-selective µ-opioid receptor antagonism does not block L-DOPA-induced dyskinesia in a rodent model. BMC research notes, 13(1), 149.
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  Dopamine-replacement utilizing L-DOPA is still the mainstay treatment for Parkinson's disease (PD), but often leads to development of L-DOPA-induced dyskinesia (LID), which can be as debilitating as the motor deficits. There is currently no satisfactory pharmacological adjunct therapy. The endogenous opioid peptides enkephalin and dynorphin are important co-transmitters in the direct and indirect striatofugal pathways and have been implicated in genesis and expression of LID. Opioid receptor antagonists and agonists with different selectivity profiles have been investigated for anti-dyskinetic potential in preclinical models. In this study we investigated effects of the highly-selective μ-opioid receptor antagonist CTAP (> 1200-fold selectivity for μ- over δ-opioid receptors) and a novel glycopeptide congener (gCTAP5) that was glycosylated to increase stability, in the standard rat LID model.
• Crown, L. M., Bartlett, M. J., Wiegand, J. L., Eby, A. J., Monroe, E. J., Gies, K. F., Wohlford, L. A., Fell, M. J., Falk, T., & Cowen, S. L. (2020). Sleep Spindles and Fragmented Sleep as Prodromal Markers in a Preclinical Model of LRRK2-G2019S Parkinson's Disease.. Frontiers in neurology, 11, 324. doi:10.3389/fneur.2020.00324
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  Sleep disturbances co-occur with and precede the onset of motor symptoms in Parkinson's disease (PD). We evaluated sleep fragmentation and thalamocortical sleep spindles in mice expressing the p.G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene, one of the most common genetic forms of PD. Thalamocortical sleep spindles are oscillatory events that occur during slow-wave sleep that are involved in memory consolidation. We acquired data from electrocorticography, sleep behavioral measures, and a rotarod-based motor enrichment task in 28 LRRK2-G2019S knock-in mice and 27 wild-type controls (8-10 month-old males). Sleep was more fragmented in LRRK2-G2019S mice; sleep bouts were shorter and more numerous, even though total sleep time was similar to controls. LRRK2-G2019S animals expressed more sleep spindles, and individual spindles were longer in duration than in controls. We then chronically administered the LRRK2-inhibitor MLi-2 in-diet to n = 12 LRRK2-G2019S and n = 15 wild-type mice for a within-subject analysis of the effects of kinase inhibition on sleep behavior and physiology. Treatment with MLi-2 did not impact these measures. The data indicate that the LRRK2-G2019S mutation could lead to reduced sleep quality and altered sleep spindle physiology. This suggests that sleep spindles in LRRK2-G2019S animals could serve as biomarkers for underlying alterations in sleep networks resulting from the LRRK2-G2019S mutation, and further evaluation in human LRRK2-G2019S carriers is therefore warranted.
• Hay, M., Polt, R., Heien, M. L., Vanderah, T. W., Largent-Milnes, T. M., Rodgers, K., Falk, T., Bartlett, M. J., Doyle, K. P., & Konhilas, J. P. (2019). A Novel Angiotensin-(1-7) Glycosylated Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Inflammation-Related Memory Dysfunction. The Journal of pharmacology and experimental therapeutics, 369(1), 9-25.
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  Increasing evidence indicates that decreased brain blood flow, increased reactive oxygen species (ROS) production, and proinflammatory mechanisms accelerate neurodegenerative disease progression such as that seen in vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease and related dementias. There is a critical clinical need for safe and effective therapies for the treatment and prevention of cognitive impairment known to occur in patients with VCID and chronic inflammatory diseases such as heart failure (HF), hypertension, and diabetes. This study used our mouse model of VCID/HF to test our novel glycosylated angiotensin-(1-7) peptide Ang-1-6-O-Ser-Glc-NH2 (PNA5) as a therapy to treat VCID and to investigate circulating inflammatory biomarkers that may be involved. We demonstrate that PNA5 has greater brain penetration compared with the native angiotensin-(1-7) peptide. Moreover, after treatment with 1.0/mg/kg, s.c., for 21 days, PNA5 exhibits up to 10 days of sustained cognitive protective effects in our VCID/HF mice that last beyond the peptide half-life. PNA5 reversed object recognition impairment in VCID/HF mice and rescued spatial memory impairment. PNA5 activation of the Mas receptor results in a dose-dependent inhibition of ROS in human endothelial cells. Last, PNA5 treatment decreased VCID/HF-induced activation of brain microglia/macrophages and inhibited circulating tumor necrosis factor , interleukin (IL)-7, and granulocyte cell-stimulating factor serum levels while increasing that of the anti-inflammatory cytokine IL-10. These results suggest that PNA5 is an excellent candidate and "first-in-class" therapy for treating VCID and other inflammation-related brain diseases.
• Figueroa, A. G., Congrove, N. R., Sillik, S. A., Sadideen, D. T., Falk, T., Rickman, C. B., & Mckay, B. S. (2018). Exosome uptake is selective but not species or tissue-specific. Investigative Ophthalmology & Visual Science, 59(9), 3993-3993.
• Flores, A. J., Bartlett, M. J., Root, B. K., Parent, K. L., Heien, M. L., Porreca, F., Polt, R. L., Sherman, S. J., & Falk, T. (2018). The combination of the opioid glycopeptide MMP-2200 and a NMDA receptor antagonist reduced L-DOPA-induced dyskinesia and MMP-2200 by itself reduced dopamine receptor 2-like agonist-induced dyskinesia. Neuropharmacology, 141, 260-271. doi:10.1016/j.neuropharm.2018.09.005
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  Dopamine (DA)-replacement therapy utilizing l-DOPA is the gold standard symptomatic treatment for Parkinson's disease (PD). A critical complication of this therapy is the development of l-DOPA-induced dyskinesia (LID). The endogenous opioid peptides, including enkephalins and dynorphin, are co-transmitters of dopaminergic, GABAergic, and glutamatergic transmission in the direct and indirect striatal output pathways disrupted in PD, and alterations in expression levels of these peptides and their precursors have been implicated in LID genesis and expression. We have previously shown that the opioid glycopeptide drug MMP-2200 (a.k.a. Lactomorphin), a glycosylated derivative of Leu-enkephalin mediates potent behavioral effects in two rodent models of striatal DA depletion. In this study, the mixed mu-delta agonist MMP-2200 was investigated in standard preclinical rodent models of PD and of LID to evaluate its effects on abnormal involuntary movements (AIMs). MMP-2200 showed antiparkinsonian activity, while increasing l-DOPA-induced limb, axial, and oral (LAO) AIMs by ∼10%, and had no effect on dopamine receptor 1 (D1R)-induced LAO AIMs. In contrast, it markedly reduced dopamine receptor 2 (D2R)-like-induced LAO AIMs. The locomotor AIMs were reduced by MMP-2200 in all three conditions. The N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 has previously been shown to be anti-dyskinetic, but only at doses that induce parkinsonism. When MMP-2200 was co-administered with MK-801, MK-801-induced pro-parkinsonian activity was suppressed, while a robust anti-dyskinetic effect remained. In summary, the opioid glycopeptide MMP-2200 reduced AIMs induced by a D2R-like agonist, and MMP-2200 modified the effect of MK-801 to result in a potent reduction of l-DOPA-induced AIMs without induction of parkinsonism.
• Ye, T., Bartlett, M. J., Schmitt, M. B., Sherman, S. J., Falk, T., & Cowen, S. L. (2018). Ten-Hour Exposure to Ketamine Enhances Corticostriatal Cross-Frequency Coupling and Broad-Band Gamma Oscillations in the Hippocampus.. Frontiers in Neural Circuits, 12:61. doi:10.3389/fncir.2018.00061.
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  Introduction: Treatment-resistant depression, post-traumatic stress disorder, chronic pain, and L-DOPA-induced dyskinesia in Parkinson’s disease are characterized by hypersynchronous neural oscillations. Sub-anesthetic ketamine is effective at treating these conditions, and this may relate to ketamine’s capacity to reorganize oscillatory activity throughout the brain. For example, a single ketamine injection increases gamma (∼40 Hz) and high-frequency oscillations (HFOs, 120–160 Hz) in the cortex, hippocampus, and striatum. While the effects of single injections have been investigated, clinical ketamine treatments can involve 5-h up to 3-day sub-anesthetic infusions. Little is known about the effects of such prolonged exposure on neural synchrony. We hypothesized that hours-long exposure entrains circuits that generate HFOs so that HFOs become sustained after ketamine’s direct effects on receptors subside.Methods: Local-field recordings were acquired from motor cortex (M1), striatum, and hippocampus of behaving rats (n = 8), and neural responses were measured while rats received 5 ketamine injections (20 mg/kg, i.p., every 2 h, 10-h exposure). In a second experiment, the same animals received injections of D1-receptor antagonist (SCH-23390, 1 mg/kg, i.p.) prior to ketamine injection to determine if D1 receptors were involved in producing HFOs.Results: Although HFOs remained stable throughout extended ketamine exposure, broad-band high-frequency activity (40–140 Hz) in the hippocampus and delta-HFO cross-frequency coupling (CFC) in dorsal striatum increased with the duration of exposure. Furthermore, while ketamine-triggered HFOs were not affected by D1 receptor blockade, ketamine-associated gamma in motor cortex was suppressed, suggesting involvement of D1 receptors in ketamine-mediated gamma activity in motor cortex.Conclusion: Prolonged ketamine exposure does not enhance HFOs in corticostriatal circuits, but, instead, enhances coordination between low and high frequencies in the striatum and reduces synchrony in the hippocampus. Increased striatal CFC may facilitate spike-timing dependent plasticity, resulting in lasting changes in motor activity. In contrast, the observed wide-band high-frequency “noise” in the hippocampus suggests that ketamine disrupts action-potential timing and reorganizes connectivity in this region. Differential restructuring of corticostriatal and limbic circuits may contribute to ketamine’s clinical benefits.
• Sherman, S. J., Estevez, M., Magill, A. R., & Falk, T. (2016). Case reports showing a long-term effect of subanesthetic ketamine infusion in reducing L-DOPA-induced dyskinesias. Case Reports in Neurology, 8, 53–8. doi:10.1159/000444278
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  Ketamine is an FDA-approved drug with a known safety profile. Low-dose subanesthetic intravenous ketamine infusion treatment has led to long-term reduction of treatment-resistant depression and of chronic pain states. We report on low-dose subanesthetic intravenous ketamine infusion treatment in Parkinson's disease (PD) patients by 5 case studies and show a long-lasting therapeutic benefit to reduce L-DOPA-induced dyskinesia (LID), improve on time, and reduce depression. Based on the literature we hypothesize that low-dose ketamine may act as a ‘chemical deep brain stimulation', by desynchronizing hypersynchronous oscillatory brain activity, including in the basal ganglia and the motor cortex. The presented PD case reports indicate tolerability, safety and long-term beneficial effects of low-dose ketamine infusion that should be further investigated in a properly controlled prospective clinical trial for treatment of LID, as well as the prevalent nonmotor features pain and depression in PD patients.
• Bartlett, M. J., Joseph, R. M., LePoidevin, L. M., Parent, K. L., Laude, N. D., Lazarus, L. B., Heien, M. L., Estevez, M., Sherman, S. J., & Falk, T. (2016). Long-term effect of sub-anesthetic ketamine in reducing l-DOPA-induced dyskinesias in a preclinical model. Neuroscience letters, 612, 121-5.
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  Low-dose sub-anesthetic ketamine infusion treatment has led to a long-term reduction of treatment-resistant depression and posttraumatic stress disorder (PTSD) symptom severity, as well as reduction of chronic pain states, including migraine headaches. Ketamine also is known to change oscillatory electric brain activity. One commonality between migraine headaches, depression, PTSD, Parkinson's disease (PD) and l-DOPA-induced dyskinesias (LID) is hypersynchrony of electric activity in the brain, including the basal ganglia. Therefore, we investigated the use of low-dose sub-anesthetic ketamine in the treatment of LID. In a preclinical rodent model of LID, ketamine (5-20mg/kg) led to long-term dose-dependent reduction of abnormal involuntary movements, only when low-dose ketamine was given for 10h continuously (5× i.p. injections two hours apart) and not after a single acute low-dose ketamine i.p. injection. Pharmacokinetic analysis of plasma levels showed ketamine and its major metabolites were not detectable any more at time points when a lasting anti-dyskinetic effect was seen, indicating a plastic change in the brain. This novel use of low-dose sub-anesthetic ketamine infusion could lead to fast clinical translation, and since depression and comorbid pain states are critical problems for many PD patients could open up the road to a new dual therapy for patients with LID.
• Flores, A. J., Bartlett, M. J., So, L. Y., Laude, N. D., Parent, K. L., Heien, M. L., Sherman, S. J., & Falk, T. (2014). Differential effects of the NMDA receptor antagonist MK-801 on dopamine receptor D1- and D2-induced abnormal involuntary movements in a preclinical model.. Neuroscience letters, 564, 48-52. doi:10.1016/j.neulet.2014.02.004
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  Dopamine-replacement therapy with l-DOPA is still the gold standard treatment for Parkinson's disease (PD). One drawback is the common development of l-DOPA-induced dyskinesia (LID) in patients, which can be as disabling as the disease itself. There is no satisfactory adjunct therapy available. Glutamatergic transmission in the basal ganglia circuitry has been shown to be an important player in the development of LID. The N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 has previously been shown to reduce l-DOPA-induced abnormal involuntary movements (AIMs) in a rat preclinical model but only at concentrations that worsen parkinsonism. We investigated the contribution of the direct and indirect striatofugal pathways to these effects. In the direct pathway, dopamine D1 receptors (D1R) are expressed, whereas in the indirect pathway, dopamine D2 receptors (D2R) are expressed. We used the 6-hydroxydopamine-lesioned hemi-parkinsonian rat model initially primed with l-DOPA to induce dyskinesia. When the rats were then primed and probed with the D1R agonist SKF81297, co-injection of MK-801 worsened the D1R-induced limb, axial, and orolingual (LAO) AIMs by 18% (predominantly dystonic axial AIMs) but did not aggravate parkinsonian hypokinesia as reflected by a surrogate measure of ipsiversive rotations in this model. In contrast, when the rats were then primed and probed with the D2R agonist quinpirole, co-injection of MK-801 reduced D2R-induced LAO AIMs by 89% while inducing ipsiversive rotations. The data show that only inhibition of the indirect striatopallidal pathway is sufficient for the full anti-dyskinetic/pro-parkinsonian effects of the NMDA receptor antagonist MK-801, and that MK-801 modestly worsens dyskinesias that are due to activation of the direct striatonigral pathway alone. This differential activation of the glutamatergic systems in D1R- and D2R-mediated responses is relevant to current therapy for PD which generally includes a mixture of dopamine agonists and l-DOPA.
• Yue, X., Hariri, D. J., Caballero, B., Zhang, S., Bartlett, M. J., Kaut, O., Mount, D. W., Wullner, U., Sherman, S. J., & Falk, T. (2014). Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease.. Neuroscience, 258, 385-400. doi:10.1016/j.neuroscience.2013.11.038
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  Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 μg) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 μg), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 μg VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and PD patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated.
• Ferng, S. J., Gonzalez, D. E., Nguyen, M. N., Sherman, S. J., Falk, T., & Rilo, H. L. (2013). Evaluation of a Parkinson's disease model in medaka fish. The FASEB Journal, 27. doi:10.1096/fasebj.27.1_supplement.567.1
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  Parkinson’s disease (PD) is the 2nd most common neurodegenerative disease. Dopaminergic (DA) neurons in the substantia nigra of the brain are the most vulnerable to PD. 6- hydroxydopamine (6-OHDA) ...
• Ferng, S. J., González, D., Nguyen, M. N., Sherman, S. J., Falk, T., & Rilo, H. (2013). Evaluation of a Parkinson's disease model in medaka fish. The FASEB Journal, 27(S1). doi:10.1096/fasebj.27.1_supplement.567.1
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  Parkinson's disease (PD) is the 2nd most common neurodegenerative disease. Dopaminergic (DA) neurons in the substantia nigra of the brain are the most vulnerable to PD. 6- hydroxydopamine (6-OHDA) is a neurotoxin structurally similar to dopamine that is transported inside the brain and destroys DA neurons. The resulting PD symptoms can be identified through behavioral analysis and verification of DA neuron loss through immunohistochemical analysis in medaka fish (Oryzias latipes). Medaka are well-suited as a PD model because they are transparent during most stages of development, produce numerous offspring, and readily absorb toxicants through their skin. To establish a PD medaka model to time and cost-efficiently screen drugs that may change the progression of PD, medaka were exposed to varying concentrations of 6-OHDA through the water they swam in. Temporary acquired PD symptoms were evidenced by an initial decrease in total distance swam by 6-OHDA-treated medaka and changes in turn angle, but a complete behavioral recovery was evident at following time points. The results indicate that medaka exposure to 6-OHDA in the water is not sufficient to induce loss of DA neurons, presumably due to a reduced blood-brain barrier penetrance of 6-OHDA in medaka as compared to the established zebrafish model. Support: Univ. of AZ (UA) from Howard Hughes Medical Inst. (#52006942); NIH NINDS 1R25NS076437; UA Dept. Neurology.
• Falk, T., Congrove, N. R., Zhang, S., Mccourt, A. D., Sherman, S. J., & Mckay, B. S. (2012). PEDF and VEGF-A output from human retinal pigment epithelial cells grown on novel microcarriers.. Journal of biomedicine & biotechnology, 2012, 278932. doi:10.1155/2012/278932
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  Human retinal pigment epithelial (hRPE) cells have been tested as a cell-based therapy for Parkinson's disease but will require additional study before further clinical trials can be planned. We now show that the long-term survival and neurotrophic potential of hRPE cells can be enhanced by the use of FDA-approved plastic-based microcarriers compared to a gelatin-based microcarrier as used in failed clinical trials. The hRPE cells grown on these plastic-based microcarriers display several important characteristics of hRPE found in vivo: (1) characteristic morphological features, (2) accumulation of melanin pigment, and (3) high levels of production of the neurotrophic factors pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A). Growth of hRPE cells on plastic-based microcarriers led to sustained levels (>1 ng/ml) of PEDF and VEGF-A in conditioned media for two months. We also show that the expression of VEGF-A and PEDF is reciprocally regulated by activation of the GPR143 pathway. GPR143 is activated by L-DOPA (1 μM) which decreased VEGF-A secretion as opposed to the previously reported increase in PEDF secretion. The hRPE microcarriers are therefore novel candidate delivery systems for achieving long-term delivery of the neuroprotective factors PEDF and VEGF-A, which could have a value in neurodegenerative conditions such as Parkinson's disease.
• Ferng, S. J., González, D., Falk, T., Rilo, H., & Sherman, S. J. (2012). Development of a Parkinsonˈs disease model in medaka fish. The FASEB Journal, 26(S1). doi:10.1096/fasebj.26.1_supplement.998.1
• Mabrouk, O. S., Falk, T., Sherman, S. J., Kennedy, R. T., & Polt, R. (2012). CNS penetration of the opioid glycopeptide MMP-2200: a microdialysis study.. Neuroscience letters, 531(2), 99-103. doi:10.1016/j.neulet.2012.10.029
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  Endogenous opioid peptides enkephalin and dynorphin are major co-transmitters of striatofugal pathways of the basal ganglia. They are involved in the genesis of levodopa-induced dyskinesia and in the modulation of direct and indirect striatal output pathways that are disrupted in Parkinson's disease. One pharmacologic approach is to develop synthetic glycopeptides closely resembling endogenous peptides to restore their normal functions. Glycosylation promotes penetration of the blood-brain barrier. We investigated CNS penetration of the opioid glycopeptide MMP-2200, a mixed δ/μ-agonist based on leu-enkephalin, as measured by in vivo microdialysis and subsequent mass spectrometric analysis in awake, freely moving rats. The glycopeptide (10 mg/kg) reaches the dorsolateral striatum (DLS) rapidly after systemic (i.p.) administration and is stably detectable for the duration of the experiment (80 min). The detected level at the end of the experiment (around 250 pM) is about 10-fold higher than the level of the endogenous leu-enkephalin, measured simultaneously. This is one of the first studies to directly prove that glycosylation of an endogenous opioid peptide leads to excellent blood-brain barrier penetration after systemic injection, and explains robust behavioral effects seen in previous studies by measuring how much glycopeptide reaches the target structure, in this case the DLS.
• Falk, T., Yue, X., Zhang, S., Mccourt, A. D., Yee, B. J., Gonzalez, R. T., & Sherman, S. J. (2011). Vascular endothelial growth factor-B is neuroprotective in an in vivo rat model of Parkinson's disease.. Neuroscience letters, 496(1), 43-7. doi:10.1016/j.neulet.2011.03.088
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  Developing novel neuroprotective strategies for the treatment of Parkinson's disease (PD) is of great importance. We have previously shown that vascular endothelial growth factor-B (VEGF-B) is up-regulated in an in vitro model of PD using the neurotoxin rotenone. Addition of exogenous VEGF-B(167) was neuroprotective in this same model, suggesting that VEGF-B is a natural response to neurodegenerative challenges. Now we have extended this research using in vivo experiments. We tested a single intra-striatal injection of 3 μg VEGF-B(186), the more diffusible VEGF-B isoform, in a mild progressive unilateral 6-hydroxydopamine (6-OHDA) rat in vivo PD model. Treatment with VEGF-B(186) 6h prior to lesioning with 6-OHDA improved amphetamine-induced rotations and forepaw preference at 2, 4 and 6 weeks post-injection, indicating a neuroprotective effect. Immunohistochemical analysis showed that VEGF-B(186) treatment partially protected dopaminergic fibers in the striatum and demonstrated a partial rescue of the dopaminergic neurons in the caudal sub-region of the substantia nigra. Altogether our data suggest that VEGF-B(186) could be a new candidate trophic factor for the treatment of PD.
• Yue, X., Falk, T., Zuniga, L. A., Szabo, L., Porreca, F., Polt, R., & Sherman, S. J. (2011). Effects of the novel glycopeptide opioid agonist MMP-2200 in preclinical models of Parkinson's disease.. Brain research, 1413, 72-83. doi:10.1016/j.brainres.2011.07.038
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  In Parkinson's disease (PD), the consequence of dopaminergic denervation is an imbalance in the activity of the direct and indirect striatofugal pathways, which include potentially important changes in opioid peptide expression and/or activity. The systemic administration of a novel glycosylated opioid peptide MMP-2200 (a.k.a. lactomorphin) was shown to have potent effects in two standard models of PD: 1) amphetamine-induced rotations in the hemi-Parkinsonian 6-hydroxydopamine (6-OHDA)-treated rat and 2) locomotion in the reserpine-treated rat. MMP-2200, an opioid mu and delta receptor agonist, reduced amphetamine-induced rotations in severely-lesioned hemi-Parkinsonian rats; this effect was fully blocked by naloxone, an opioid receptor antagonist. The selective δ-opioid receptor antagonist naltrindole only partially blocked the effect of MMP-2200. MMP-2200 alone did not induce rotations. This effect was also observed in a mild progressive rat 6-OHDA-lesion model. In animals treated with reserpine, profound akinesia was induced that was reversed with apomorphine. There was a prominent overshoot in animals that received apomorphine compared to non-reserpine treated animals, reflecting the well described phenomenon of dopamine supersensitivity indicating that apomorphine not only reversed akinesia but also induced hyper-kinesia. The opioid peptide MMP-2200 blocked the apomorphine-induced hyper-kinesia. This effect of MMP-2200 was prevented by pre-administration of naloxone. MMP-2200 had no effect in preventing the reserpine-induced akinesia, nor did it affect locomotion in control animals. Taken together, the results from these two models are consistent with the glycopeptide opioid agonist MMP-2200 having a potent effect on movements related to dopaminergic hyper-stimulation following striatal dopamine depletion that are best explained by a reduction in the downstream effects of dopamine agonists in these models.
• Falk, T., Zhang, S., & Sherman, S. J. (2009). Pigment epithelium derived factor (PEDF) is neuroprotective in two in vitro models of Parkinson's disease.. Neuroscience letters, 458(2), 49-52. doi:10.1016/j.neulet.2009.04.018
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  Transplantation of retinal pigment epithelial (RPE) cells in the basal ganglia has been proposed as a novel cell-based therapy for Parkinson's disease (PD), by providing a constant source of dopamine replacement via the melanin synthetic pathway enzyme tyrosinase. We have demonstrated previously that human RPE cells also produce a neurotrophic effect on primary cultures of rat striata mesencephalic (dopaminergic) neurons and showed that pigment epithelium derived factor (PEDF) accounted for a major portion of the neurotrophic effect. We now have also begun studies that demonstrate that the neurotrophic effect of PEDF corresponds to neuroprotection against toxins used to produce experimental PD. This was shown in (1) rotenone and (2) 6-hydroxydopamine (6-OHDA) in vitro models. The toxins were added at day 10 in culture, PEDF was added 1h prior. The cultures were fixed and analyzed after tyrosine hydroxylase (TH) immunocytochemical staining. Cell count of TH+ neurons clearly shows the neuroprotective potential of PEDF in both neurotoxin models. The neurotoxic effect of rotenone (25nM) on dopaminergic neurons is reversed by addition of PEDF. At a concentration of 1ng/ml PEDF the neurotoxic effect of rotenone is completely counteracted. PEDF (1ng/ml) has also a neuroprotective effect in the 6-OHDA midbrain in vitro model. The effect is most pronounced at concentrations of 25microM and 50microM 6-OHDA. We conclude that the neurotrophic factor PEDF, produced from RPE cells, can improve neuronal survival in models of PD, and plan to test if this effect can be observed using in vivo models of PD following RPE transplantation.
• Falk, T., Zhang, S., & Sherman, S. J. (2009). Vascular endothelial growth factor B (VEGF-B) is up-regulated and exogenous VEGF-B is neuroprotective in a culture model of Parkinson's disease.. Molecular neurodegeneration, 4(1), 49. doi:10.1186/1750-1326-4-49
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  Parkinson's disease (PD) results from the degeneration of dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine released in the striatum. Current oral dopamine replacement or surgical therapies do not address the underlying issue of neurodegeneration, they neither slow nor halt disease. Neurotrophic factors have shown preclinical promise, but the choice of an appropriate growth factor as well as the delivery has proven difficult. In this study, we used a rotenone rat midbrain culture model to identify genes that are changed after addition of the neurotoxin. (1) We challenged rat midbrain cultures with rotenone (20 nM), a pesticide that has been shown to be toxic for dopaminergic neurons and that has been a well-characterized model of PD. A gene chip array analysis demonstrated that several genes were up-regulated after the rotenone treatment. Interestingly transcriptional activation of vascular endothelial growth factor B (VEGF-B) was evident, while vascular endothelial growth factor A (VEGF-A) levels remained unaltered. The results from the gene chip array experiment were verified with real time PCR and semi-quantitative western analysis using beta-actin as the internal standard. (2) We have also found evidence that exogenously applied VEGF-B performed as a neuroprotective agent facilitating neuron survival in an even more severe rotenone culture model of PD (40 nM rotenone). VEGF-B has very recently been added to the list of trophic factors that reduce effects of neurodegeneration, as was shown in an in vivo model of motor neuron degeneration, while lacking potential adverse angiogenic activity. The data of an in vivo protective effect on motor neurons taken together with the presented results demonstrate that VEGF-B is a new candidate trophic factor distinct from the GDNF family of trophic factors. VEGF-B is activated by neurodegenerative challenges to the midbrain, and exogenous application of VEGF-B has a neuroprotective effect in a culture model of PD. Strengthening this natural protective response by either adding exogenous VEGF-B or up-regulating the endogenous VEGF-B levels may have the potential to be a disease modifying therapy for PD. We conclude that the growth factor VEGF-B can improve neuronal survival in a culture model of PD.
• Falk, T., Xie, J. Y., Zhang, S., Kennedy, J., Bennett, J., Yool, A. J., & Sherman, S. J. (2008). Over-expression of the potassium channel Kir2.3 using the dopamine-1 receptor promoter selectively inhibits striatal neurons.. Neuroscience, 155(1), 114-27. doi:10.1016/j.neuroscience.2008.04.075
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  Dysfunction of basal ganglia circuits underlies a variety of movement disorders and neuropsychiatric conditions. Selective control of the electrical activity of striatal outflow pathways by manipulation of ion channel function presents a novel therapeutic approach. Toward this end, we have constructed and studied in vitro an adenoviral gene transfer vector that employs the promoter region of the dopamine-1 receptor to drive expression of the inward rectifier K(+) channel Kir2.3. The use of this neuronal promoter confers cell-type specificity and a physiological level of trans-gene expression in rat primary striatal cultures. The electrophysiological properties were confirmed in transfected human embryonic kidney cells, in which an inwardly-rectifying, Cs(+)-sensitive current was measured by voltage clamp. Current clamp studies of transduced striatal neurons demonstrated an increase in the firing threshold, latency to first action potential and decrease in neuronal excitability. Neurotoxin-induced activation of c-Fos, a marker of neuronal activity, was blocked in transduced neurons indicating that the decrease in electrical excitability was physiologically significant. When used in vivo, this strategy may have the potential to positively impact movement disorders by selectively changing activity of neurons belonging to the direct striatal pathway, characterized by the expression of dopamine-1 receptors.
• Falk, T., Zhang, S., Erbe, E. L., & Sherman, S. J. (2006). Neurochemical and electrophysiological characteristics of rat striatal neurons in primary culture.. The Journal of comparative neurology, 494(2), 275-89. doi:10.1002/cne.20819
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  Neurons maintained in dispersed primary culture offer a number of advantages as a model system and are particularly well-suited for studies of the intrinsic electrical properties of neurons by patch clamp. We have characterized the immunocytochemical and electrophysiological properties of cultured rat striatal neurons as they develop in vitro in order to compare this model system with the known properties found in vivo. We found a high abundance of cells in vitro corresponding to the principal striatal output neuron, the medium spiny neuron. Immunocytochemical studies indicate that these cells have both dopamine-1 and dopamine-2 receptors and that there is overlap in their expression within the population of neurons. Semiquantitative analysis revealed bimodal distributions of dopamine receptor expression among the population of neurons. The principal peptide neurotransmitters substance P and enkephalin were present but at reduced levels compared with adult preparations. Other striatal markers such as calbindin, calretinin, and the cannabinoid-1 receptor were abundant. An immunocytochemical survey of voltage-gated K(+) channel subunits characteristic of adult tissue demonstrated the presence in vitro of Kv1.1, Kv1.4, Kv4.2, Kv4.3, and Kvbeta1.1, which have been associated with the rapidly inactivating currents. Electrophysiological studies employing voltage clamp revealed that outward currents had a large inactivating (A-type) component characteristic of mature basal ganglia. Current clamp studies reveal complex spontaneous firing patterns in a subset of neurons, including bursting behaviors superimposed on a slow depolarization. The inward rectifying channels Kir2.1 and Kir2.3, which are specific to particular compartments in adult striatum, were present in culture.
• Mckay, B. S., Goodman, B., Falk, T., & Sherman, S. J. (2006). Retinal pigment epithelial cell transplantation could provide trophic support in Parkinson's disease: results from an in vitro model system.. Experimental neurology, 201(1), 234-43. doi:10.1016/j.expneurol.2006.04.016
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  Transplantation of retinal pigment epithelial (RPE) cells in the basal ganglia could provide a novel cell-based therapy for Parkinson's disease by providing a constant source of dopamine replacement via the melanin synthetic pathway enzyme tyrosinase. We now demonstrate that human RPE cells also produce a neurotrophic effect on primary cultures of rat striatal (enkephalinergic) and mesencephalic (dopaminergic) neurons. Differentiation of RPE cells to a pigmented monolayer using a Ca(++)-switch protocol increased the potency of the neurotrophic effect on dopaminergic neurons. Conditioned medium derived from differentiated RPE cells increased neurite outgrowth in dopaminergic neurons by 125% compared to 25% for undifferentiated RPE cells. The neurotrophic effect was not due to tyrosinase activity. Differentiation of RPE cells doubled the production of pigment-derived epithelial factor (PEDF). However, PEDF accounted for only a portion of the neurotrophic effect as determined by depletion experiments and dose-response comparisons with purified PEDF, indicating that differentiation increased the production of other trophic factors as well. Conditioned medium from differentiated RPE cells also provided a neurotrophic effect on a subset of enkephalinergic striatal neurons increasing neurite outgrowth by 78%. Survival of enkephalinergic neurons in vitro was increased by RPE conditioned medium. In untreated cultures the number of enkephalinergic neurons declined 62% over a 2-week period compared to a 29% decline in RPE-treated cultures. These results indicate that transplantation RPE cells could potentially provide a dual benefit in Parkinson's disease producing both dopamine and neurotrophic support of the basal ganglia.
• Falk, T., Erbe, E. L., Yool, A. J., & Shermann, S. J. (2004). Neurochemical and electrophysiological characterization of cultured rat striatal neurons as a model system for gene therapy. Biophysical Journal, 86(1).
• Falk, T., Kilani, R. K., Borders, R. S., Strazdas, L. A., Steidl, J. V., Yool, A. J., & Sherman, S. J. (2003). Developmental regulation of the A-type potassium-channel current in hippocampal neurons: role of the Kvbeta 1.1 subunit.. Neuroscience, 120(2), 387-404. doi:10.1016/s0306-4522(03)00044-7
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  The rapidly inactivating A-type K+ current (IA) is prominent in hippocampal neurons; and the speed of its inactivation may regulate electrical excitability. The auxiliary K+ channel subunit Kvbeta 1.1 confers fast inactivation to Shaker-related channels and is postulated to affect IA. Whole-cell patch clamp recordings of rat hippocampal pyramidal neurons in primary culture showed a developmental decrease in the time constant of inactivation (tau(in)) of voltage-gated K+ currents: 17.9+/-1.5 ms in young neurons (5-7 days in vitro; n=53, mean+/-S.E.M.); 9.9+/-1.0 ms in mature neurons (12-15 days in vitro; n=72, mean+/-S.E.M., P
• Falk, T., Kilani, R. K., Yool, A. J., & Sherman, S. J. (2001). Viral vector-mediated expression of K+ channels regulates electrical excitability in skeletal muscle.. Gene therapy, 8(18), 1372-9. doi:10.1038/sj.gt.3301539
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  Modification of K+ currents by exogenous gene expression may lead to therapeutic interventions in skeletal muscle diseases characterized by alterations in electrical excitability. In order to study the specific effects of increasing outward K+ currents, we expressed a modified voltage-dependent K+ channel in primary cultured rat skeletal muscle cells. The rat Kv1.4 channel was expressed as an N-terminal fusion protein containing a bioluminescent marker (green fluorescent protein). Transgene expression was carried out using the helper-dependent herpes simplex 1 amplicon system. Transduced myoballs, identified using fluorescein optics and studied electrophysiologically with single-cell patch clamp, exhibited a greater than two-fold increase in K+ conductance by 20-30 h after infection. This increase in K+ current led to a decrease in membrane resistance and a 10-fold increase in the current threshold for action potential generation. Electrical hyperexcitability induced by the Na+ channel toxin anemone toxin II (1 microM) was effectively counteracted by overexpression of Kv1.4 at 30-32 h after transduction. Thus, virally induced overexpression of a voltage-gated K+ channel in skeletal muscle has a powerful effect in reducing electrical excitability.
• Falk, T., Strazdas, L. A., Borders, R. S., Kilani, R. K., Yool, A. J., & Sherman, S. J. (2001). A herpes simplex viral vector expressing green fluorescent protein can be used to visualize morphological changes in high-density neuronal culture. Electronic Journal of Biotechnology, 4(1), 20-21. doi:10.4067/s0717-34582001000100004
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  High-density cultures of mammalian neurons offer a model system for studies of brain development, but the morphological features of individual neurons is difficult to ascertain. We show that a herpes virus vector expressing a bioluminescent protein allows detailed morphometric analyses of living neurons in complex culture environments. Expression of enhanced green fluorescent protein (eGFP) was constitutively driven in neurons using the herpes simplex virus amplicon system. This system allowed us to make novel observations regarding development in high-density cultures from rat hippocampus and cerebellum. After the phase of initial neurite outgrowth, maturing neurons continue to show rapid remodeling of the neurite branches (0.79 ± 0.11 mm/h per neurite; mean ± SEM, n=8), and displacement of the soma within the neurite arbor (1.35 ± 0.74 mm/h). These results demonstrate that a substantial capacity for morphological plasticity persists in maturing mammalian CNS neurons after cessation of net neurite outgrowth in early development.
• Falk, T., Garver, W. S., Erickson, R. P., Wilson, J. M., & Yool, A. J. (1999). Expression of Niemann-Pick type C transcript in rodent cerebellum in vivo and in vitro.. Brain research, 839(1), 49-57. doi:10.1016/s0006-8993(99)01678-9
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  This study assesses the developmental expression of the Niemann-Pick type C mRNA in vivo and in vitro in rat cerebellum. NPC is an autosomal recessive neurovisceral lipid storage disease associated with an alteration in cholesterol trafficking. In the mouse model of NPC and in the early onset form of human NPC, Purkinje neurons are among the first neurological targets, suffering stunted growth during postnatal development and dying, leading to ataxia. Recently, the genes responsible for human (NPC1) and mouse (Npc1) NPC disease have been cloned. Based on a highly homologous domain, we designed primers to look for levels of Npc1 mRNA with a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) approach using cyclophilin as an internal standard. Total RNA was isolated from various postnatal developmental stages of the rat cerebellum as template for the analyses. Npc1 transcripts were observed at postnatal day 0 and at later stages of development, both in vivo and in vitro from primary cerebellar cultures. To identify the location of Npc1 inside the cerebellum, we performed immunostaining with an anti-Npc1 antibody in primary rat cerebellar cultures identifying reactive Purkinje neurons by double-labeling with the Purkinje specific marker calbindin and sub-populations of glial cells. In summary, Npc1 is expressed in rat cerebellum in vivo and in vitro and is expressed during early postnatal development as well as in the adult cerebellum. Since Npc1 is expressed at similar levels throughout development, the vulnerability of Purkinje neurons to this disease is likely to involve disruption of an interaction with other developmentally-regulated proteins.
• Falk, T., Muller, Y. L., & Yool, A. J. (1999). Differential expression of three classes of voltage-gated Ca(2+) channels during maturation of the rat cerebellum in vitro.. Brain research. Developmental brain research, 115(2), 161-70. doi:10.1016/s0165-3806(99)00060-7
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  Voltage-gated Ca(2+) channels provide a mode of Ca(2+) influx that is essential for intracellular signaling in many cells. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the relative amounts of mRNAs encoding three classes of Ca(2+) channels (alpha1A, alpha1B and alpha1E) during development, in cultures established from prenatal rat cerebellar cortex. Ca(2+) channel transcript levels were standardized to a constitutive marker (cyclophilin). For all three classes of Ca(2+) channels, transcript levels were highest at early stages (4-10 days in vitro) and declined with age. This developmental pattern was differentially regulated by a depolarizing agent, tetraethylammonium chloride (TEA, 1 mM). Chronic depolarization yielded a significant elevation in transcript levels for alpha1B (N-type) and alpha1E (R-type) Ca(2+) channels during neuronal maturation (10-21 days in vitro), but dramatically suppressed transcript levels for the alpha1A (P-type) Ca(2+) channel at all stages of development. The effects of TEA on alpha1A, alpha1B and alpha1E transcript levels were mimicked by increasing external K(+) (from 5 to 10 mM). The regulatory effects of depolarization on transcript levels were dependent on extracellular Ca(2+) for alpha1E but not for alpha1A. For alpha1B, transcript levels depended on extracellular Ca(2+) only for increased K(+) as the depolarizing stimulus, but not for TEA. These results suggest that levels of Ca(2+) channel transcripts in rat cerebellum are developmentally regulated in vitro and can be influenced differentially by transmembrane signaling via chronic depolarization and Ca(2+) entry. Dynamic regulation of Ca(2+) channel expression may be relevant to the different functional roles of Ca(2+) channels and their regional localization within neurons.
• Kilani, R. K., Falk, T., Yool, A. J., & Sherman, S. J. (1999). Expression of a potassium channel -reporter gene fusion protein in cultured hippocampal neurons. Journal of Investigative Medicine, 47(2).
• Bauer, C. K., Falk, T., & Schwarz, J. R. (1996). An endogenous inactivating inward-rectifying potassium current in oocytes of Xenopus laevis.. Pflugers Archiv : European journal of physiology, 432(5), 812-20. doi:10.1007/s004240050203
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  An endogenous inward-rectifying K+ current is described, which is present in native oocytes of some Xenopus laevis donors. Experiments were performed using defolliculated oocytes from donor frogs obtained from two different suppliers. In all oocytes from animals from one source, an inward-rectifying K+ current could be elicited with negative pulses from a holding potential of -20 mV in external solutions with a high K+ concentration. Increasing external K+ concentrations increased the amplitude of this current and shifted the reversal potential towards more positive potentials. In 118 mM KCl, the inward-rectifying K+ current partially inactivated between -20 and -80 mV and completely inactivated at more negative membrane potentials; 50% steady-state inactivation occurred near -50 mV. The time course of inactivation of the inward-rectifying current could be well fitted with two exponentials. The slow time constant had values of about 500 ms and was voltage independent. In contrast, the fast time constant and the time to reach the peak inward current decreased with more negative membrane potentials. Ba2+, Cs+, quinine (all 5 mM) and 50 mM tetraethylammonium partially blocked the inward-rectifying K+ current, whereas 10 mM 4-aminopyridine was without blocking effect. The oxidant chloramine-T blocked the inward-rectifying K+ current without slowing its inactivation.
• Falk, T., Meyerhof, W., Corrette, B. J., Schafer, J., Bauer, C. K., Schwarz, J. R., & Richter, D. (1995). Cloning, functional expression and mRNA distribution of an inwardly rectifying potassium channel protein.. FEBS letters, 367(2), 127-31. doi:10.1016/0014-5793(95)00527-g
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  In GH3/B6 cells at least two different inward K+ currents are observed that are regulated by thyrotropin-releasing hormone and somatostatin, respectively. Using a polymerase chain reaction based approach a cDNA was isolated and functionally expressed in human embryonic kidney cells that encodes an inward rectifier K+ channel, rIRK3, with a predicted molecular mass of 49.7 kDa. Corresponding transcripts of 2.6 kb have been detected in rat brain, pituitary and GH3/B6 cells. In situ hybridization revealed that rIRK3 mRNA is distributed throughout the brain and occurs predominantly in the piriform cortex, indusium griseum, supraoptic nucleus, facial nucleus and cerebellar Purkinje cells.

Presentations

• Morrison, H. W., Pottenter, A. E., Bartlett, M. J., & Falk, T. (2020, April). Ketamine’s Effects to Improve Dyskinesia in a Model of Parkinson’s Disease. Western Institute of Nursing: 53rd Annual Communicating Nursing Research Conference. Portland, OR.
• Bartlett, M. J., Cristiani, S., Smidt, S. I., Farrell, D. C., Doyle, K., Heien, M. L., Sherman, S. J., & Falk, T. (2018, Fall). VEGF-B overexpression in PINK1 gene knock out rats improves motor function: Is this effect due to neuroprotection or to functional improvement of dopaminergic neurons?. Society for Neuroscience Meeting.
• Cowen, S. L., Heien, M. L., Falk, T., Bartlett, M. J., Wiegand, J. P., Crown, L. M., & Richard, C. (2017, August). Altered Sleep Spindles in a LRRK2 Mouse Model of Parkinson's Disease. UROC Minority Health Disparities Summer Research Program Poster Session. Tucson, AZ.
• Bartlett, M. J., Silashki, B. D., Muller, D. C., Tran, C. T., Sherman, S. J., & Falk, T. (2016, Fall). AAV-mediated over-expression of VEGF-B in PINK1 gene knockout rats: A behavioral evaluation.. Society for Neuroscience Abstracts.
• Falk, T. (2016, Summer). Sub-anesthetic ketamine infusions as a treatment of pain and Parkinson’s disease. Pain Mechanisms and Therapeutics Conference Abstracts.

Poster Presentations

• Bernard, K., Lujan, A., Corenblum, M. J., Saez, J. L., Bartlett, M. J., Tanguturi, P., Apostol, C. R., Szabò, L. Z., Streicher, J. M., Polt, R. L., Falk, T., & Madhavan, L. (2022, Spring). Multimodal effects of systemic PACAP glycopeptide delivery in rodent models of Parkinson’s disease.. 16th International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders, AD/PD™.
• Bernard, K., Mota, J., Corenblum, M., Polt, R. L., Hay, M., Madhavan, L., & Falk, T. (2023, Fall). PNA5, a glycosylated Angiotensin (1-7) peptide, improves cognition in a chronic progressive mouse model of Parkinson’s disease.. Society for Neuroscience Meeting. Washington DC.
• Falk, T., Richards, S. S., Bartlett, M. J., Lind, A., Hsu, C., & Sherman, S. J. (2023, Fall 2023). Subanesthetic infusion of ketamine produces long-term reduction in levodopa-induced dyskinesia and depression in individuals with Parkinson’s Disease. . International Parkinson and Movement Disorders Society Abstracts. Copenhagen, Denmark.
• Lopez-Smith, K., Bernard, K., Falk, T., & Rodgers, K. E. (2023, Fall). The Impact of Diabetes Therapies Leading to Subsequent Parkinson’s Disease Using Health Claims Database. . Sixth Annual Conference on Native American Nutrition..
• Parmar, R., Stopera, C., Bartlett, M. J., Esqueda, A., Sherman, S. J., & Falk, T. (2023, Fall). Naloxone partially blocks the anti-dyskinetic and enhances the antiparkinsonian effects of sub-anesthetic ketamine.. Society for Neuroscience Meeting. Washington DC.
• Stopera, C., Bartlett, M. J., Cowen, S. L., Sherman, S. J., & Falk, T. (2023, Fall). Pravastatin sensitizes parkinsonian rats to L-DOPA and blocks the long-term anti-dyskinetic activity of sub-anesthetic ketamine. Society for Neuroscience Meeting. Washington DC.
• Stopera, C., Bartlett, M. J., Sexauer, M. R., Bernard, K., Sherman, S. J., Stancati, J. A., Steece-Collier, K., Morrison, H. W., & Falk, T. (2022, Spring). Analysis of neuroprotective and anti-inflammatory activity of sub-anesthetic ketamine-treatment in the progressive unilateral 6-OHDA-lesion rat model.. 16th International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders, AD/PD™.
• Vishwanath, A., Bartlett, M. J., Falk, T., & Cowen, S. L. (2022, Spring). Ketamine disrupts 80-Hz gamma oscillations and reduces burst firing in naïve and parkinsonian rats with levodopa-induced dyskinesia.. 16th International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders, AD/PD™.
• Vishwanath, A., Bartlett, M. J., Keener, A., Falk, T., & Cowen, S. L. (2023, Fall). In a hemi-lesioned model of L-DOPA-induced dyskinesia neuronal firing was reduced in the un-lesioned striatum and ketamine reduced burst-like firing in striatal neurons bilaterally. . Society for Neuroscience. Washington DC.
• Bartlett, M. J., Stopera, C., Esqueda, A., Sherman, S. J., & Falk, T. (2021, Fall). Analysis of the role of opioid receptors in the anti-dyskinetic effects of sub-anesthetic ketamine.. Society for Neuroscience Meeting.
• Bartlett, M. J., Stopera, C., Sexauer, M. R., Vishwanath, A., Jordan, G. A., Cowen, S. L., & Falk, T. (2021, January). The string-pulling task as a novel and simple behavior to test for parkinsonian deficits in unilaterally 6-OHDA-lesioned rodents.. Society for Neuroscience Global Connectome Conference.
• Bernard, K., Bartlett, M. J., Liu, C., Molnar, G., Apostol, C., Szabo, L., Sherman, S. J., Madhavan, L., Streicher, J. M., Polt, R. L., Heien, M. L., & Falk, T. (2021, January). Evaluation of a neuroprotective PACAP glycopeptide as systemically delivered CNS active drug to treat Parkinson’s disease.. Society for Neuroscience Global Connectome Conference.
• Bernard, K., Bartlett, M. J., Liu, C., Molnar, G., Apostol, C., Szabo, L., Sherman, S. J., Madhavan, L., Streicher, J. M., Polt, R. L., Heien, M. L., & Falk, T. (2021, Spring). Evaluation of a neuroprotective PACAP glycopeptide as systemically delivered CNS active drug to treat motor and cognitive symptoms in two rodent models of Parkinson’s disease.. 15th International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders, AD/PD™.
• Bernard, K., Lujan, A., Morrison, H. W., Bartlett, M. J., Liu, C., Molnar, G., Apostol, C. R., Szabò, L., Sherman, S. J., Madhavan, L., Streicher, J. M., Polt, R. L., Heien, M. L., & Falk, T. (2021, Fall). Evaluation of a systemically delivered PACAP glycopeptide as a neuroprotective agent in 2 rodent models of Parkinson’s Disease.. Society for Neuroscience Meeting.
• Falk, T., Bartlett, M. J., Stopera, C., Ye, T., Liu, C., Heien, M. L., Cowen, S. L., & Sherman, S. J. (2021, Spring). Update on preclinical and clinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia. 6th Annual ABRC-Flinn Research Conference. Phoenix, AZ.
• Hoyer-Kimura, C., Konhilas, J. P., Mansour, H. M., Polt, R. L., Bartlett, M., Falk, T., Ossanna, N., Doyle, K., & Hay, M. (2021, March/Spring). Novel Therapeutic and Inflammatory Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia.. AD/PD 2021 15th International Conference on Alzheimer’s and Parkinson’s Diseases Virtual ConferenceAD/PD.
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  Oral e-Poster presentation
• Stopera, C., Bartlett, M. J., Bernard, K., Sexauer, M. R., Esqueda, A., Morrison, H. W., Sherman, S. J., & Falk, T. (2021, January). Behavioral analysis in the progressive unilateral 6-OHDA-lesion rat model indicate a neuroprotective effect of sub-anesthetic ketamine-treatment.. Society for Neuroscience Global Connectome Conference.
• Stopera, C., Bartlett, M. J., Sexauer, M. R., Bernard, K., Stancati, J., Sherman, S. J., Steece-Collier, K., Morrison, H. W., & Falk, T. (2021, November). Analysis of neuroprotective and anti-inflammatory activity of sub-anesthetic ketamine-treatment in the progressive unilateral 6-OHDA-lesion rat model.. Society for Neuroscience Meeting.
• Vishwanath, A., Bartlett, M. J., Jordan, G. A., Sherman, S. J., Falk, T., & Cowen, S. L. (2021, January). Ketamine disrupts 80-Hz gamma oscillations in parkinsonian rats with L-DOPA-induced dyskinesia.. Society for Neuroscience Global Connectome Conference.
• Apostol, C., Liu, C., Bartlett, M. J., Bernard, K., Molnar, G., Szabo, L., Rowe, R., Ronaldson, P. T., Streicher, J. M., Falk, T., Heien, M. L., & Polt, R. L. (2020, Summer). Glycosylated PACAP Hormones as Potential Therapy for Parkinsonism, Stroke and Traumatic Brain Injury.. American Chemical Society National Meeting.
• Bernard, K., Apostol, C., Liu, C., Bartlett, M. J., Molnar, G., Szabo, L., Ronaldson, P. T., Streicher, J. M., Heien, M. L., Polt, R. L., & Falk, T. (2020, Summer). Preclinical evaluation of glycosylated PACAP Hormones to treat Parkinson’s disease and Stroke.. Arizona Alzheimer’s Consortium Annual Abstracts.
• Falk, T., Bartlett, M. J., Ye, T., Farrell, D. C., Heien, M. L., Cowen, S. L., & Sherman, S. J. (2020, Spring). Preclinical and clinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia.. 5th Annual ABRC-Flinn Research Conference, Phoenix, AZ.
• Falk, T., Bartlett, M. J., Ye, T., Farrell, D. C., Heien, M. L., Steece-Collier, K., Cowen, S. L., & Sherman, S. J. (2020, Summer). Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia.. European Neuroscience Virtual Forum Abstracts.
• Liu, C., Bartlett, M. J., Apostol, C., Szabo, L., Polt, R. L., Falk, T., & Heien, M. L. (2020, Fall). Glycosylation improves stability of neuropeptides and elevates blood brain barrier (BBB) penetration.. ASMS Conference on Mass Spectrometry and Allied Topics Abstracts.
• Apostol, C. C., Liu, C., Szabo, L., Bartlett, M. J., Molnar, G., Falk, T., Heien, M. L., Streicher, J. M., & Polt, R. L. (2018, Fall). Design and Synthesis of Brain Penetrant Glycopeptide Analogues of Pituitary Adenylate Cyclase Activating Peptide (PACAP) for the Treatment of Parkinson’s Disease. Peptide Therapeutic Symposium at the Salk Institute in San Diego.
• Bartlett, M. J., Cristiani, S., Silashki, B. D., Muller, D. C., Farrell, D. C., Parent, K. L., Doyle, K., Heien, M. L., Sherman, S. J., & Falk, T. (2018, Summer). AAV2/1-hVEGF-B overexpression improves motor outcomes in PINK1 gene knockout rat: An insight into potential mechanisms.. 2nd Pan American Parkinson's Disease and Movement Disorders Congress.
• Bartlett, M. J., Flores, A. J., Dollish, H. K., Doyle, K., Steece-Collier, K., Sherman, S. J., & Falk, T. (2018, Summer). Sub-anesthetic ketamine prevents levodopa-induced dyskinesia and improves motor function in a 6-OHDA rat model of Parkinson’s disease. 2nd Pan American Parkinson's Disease and Movement Disorders Congress.
• Crown, L. M., Wiegand, J., Bartlett, M. J., Eby, A., Monroe, E., Wohlford, L., Falk, T., & Cowen, S. L. (2018, Fall). The frequency of sleep spindle oscillations is increased in the G2019S LRRK2 mouse model of Parkinson’s disease. New Mexico EEG and Behavior Conference.
• Crown, L. M., Wohlford, L., Bartlett, M. J., Eby, A., Wiegand, J., Gies, K., Falk, T., & Cowen, S. L. (2018, Fall). Six month-old LRRK2 G2019S knock-in mice do not express motor learning deficits on the rotarod task. Society for Neuroscience Meeting.
• Falk, T., Bartlett, M. J., Flores, A. J., Dollish, H. K., Stancati, J. A., Doyle, K., Heien, M. L., Steece-Collier, K., & Sherman, S. J. (2018, Fall). Neuroplastic effects in the striatum contribute to the suppression of L-DOPA-induced dyskinesia by sub-anesthetic ketamine. Society for Neuroscience Meeting.
• Figueroa, A. G., Sillik, S. A., Congrove, N., Sadideen, D. T., Falk, T., Bowes Rickman, C., & Mckay, B. S. (2018, Spring). Exosome uptake is selective but not species or tissue-specific. ARVO Annual Meeting.
• Liu, C., Bartlett, M. J., Smith, C. L., Hanrahan, D., Szabo, L., Falk, T., Polt, R. L., & Heien, M. L. (2018, Summer). Blood brain barrier penetration of glycosylated peptides by ‘shotgun microdialysis’ coupled with LC-MS3. ASMS Conference on Mass Spectrometry and Allied Topics Abstracts.
• Nava, R., Flores, A. J., Bartlett, M. J., Sexauer, M. R., Siegenthaler, J., Heien, M. L., Sherman, S. J., Porreca, F., & Falk, T. (2018, Fall). The kappa opioid receptor antagonist nor-BNI accelerates development of L-DOPA-induced dyskinesia in a model of mild Parkinson’s disease. Society for Neuroscience Meeting.
• Polt, R. L., Szabo, L., Smith, C. L., Liu, C., Molnar, G., Heien, M. L., Bartlett, M. J., Apostol, C. R., Hay, M., Falk, T., & Streicher, J. M. (2018, Fall). Glycopeptides as Systemically Delivered CNS Active Drugs from Endogenous Peptide Hormones. Society for Neuroscience.
• Pottenger, A. E., Bartlett, M. J., Falk, T., & Morrison, H. W. (2018, Fall). Evaluating the effects of Sub-Anesthetic Ketamine on Microglia Morphology in a Pre-Clinical Model of L-DOPA-Induced Dyskinesia. Society for Neuroscience Meeting.
• Streicher, J. M., Falk, T., Hay, M., Apostol, C. R., Bartlett, M. J., Heien, M. L., Molnar, G., Liu, C., Smith, C. L., Szabo, L., & Polt, R. L. (2018, Fall). Glycopeptides as Systemically Delivered CNS Active Drugs from Endogenous Peptide Hormones. Society for Neuroscience Meeting.
• Ye, T., Bartlett, M. J., Falk, T., & Cowen, S. L. (2018, Fall). L-DOPA-induced striatal gamma oscillations split into low- and high-frequency components following ketamine exposure in an animal model of L-DOPA-induced dyskinesia. Society for Neuroscience Meeting.
• Bartlett, M. J., Flores, A. J., Dollish, H. K., Doyle, K., Pottinger, A., Morrison, H. W., Sherman, S. J., & Falk, T. (2017, December). Neuroplastic effects contribute to the suppression of L-DOPA-induced dyskineasis by sub-anesthetic ketamine. Neurobiology, Aging, Dementias and Movement Disorders Division Meeting. Scottsdale, Arizona: Arizona Wellbeing Commons Division.
• Bartlett, M. J., Flores, A. J., Ye, T., Dollish, H. K., Doyle, K., Cowen, S. L., Sherman, S. J., & Falk, T. (2017, Summer). Mechanisms of sub-anesthetic ketamine infusions to reduce levodopa-induced dyskinesia: effects on striatal mTOR signaling and beta band oscillations in striatum and motor cortex.. International Parkinson and Movement Disorders Society Abstracts.
• Bartlett, M. J., Muller, D. C., Silashki, B. D., Parent, K. L., Farrell, D. C., Doyle, K., Heien, M. L., Sherman, S. J., & Falk, T. (2017, November). AAV2/1 VEGF-B overexpression improves motor function and prevents dopamine loss in PINK1 gene knock out rats.. Society for Neuroscience Abstracts.
• Cowen, S. L., Bartlett, M. J., Ye, T., & Falk, T. (2017, Novermber). Oscillatory Signatures of L-DOPA-induced Dyskinesia Are Not Reduced by Ketamine. Society for Neuroscience Meeting. Washington DC.
• Falk, T., Bartlett, M. J., Muller, D. C., Silashki, B. D., Farrell, D. C., Parent, K. L., Heien, M. L., & Sherman, S. J. (2017, Summer). AAV-mediated over-expression of VEGF-B in PINK1 gene knockout rats increases striatal dopamine content.. International Parkinson and Movement Disorders Society Abstracts.
• Falk, T., Sherman, S. J., Cowen, S. L., Doyle, K., Dollish, H. K., Ye, T., Flores, A. J., & Bartlett, M. J. (2017, Summer). Mechanisms of sub-anesthetic ketamine infusions to reduce levodopa-induced dyskinesia: effects on striatal mTOR signaling and beta band oscillations in striatum and motor cortex.. International Parkinson and Movement Disorders Society Abstracts.
• Figueroa, A., Falk, T., & Mckay, B. S. (2017, Fall). Myocilin-Associated Exosome Release in Glaucoma-Related Diseases.. Minority Access, 18th Annual Conference Abstracts.
• Flores, A. J., Bartlett, M. J., Dollish, H. K., Doyle, K., Sherman, S. J., & Falk, T. (2017, November). Role of BDNF and mTOR pathways in the suppression of L-DOPA-induced dyskineasis by sub-anesthetic ketamine.. Society for Neuroscience Abstracts.
• Kramer, C., Bartlett, M. J., Jones, E. M., Stagg, C. J., Polt, R. L., Falk, T., & Heien, M. L. (2017, Spring). Shotgun microdialysis” with LC-MS3 quantitation for the screening of BBB penetration properties of peptide-based drugs. ASMS Conference on Mass Spectrometry and Allied Topics Abstracts.
• Parent, K. L., Parent, K. L., Bartlett, M. J., Bartlett, M. J., Crown, L. M., Crown, L. M., Giess, K. F., Giess, K. F., Miller, M., Miller, M., Falk, T., Falk, T., Cowen, S. L., Cowen, S. L., Heien, M. L., & Heien, M. L. (2017, Spring). Longitudinal studies of tonic dopamine for investigation of neural disorders. PittCon Conference Abstracts.
• Wiegand, J. P., Gies, K., Bartlett, M. J., Falk, T., & Cowen, S. L. (2017, November). Altered sleep physiology in a LRRK2 mouse model in Parkinson's Disease. Society for Neuroscience Meeting. Washington DC.
• Wiegand, J., Bartlett, M. J., Giess, K., Falk, T., & Cowen, S. L. (2017, November). Altered slow-wave sleep in the LRRK2 mouse model of Parkinson’s disease.. Society for Neuroscience Abstracts.
• Ye, T., Bartlett, M. J., Falk, T., & Cowen, S. L. (2017, November). Oscillatory signatures of L-DOPA-induced dyskinesia are not reduced by ketamine.. Society for Neuroscience Abstracts.
• Bartlett, M. J., Flores, A. J., Zehri, A., Sherman, S. J., & Falk, T. (2016, Fall). Low-Dose Sub-Anesthetic Ketamine Infusions Reduce the Development of L-DOPA-Induced Dyskinesias in a Preclinical Model.. 4th World Parkinson Congress Abstracts.
• Crown, L. M., Parent, K. L., Bartlett, M. J., Miller, M. A., Gies, K. F., Falk, T., Heien, M. L., & Cowen, S. L. (2016, Spring). Ketamine injection acutely and rapidly decreases tonic dopamine levels in the rat dorsal striatum. Science of Consciousness Conference Abstracts.
• Falk, T., Bartlett, M. J., Ye, T., Lazarus, L. B., Heien, M. L., Cowen, S. L., & Sherman, S. J. (2016, Summer). Preclinical evaluation of sub-anesthetic ketamine infusion to reduce L-DOPA-induced dyskinesias: is it a 'chemical' DBS?. International Parkinson and Movement Disorders Society Abstracts.
• Flores, A. J., Bartlett, M. J., Zehri, A. H., Parent, K. L., Heien, M. L., Sherman, S. J., & Falk, T. (2016, Fall). Development of L-DOPA-induced dyskinesias is reduced in a rat model after sub-anesthetic ketamine infusions.. Society for Neuroscience Abstracts.
• Parent, K. L., Bartlett, M. J., Crown, L. M., Gies, K. F., Falk, T., Cowen, S. L., & Heien, M. L. (2016, Summer). Real-time measurement of ketamine-induced tonic dopamine fluctuations in freely moving rats. Monitoring Molecules in Neuroscience Meeting Abstracts.
• Schmit, M. D., Dollish, H. K., Falk, T., & Cowen, S. L. (2016, Fall). BRIAN: The Brains of Neuroscience Outreach. BRAIN AWARENESS CAMPAIGN EVENT at Society for Neuroscience Meeting.
• Schmit, M. D., Ye, T., Bartlett, M. J., Falk, T., & Cowen, S. L. (2016, Fall). Directional Propagation of Ketamine-induced High-Frequency Oscillations between the Striatum, Hippocampus, and Motor Cortex.. Society for Neuroscience Abstracts.
• Sherman, S. J., & Falk, T. (2016, Summer). Patient case reports supporting a long-term effect of sub-anesthetic ketamine infusion in reducing L-DOPA-induced dyskinesias. International Parkinson and Movement Disorders Society Abstracts.
• Wiegand, J., Giess, K. F., Bartlett, M. J., Falk, T., & Cowen, S. L. (2016, Fall). Stronger cortical spindles and less power variability in hippocampal ripples in a LRRK2 mouse model of Parkinson’s disease. Society for Neuroscience Abstracts.
• Wiegand, J., Giess, K., Bartlett, M. J., Falk, T., & Cowen, S. L. (2016, Fall). Increased power of sleep spindle oscillations in the LRRK2 mouse model of Parkinson’s disease.. 4th World Parkinson Congress Abstracts.
• Witte, R. S., Qin, Y., Ingram, P., Burton, A., Tseng, H., Hill, D. F., Wilhite, C. A., Falk, T., Xu, Z., O'Donell, M., & Cowen, S. L. (2016, Fall). Acoustoelectric Brain Imaging of Deep Dipole Sources in a Human Head Phantom. 3rd Annual BRAIN Initiative® Investigators Meeting.
• Ye, T., Bartlett, M. J., Schmit, M. B., Sherman, S. J., Falk, T., & Cowen, S. L. (2016, Fall). Alterations of oscillatory activity in the striatal-cortical circuit following repeated sub-anesthetic ketamine administration in 6-OHDA-lesioned rats.. Society for Neuroscience Abstracts.
• Ye, T., Bartlett, M. J., Schmit, M., Sherman, S. J., Falk, T., & Cowen, S. L. (2016, Fall). Gamma-band oscillatory activity in the motor cortex is progressively enhanced following repeated ketamine administration in 6-OHDA-lesioned rats.. 4th World Parkinson Congress Abstracts.
• Bartlett, M. J., Caballero, B., Zhang, S., Mount, D. W., Sherman, S. J., & Falk, T. (2015, Summer). Neuroprotection of VEGF-B against mitochondrial toxins in culture and in vivo models of Parkinson’s disease: Mechanistic insights. 35th Blankenese Conference; Brain Repair: From Regeneration to Cellular Reprogramming. Hamburg, Germany.
• Bartlett, M. J., LePoidevin, L. M., Joseph, R. M., Parent, K. L., Laude, N. D., Lazarus, L. B., Heien, M. L., Estevez, M., Sherman, S. J., & Falk, T. (2015, Fall). Long-term effect of sub-anesthetic ketamine-infusion in reducing L-DOPA-induced dyskinesia. Society for Neuroscience Abstracts.
• Lazarus, L. B., Bartlett, M. J., Falk, T., & Heien, M. L. (2015, Fall). Fast ESI-MS/MS Determination of Ketamine and metabolites in whole blood. American Society for Mass Spectrometry Meeting Abstracts.
• Miller, M. A., Parent, K. L., Bartlett, M. J., Hill, D. F., Atcherley, C. W., Falk, T., Heien, M. L., & Cowen, S. L. (2015, Fall). Modulation of basal dopamine in the nucleus accumbens following repeated low-dose ketamine exposure as measured using fast-scan controlled-adsorption voltammetry. Society for Neuroscience Abstracts.
• Sherman, S. J., Magill, A. R., Barlett, M. J., Heien, M. L., Estevez, M., & Falk, T. (2015, Summer). Case reports showing a long-term effect of sub-anesthetic ketamine infusion in reducing L-DOPA-induced dyskinesias. American Neurological Association Meeting Abstracts.
• Ye, T., Bartlett, M. J., Wiegand, J. P., Sherman, S. J., Falk, T., & Cowen, S. L. (2015, Fall). Modulation of high-frequency oscillations and beta coherence in striato-cortico-limbic circuits following repeated sub-anesthetic ketamine exposure. Society for Neuroscience Abstracts.

Reviews

• Caballero, B., Sherman, S. J., & Falk, T. (2017. Insights into mechanism of the protective effects of VEGF-B in dopaminergic neurons.(pp Article ID 4263795, 13 pages). Parkinson's Disease.
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  Vascular endothelial growth factor-B (VEGF-B), when initially discovered, was thought to be an angiogenic factor, due to its intimate sequence homology and receptor binding similarity to the prototype angiogenic factor, vascular endothelial growth factor-A (VEGF-A). Studies demonstrated that VEGF-B, unlike VEGF-A, did not play a significant role in angiogenesis or vascular permeability and has become an active area of interest because of its role as a survival factor in pathological processes in a multitude of systems, including the brain. By characterization of important downstream targets of VEGF-B that regulate different cellular processes in the nervous system and cardiovascular system, it may be possible to develop more effective clinical interventions in diseases such as Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS), and ischemic heart disease, which all share mitochondrial dysfunction as part of the disease. Here we summarize what is currently known about the mechanism of action of VEGF-B in pathological processes. We explore its potential as a homeostatic protective factor that improves mitochondrial function in the setting of cardiovascular and neurological disease, with a specific focus on dopaminergic neurons in Parkinson’s disease.
• Falk, T., Gonzalez, R. T., & Sherman, S. J. (2010. The yin and yang of VEGF and PEDF: multifaceted neurotrophic factors and their potential in the treatment of Parkinson's Disease.(pp 11(8), 2875-900). International journal of molecular sciences.
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  Over the last few decades, vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) have emerged as multifaceted players in not only the pathogenesis, but potential treatment, of numerous diseases. They activate diverse intracellular signaling cascades known to have extensive crosstalk, and have been best studied for their effects in cardiology and cancer biology. Recent work with the two factors indicates that the activity of one growth factor is often directly related to the action of the other. Their respective neuroprotective effects, in particular, raise important questions regarding the treatment of neurodegenerative disorders, including Parkinson's disease.

Others

• Falk, T. (2022, Fall). MDS 2022 | Low-dose ketamine produces long-term reduction in levodopa-induced dyskinesia
  . VJ Neurology, The Video Journal of Neurology. https://vjneurology.com/video/4sygods1txk-low-dose-ketamine-produces-long-term-reduction-in-levodopa-induced-dyskinesia/
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  Interview with Dr. Falk
• Falk, T. (2021, January). “Pharma company licenses UArizona researchers’ method for treating Parkinson’s disease with ketamine”. Arizona Jewish Post. https://azjewishpost.com/2021/pharma-company-licenses-uarizona-researchers-method-for-treating-parkinsons-disease-with-ketamine/
• Falk, T. (2020, December). Mary M. Chapman: “FDA Guidance Sought for Planned Trial of Ketamine to Treat Dyskinesia”. Parkinsons News Today. https://parkinsonsnewstoday.com/2020/12/21/pharmather-asks-fda-help-planned-trial-ketamine-treat-dyskinesia/
• Falk, T. (2020, October). Forest Ray: “PharmaTher Seeking FDA Orphan Drug Designation for Ketamine for Dyskinesia”. Parkinsons News Today. https://parkinsonsnewstoday.com/2020/10/26/pharmather-seeking-fda-orphan-drug-designation-for-ketamine-for-parkinsons-dyskinesia/
• Falk, T. (2020, October). “PharmaTher Announces Exclusive License Agreement with the University of Arizona for the Commercialization of Ketamine in the Treatment of Parkinson’s Disease”. Globeswire.com. https://www.globenewswire.com/news-release/2020/10/15/2109164/0/en/Pharmather-Announces-Exclusive-License-Agreement-with-the-University-of-Arizona-for-the-Commercialization-of-Ketamine-in-the-Treatment-of-Parkinson-s-Disease.html
• Falk, T. (2018, August). "Researcher's work to improve Parkinson's disease treatment". Whealthnews.com. https://whealthnews.com/mnenia/researchers-work-to-improve-parkinson-s-disease-treatment/
• Falk, T. (2018, August). Jeff Gardner: "Ketamine for Parkinson's Patients". Tucson Weekly. https://www.tucsonweekly.com/tucson/mad-science/Content?oid=19523740
• Falk, T. (2018, August). Vikram Wankhade: "UA holds clinical trial to repurpose ketamine for Parkinson's patients". Healthcaremotives.com. http://healthcaremotives.com/clinical-trial-ketamine-parkinsons-patients/
• Falk, T. (2018, December). Channing Frampton: "Ketamine eases debilitaling side effecs of a Parkinson's treatment drug". WINK News. http://www.winknews.com/2018/12/10/ketamine-eases-debilitating-side-effects-of-a-parkinsons-treatment-drug/
• Falk, T. (2018, December). Jessica Migala: "13 Amazing Medical Breakthroughs of 2018". Reader’s Digest. https://www.rd.com/health/conditions/medical-breakthroughs-of-2018/
• Falk, T. (2018, Decemer). Chelly Boutott: “HealthWatch: KETAMINE STILLS PARKINSON’S”. Nexstar Broadcasting, Inc.. https://www.wearegreenbay.com/news/healthwatch-ketamine-stills-parkinsons/
• Falk, T. (2018, Fall). “YOUR HEALTH: An old drug to help Parkinson’s patients facing side effects”. WQAD8 (ABC). https://www.wqad.com/article/news/health/your-health/your-health-an-old-drug-to-help-parkinsons-patients-facing-side-effects/526-87e4efb7-5e57-45b4-8d67-35d1d2ea2b62
• Falk, T. (2018, July). "UA Clinical Trial to Repurpose Ketamine for Parkinson's Patients". EurekAlert. https://www.eurekalert.org/pub_releases/2018-07/uoah-uct071818.php
• Falk, T. (2018, July). Bridget Dowd: "UA Researchers Repurpose Ketamine for Parkinson's Patients". KJZZ 91.5 FM Radio, Phoenix, AZ.
• Falk, T. (2018, July). Judy Georg: "AI Dementia Detection; Cell Phones and Memory; Ketamine for PD?". MedPage Today. https://www.medpagetoday.com/neurology/generalneurology/74190
• Falk, T. (2018, July). Maria Cohut: "Ketamine for Parkinson's?: Clinical Trials in the Works". Medical News Today. https://www.medicalnewstoday.com/articles/322524.php
• Falk, T. (2018, July). Patricia Inacio: "Ketamine Studied for Relief of Levodopa-associated Involuntary Movements". Parkinson’s News Today. https://parkinsonsnewstoday.com/2018/07/23/ketamine-tested-easing-levodopa-involuntary-movements-parkinsons/
• Falk, T. (2018, July). UA clinical trial aimed at helping people with Parkinson's disease; rebroadcast. KFOR-OKC (NBC).
  More info

  rebroadcast:• KOMU (NBC)• KWQC-DAV• KWES (NBC)• KAVU (ABC)• KXAN-AUS• KSPR (ABC)• KPVI (NBC)• KMTR (NBC)• KNTV-SF (NBC)• KECY-TV (FOX)• WDSU-NO (NBC)• WRLH-RIC
• Falk, T. (2018, July). UA to begin clinical trial to test treatment for Parkinson's disease. KVOA TV, Tucson, AZ.
• Falk, T. (2018, June). "Developing a New Theraputic Approach to Treat Parkinson's Disease". Arizona Public Media. https://www.azpm.org/p/home-art-radio/2018/6/29/132418-episode-137-developing-a-new-therapeutic-approach-to-treat-parkinsons-disease/
• Falk, T. (2018, October). An existing drug can help curb side effects of Parkinson's medication. WNDU, South Bend, IN.
• Falk, T. (2018, October). Health Beat: Ketamine Stills Parkinson's. 69 News, Allentown, PA.
• Falk, T. (2018, October). Healthcast: Ketamine stills Parkinson's Disease. KFDX 3.Texomas, Wichita Falls, TX.
• Falk, T. (2018, October). Healthy Living: Ketamine vs. Parkinson's. 9&10 News, Cadillac, MI.
• Falk, T. (2018, October). Ketamine stills Parkinson. Ivanhoe Broadcast News. https://www.ivanhoe.com/interview/ketamine-stills-parkinsons-in-depth-doctor-interview/
  More info

  https://www.youtube.com/watch?v=8XTwCjtcruM
• Falk, T. (2018, October). New treatment for Parkinson's patients. UPmatters.com, Marquette, WI.
• Falk, T. (2018, October). Roisin McCormack: "Could a horse tranquilliser helo treat Parkinson's?". Parkinson’s Life Online Magazine. https://parkinsonslife.eu/could-a-horse-tranquiliser-help-treat-parkinsons/
• Falk, T. (2018, Summer). Marissa Heffernan: “Researchers work to improve Parkinson's disease treatment”. The Daily Wildcat, Tucson, AZ, Volume 112, Issue 1, page 19. http://www.wildcat.arizona.edu/article/2018/08/n-ketamine
• Falk, T. (2013, January). Bethany Barnes “Researchers look at melanoma-Parkinson's link”. Northwest Parkinson's Foundation webpage, 01/02/2013. https://nwpf.org/stay-informed/news/2013/01/researchers-look-at-melanoma-parkinsons-link/
• Falk, T. (2009, Summer). Dayton Fandray: “Personalizing Medicine - The Human Genome Project gives direction to the future of health care”. Alaska Airlines Magazine 2009, pp.46-49 and 106-110.
  More info

  featuring Dr. Falk and his work with gene therapy and Parkinson’s disease