- Assistant Professor, Neurology
- Assistant Professor, Evelyn F Mcknight Brain Institute
- Assistant Professor, Molecular and Cellular Biology
- Assistant Professor, BIO5 Institute
- Assistant Professor, Medicine
- Assistant Professor, Neuroscience - GIDP
- Assistant Professor, Physiological Sciences - GIDP
Lalitha Madhavan, MD, PhD
My research goals have been largely motivated by clinical concerns. After training as a physician, I moved into bench research feeling that advances in basic science are needed to support care with respect to brain disorders. In this context, my long-standing interests have been in stem cell biology and neurodegenerative disorders, especially Parkinson’s disease (PD). I have significant expertise with a variety of stem cells and with cellular/animal models of neurodegeneration, which has been applied over the past several years towards studying fundamental aspects of stem cell function, as well as stem cell therapeutic ability, in the context of PD. Current endeavors in my laboratory continue in this vein, and center on investigating stem cell potential within the framework of aging and PD utilizing rodent and human model systems.
- Ph.D. Neuroscience
- M.B.B.S. Medicine
- Assistant Professor, University of Arizona, Arizona (2011 - Ongoing)
- Post-doctoral fellow, University of Cincinnati, Cincinnati, Ohio (2006 - 2011)
- Graduate Research Assistant, Iowa State University, Ames, Iowa (1999 - 2006)
- Undergraduate Biology Research Program Honorable Mention Award
- UA Undergraduate Biology Research Program, Spring 2017
- University’s Visionary Leadership Maria Teresa Velez Outstanding Faculty Mentor Award
- University of Arizona, Office for Diversity and Inclusive Excellence and the Commission on the Status of Women, Spring 2017
Developmental Neuroscience, Stem Cell Biology, Disorders of the Nervous System
Broad Interests: Neuroscience and Stem Cell BiologySpecific Interests: Aging and Neurodegeneration, Role of endogenous neural stem cells in development and disease, Graft-host interactions after neural transplantation, Central nervous system plasticity and regeneration, Disease modeling using patient-specific iPS cells and their derivatives
Honors Independent StudyNSCS 299H (Fall 2016)
Honors ThesisNSCS 498H (Fall 2016)
Prin Cell+Molec NeurobioBIOC 588 (Fall 2016)
Prin Cell+Molec NeurobioMCB 588 (Fall 2016)
Prin Cell+Molec NeurobioNRSC 588 (Fall 2016)
Internship in Applied BiosciABS 593A (Summer I 2016)
Honors Independent StudyMCB 499H (Spring 2016)
Honors Independent StudyNSCS 299H (Spring 2016)
Independent StudyPSIO 399 (Spring 2016)
Internship in Applied BiosciABS 593A (Spring 2016)
DissertationPS 920 (Fall 2015)
Honors Independent StudyNSCS 299H (Fall 2015)
Honors Independent StudyNSCS 499H (Fall 2015)
Independent StudyPSIO 399 (Fall 2015)
Introduction to ResearchMCB 795A (Fall 2015)
Prin Cell+Molec NeurobioBIOC 588 (Fall 2015)
Prin Cell+Molec NeurobioCMM 588 (Fall 2015)
Prin Cell+Molec NeurobioMCB 588 (Fall 2015)
Prin Cell+Molec NeurobioNRSC 588 (Fall 2015)
Prin Cell+Molec NeurobioPSIO 588 (Fall 2015)
Honors Independent StudyNSCS 299H (Spring 2015)
Honors ThesisPSIO 498H (Spring 2015)
Honors Independent StudyNSCS 299H (Fall 2014)
Honors ThesisPSIO 498H (Fall 2014)
Prin Cell+Molec NeurobioBIOC 588 (Fall 2014)
Prin Cell+Molec NeurobioCMM 588 (Fall 2014)
Prin Cell+Molec NeurobioMCB 588 (Fall 2014)
Prin Cell+Molec NeurobioNRSC 588 (Fall 2014)
ResearchPS 900 (Fall 2014)
Honors Independent StudyPSIO 399H (Spring 2014)
Introduction to ResearchMCB 795A (Spring 2014)
Honors Independent StudyNSCS 499H (Fall 2013)
Honors Independent StudyPSIO 399H (Fall 2013)
Prin Cell+Molec NeurobioCMM 588 (Fall 2013)
Prin Cell+Molec NeurobioMCB 588 (Fall 2013)
Prin Cell+Molec NeurobioNRSC 588 (Fall 2013)
Prin Cell+Molec NeurobioPSIO 588 (Fall 2013)
- Madhavan, L. (2015). Neural Stem Cells for Intrinsic Brain Repair in Aging and Neural Degeneration. In Neural Stem Cells in Health and Disease. World Scientific Publishing Company.
- Madhavan, L., & Corenblum, M. J. (2017). Small-scale propagation of human iPSCs in serum-free conditions for routine immunocytochemical characterization. Journal of Visualized Experiments, 120. doi:10.3791/55260
- Corenblum, M. J., Ray, S., Remley, Q. W., Long, M., Harder, B., Zhang, D. D., Barnes, C. A., & Madhavan, L. (2016). Reduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle-age period. Aging cell, 15(4), 725-36.More infoAlthough it is known that the regenerative function of neural stem/progenitor cells (NSPCs) declines with age, causal mechanisms underlying this phenomenon are not understood. Here, we systematically analyze subventricular zone (SVZ) NSPCs, in various groups of rats across the aging spectrum, using in vitro and in vivo histological and behavioral techniques. These studies indicate that although NSPC function continuously declines with advancing age, there is a critical time period during middle age (13-15 months) when a striking reduction in NSPC survival and regeneration (proliferation and neuronal differentiation) occurs. The studies also indicate that this specific temporal pattern of NSPC deterioration is functionally relevant at a behavioral level and correlates with the decreasing expression of the redox-sensitive transcription factor, Nrf2, in the NSPCs. When Nrf2 expression was suppressed in 'young' NSPCs, using short interfering RNAs, the survival and regeneration of the NSPCs was significantly compromised and mirrored 'old' NSPCs. Conversely, Nrf2 overexpression in 'old' NSPCs rendered them similar to 'young' NSPCs, and they showed increased survival and regeneration. Furthermore, examination of newborn Nrf2 knockout (Nrf2 -/-) mice revealed a lower number of SVZ NSPCs in these animals, when compared to wild-type controls. In addition, the proliferative and neurogenic potential of the NSPCs was also compromised in the Nrf2-/- mice. These results identify a novel regulatory role for Nrf2 in NSPC function during aging and have important implications for developing NSPC-based strategies to support healthy aging and to treat age-related neurodegenerative disorders.
- Umashankar, A., Corenblum, M. J., Ray, S., Valdez, M., Yoshimaru, E. S., Trouard, T. P., & Madhavan, L. (2016). Effects of the iron oxide nanoparticle Molday ION Rhodamine B on the viability and regenerative function of neural stem cells: relevance to clinical translation. International Journal of Nanomedicine, 11, 1731-48.More infoAn essential component of developing successful neural stem cell (NSC)-based therapies involves the establishment of methodologies to noninvasively monitor grafted NSCs within brain tissues in real time. In this context, ex vivo labeling with ultrasmall superparamagnetic iron oxide (USPIO) particles has been shown to enable efficient tracking of transplanted NSCs via magnetic resonance imaging (MRI). However, whether and how USPIO labeling affects the intrinsic biology of NSCs is not thoroughly understood, and remains an active area of investigation. Here, we perform a comprehensive examination of rat NSC survival and regenerative function upon labeling with the USPIO, Molday ION Rhodamine B (MIRB), which allows for dual magnetic resonance and optical imaging. After optimization of labeling efficiency, two specific doses of MIRB (20 and 50 μg/mL) were chosen and were followed for the rest of the study. We observed that both MIRB doses supported the robust detection of NSCs, over an extended period of time in vitro and in vivo after transplantation into the striata of host rats, using MRI and post hoc fluorescence imaging. Both in culture and after neural transplantation, the higher 50 μg/mL MIRB dose significantly reduced the survival, proliferation, and differentiation rate of the NSCs. Interestingly, although the lower 20 μg/mL MIRB labeling did not produce overtly negative effects, it increased the proliferation and glial differentiation of the NSCs. Additionally, application of this dose also changed the morphological characteristics of neurons and glia produced after NSC differentiation. Importantly, the transplantation of NSCs labeled with either of the two MIRB doses upregulated the immune response in recipient animals. In particular, in animals receiving the 50 μg/mL MIRB-labeled NSCs, this immune response consisted of an increased number of CD68(+)-activated microglia, which appeared to have phagocytosed MIRB particles and cells contributing to an exaggerated MRI signal dropout in the animals. Overall, these results indicate that although USPIO particles, such as MIRB, may have advantageous labeling and magnetic resonance-sensitive features for NSC tracking, a further examination of their effects might be necessary before they can be used in clinical scenarios of cell-based transplantation.
- Corenblum, M. J., Flores, A. J., Badowski, M., Harris, D. T., & Madhavan, L. (2015). Systemic human CD34(+) cells populate the brain and activate host mechanisms to counteract nigrostriatal degeneration. Regenerative medicine, 10(5), 563-77.More infoHere we investigated the neuroprotective potential of systemic CD34(+) human cord blood cells (hCBCs) in a 6-hydroxydopamine rat model of Parkinson's disease.
- Madhavan, L. (2015). Redox-based regulation of neural stem cell function and Nrf2. Biochemical Society transactions, 43(4), 627-31.More infoNeural stem cells (NSCs) play vital roles in the development and maintenance of brain tissues throughout life. They can also potentially act as powerful sources of regeneration and repair during pathology to replace degenerating cells and counteract deleterious changes in the tissue microenvironment. However, both aging and neurodegeneration involve an up-regulation of processes, such as oxidative stress, inflammation, somatic mutations, and reduction in growth factors in neural tissues, which threaten the robust functioning of NSCs. Nevertheless, recent evidence also indicates that NSCs may possess the intrinsic capability to cope with such stressors in their microenvironment. Whereas the mechanisms governing the responses of NSCs to stress are diverse, a common theme that is emerging suggests that underlying changes in intracellular redox status are crucial. Here we discuss such redox-based regulation of NSCs, particularly in relation to nuclear erythroid factor 2-like 2 (Nrf2), which is a key cellular stress resistance factor, and its implications for successfully harnessing NSC therapeutic potential towards developing cell-based therapeutics for nervous system disorders.
- Madhavan, L., Daley, B. F., Davidson, B. L., Boudreau, R. L., Lipton, J. W., Cole-Strauss, A., Steece-Collier, K., & Collier, T. J. (2015). Sonic Hedgehog Controls the Phenotypic Fate and Therapeutic Efficacy of Grafted Neural Precursor Cells in a Model of Nigrostriatal Neurodegeneration. PloS one, 10(9), e0137136.More infoThe expression of soluble growth and survival promoting factors by neural precursor cells (NPCs) is suggested to be a prominent mechanism underlying the protective and regenerative effects of these cells after transplantation. Nevertheless, how and to what extent specific NPC-expressed factors contribute to therapeutic effects is not well understood. Using RNA silencing, the current study investigated the roles of two donor NPC molecules, namely glial cell-line derived neurotrophic factor (GDNF) and sonic hedgehog (SHH), in the protection of substantia nigra dopamine neurons in rats treated with 6-hydroxydopamine (6-OHDA). Analyses indicate that as opposed to the knock-down of GDNF, SHH inhibition caused a profound decline in nigrostriatal neuroprotection. Further, SHH silencing also curbed endogenous neurogenesis and the migration of host brdU+/dcx+ neural precursors into the striatum, which was present in the animals receiving control or GDNF silenced NPCs. A change in graft phenotype, mainly reflected by a reduced proportion of undifferentiated nestin+ cells, as well as a significantly greater host microglial activity, suggested an important role for these processes in the attenuation of neuroprotection and neurogenesis upon SHH silencing. Overall these studies reveal core mechanisms fundamental to grafted NPC-based therapeutic effects, and delineate the particular contributions of two graft-expressed molecules, SHH and GDNF, in mediating midbrain dopamine neuron protection, and host plasticity after NPC transplantation.
- Paumier, K. L., Sortwell, C. E., Madhavan, L., Terpstra, B., Celano, S. L., Green, J. J., Imus, N. M., Marckini, N., Daley, B., Steece-Collier, K., & Collier, T. J. (2015). Chronic amitriptyline treatment attenuates nigrostriatal degeneration and significantly alters trophic support in a rat model of parkinsonism. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 40(4), 874-83.More infoIn addition to alleviating depression, long-term adaptive changes induced by antidepressants may regulate neural plasticity in the diseased brain, providing symptomatic and disease-modifying effects in Parkinson's disease. The present study investigated whether chronic treatment with a frequently prescribed tricyclic antidepressant was neuroprotective in a 6-hydroxydopamine (6-OHDA) rat model of parkinsonism. In lesioned animals, chronic amitriptyline (AMI; 5 mg/kg) treatment resulted in a significant sparing of tyrosine hydroxylase-immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) compared with saline treatment. Additionally, striatal fibers were preserved and functional motor deficits were attenuated. Although 6-OHDA lesions did not induce anhedonia in our model, the dose of AMI utilized had antidepressant activity as demonstrated by reduced immobility. Recent in vitro and in vivo data provide evidence that trophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) may be key mediators of the therapeutic response to antidepressants. Therefore, we investigated whether AMI mediates changes in these specific trophic factors in the intact and degenerating nigrostriatal system. Chronic AMI treatment mediates an increase in nigral BDNF both before and during ongoing degeneration, suggesting it may contribute to neuroprotection observed in vivo. However, over time, AMI reduced BDNF levels in the striatum, indicating tricyclic therapy differentially regulates trophic factors within the nigrostriatal system. Combined, these results suggest that AMI treatment attenuates dopamine neuron loss and elicits significant trophic changes relevant to dopamine neuron survival.
- Paumier, K. L., Sortwell, C. E., Madhavan, L., Terpstra, B., Daley, B. F., & Collier, T. J. (2015). Tricyclic antidepressant treatment evokes regional changes in neurotrophic factors over time within the intact and degenerating nigrostriatal system. Experimental neurology, 266, 11-21.More infoIn addition to alleviating depression, trophic responses produced by antidepressants may regulate neural plasticity in the diseased brain, which not only provides symptomatic benefit but also potentially slows the rate of disease progression in Parkinson's disease (PD). Recent in vitro and in vivo data provide evidence that neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) may be key mediators of the therapeutic response to antidepressants. As such, we conducted a cross-sectional time-course study to determine whether antidepressant-mediated changes in neurotrophic factors occur in relevant brain regions in response to amitriptyline (AMI) treatment before and after intrastriatal 6-hydroxydopamine (6OHDA). Adult male Wistar rats were divided into seven cohorts and given daily injections (i.p.) of AMI (5mg/kg) or saline throughout the duration of the study. In parallel, various cohorts of intact or parkinsonian animals were sacrificed at specific time points to determine the impact of AMI treatment on trophic factor levels in the intact and degenerating nigrostriatal system. The left and right hemispheres of the substantia nigra, striatum, frontal cortex, piriform cortex, hippocampus, and anterior cingulate cortex were dissected, and BDNF and GDNF levels were measured with ELISA. Results show that chronic AMI treatment elicits effects in multiple brain regions and differentially regulates levels of BDNF and GDNF depending on the region. Additionally, AMI halts the progressive degeneration of dopamine (DA) neurons elicited by an intrastriatal 6-OHDA lesion. Taken together, these results suggest that AMI treatment elicits significant trophic changes important to DA neuron survival within both the intact and degenerating nigrostriatal system.
- Gombash, S. E., Lipton, J. W., Collier, T. J., Madhavan, L., Steece-Collier, K., Cole-Strauss, A., Terpstra, B. T., Spieles-Engemann, A. L., Daley, B. F., Wohlgenant, S. L., Thompson, V. B., Manfredsson, F. P., Mandel, R. J., & Sortwell, C. E. (2012). Striatal pleiotrophin overexpression provides functional and morphological neuroprotection in the 6-hydroxydopamine model. Molecular therapy : the journal of the American Society of Gene Therapy, 20(3), 544-54.More infoNeurotrophic factors are integrally involved in the development of the nigrostriatal system and in combination with gene therapy, possess great therapeutic potential for Parkinson's disease (PD). Pleiotrophin (PTN) is involved in the development, maintenance, and repair of the nigrostriatal dopamine (DA) system. The present study examined the ability of striatal PTN overexpression, delivered via psueudotyped recombinant adeno-associated virus type 2/1 (rAAV2/1), to provide neuroprotection and functional restoration from 6-hydroxydopamine (6-OHDA). Striatal PTN overexpression led to significant neuroprotection of tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) and THir neurite density in the striatum, with long-term PTN overexpression producing recovery from 6-OHDA-induced deficits in contralateral forelimb use. Transduced striatal PTN levels were increased threefold compared to adult striatal PTN expression and approximated peak endogenous developmental levels (P1). rAAV2/1 vector exclusively transduced neurons within the striatum and SNpc with approximately half the total striatal volume routinely transduced using our injection parameters. Our results indicate that striatal PTN overexpression can provide neuroprotection for the 6-OHDA lesioned nigrostriatal system based upon morphological and functional measures and that striatal PTN levels similar in magnitude to those expressed in the striatum during development are sufficient to provide neuroprotection from Parkinsonian insult.
- Madhavan, L., Daley, B. F., Sortwell, C. E., & Collier, T. J. (2012). Endogenous neural precursors influence grafted neural stem cells and contribute to neuroprotection in the parkinsonian rat. The European journal of neuroscience, 35(6), 883-95.More infoNeuroprotective and neurorescue effects after neural stem/precursor cell (NPC) transplantation have been reported, but the mechanisms underlying such phenomena are not well understood. Our recent findings in a rat Parkinson's disease (PD) model indicate that transplantation of NPCs before a 6-hydroxydopamine (6-OHDA) insult can result in nigrostriatal protection which is associated with endogenous NPC proliferation, migration and neurogenesis. Here, we sought to determine whether the observed endogenous NPC response (i) contributes to transplanted NPC-mediated neuroprotection; and/or (ii) affects graft phenotype and function. Host Fischer 344 rats were administered the antimitotic agent cytosine-β-d-arabinofuranoside (Ara-C) to eliminate actively proliferating endogenous neural precursors before being transplanted with NPCs and treated with 6-OHDA to induce nigrostriatal degeneration. Behavioral and histological analyses demonstrate that the neuroprotective response observed in NPC transplanted animals which had not received Ara-C was significantly attenuated in animals which did receive pre-transplant Ara-C. Also, while grafts in Ara-C-treated animals showed no decrease in cell number, they exhibited significantly reduced expression of the neural stem cell regulators nestin and sonic hedgehog. In addition, inhibition of the endogenous NPC response resulted in an exaggerated host glial reaction. Overall, the study establishes for the first time that endogenous NPCs contribute to transplanted NPC-mediated therapeutic effects by affecting both grafted and mature host cells in unique ways. Thus, both endogenous and transplanted NPCs are important in creating an environment suitable for neural protection and rescue, and harnessing their synergistic interaction may lead to the optimization of cell-based therapies for PD.
- Paumier, K. L., Siderowf, A. D., Auinger, P., Oakes, D., Madhavan, L., Espay, A. J., Revilla, F. J., Collier, T. J., & , P. S. (2012). Tricyclic antidepressants delay the need for dopaminergic therapy in early Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society, 27(7), 880-7.More infoThis study examined whether antidepressants delay the need for dopaminergic therapy or change the degree of motor impairment and disability in a population of early Parkinson's disease (PD) patients. Preclinical studies have indicated that antidepressants modulate signaling pathways involved in cell survival and plasticity, suggesting they may serve to both treat PD-associated depression and slow disease progression. A patient-level meta-analysis included 2064 patients from the treatment and placebo arms of the following trials: FS1, FS-TOO, ELLDOPA, QE2, TEMPO, and PRECEPT. Depression severity was determined at baseline, and antidepressant use was reported in a medication log each visit. Kaplan-Meier curves and time-dependent Cox proportional hazards models determined associations between depression severity and antidepressant use with the primary outcome, time to initiation of dopaminergic therapy. ANCOVAs determined associations with the secondary outcome, degree of motor impairment and disability, reported as annualized change in UPDRS scores from baseline to final visit. When controlling for baseline depression, the initiation of dopaminergic therapy was delayed for subjects taking tricyclic antidepressants compared with those not taking antidepressants. No significant differences were found in UPDRS scores for subjects taking antidepressants compared with those not taking antidepressants. Tricyclic antidepressants are associated with a delay in reaching the end point of need to start dopaminergic therapy. The lack of change in overall UPDRS scores suggests the delay was not attributable to symptomatic effects.
- Kordower, J. H., Dodiya, H. B., Kordower, A. M., Terpstra, B., Paumier, K., Madhavan, L., Sortwell, C., Steece-Collier, K., & Collier, T. J. (2011). Transfer of host-derived α synuclein to grafted dopaminergic neurons in rat. Neurobiology of disease, 43(3), 552-7.More infoMultiple laboratories have recently demonstrated that long-term dopaminergic transplants form Lewy bodies in patients with Parkinson's disease. Debate has arisen as to whether these Lewy bodies form from the transfer of α synuclein from the host to the graft or whether they form from intrinsic responses of the graft from being placed into what was, or became, an inflammatory focus. To test whether the former hypothesis was possible, we grafted fetal rat ventral mesencephalon into the dopamine depleted striatum of rats that had previously received 6-hydroxydopamine lesions. One month after the transplant, rats received viral over expression of human α synuclein (AAV2/6-α synuclein) or green fluorescent protein (AAV2/6-GFP) into the striatum rostral to the grafts. Care was taken to make sure that the AAV injections were sufficiently distal to the graft so no cells would be directly transfected. All rats were sacrificed five weeks after the virus injections. Double label immunohistochemistry combined with confocal microscopy revealed that a small number of grafted tyrosine hydroxylase (TH) neurons (5.7% ± 1.5% (mean ± SEM) of grafted dopamine cells) expressed host derived α synuclein but none of the grafted cells expressed host-derived GFP. The α synuclein in a few of these cells was misfolded and failed to be digested with proteinase K. These data indicate that it is possible for host derived α synuclein to transfer to grafted neurons supporting the concept that this is one possible mechanism by which grafted dopamine neurons form Lewy bodies in Parkinson's disease patients.
- Madhavan, L., & Collier, T. J. (2010). A synergistic approach for neural repair: cell transplantation and induction of endogenous precursor cell activity. Neuropharmacology, 58(6), 835-44.More infoStem cell research offers enormous potential for treating many diseases of the nervous system. At present, therapeutic strategies in stem cell research segregate into two approaches: cell transplantation or endogenous cell stimulation. Realistically, future cell therapies will most likely involve a combination of these two approaches, a theme of our current research. Here, we propose that there exists a 'synergy' between exogenous (transplanted) and endogenous stem cell actions that can be utilized to achieve therapeutic ends. Elucidating mechanisms underlying this exogenous-endogenous stem cell synergism may lead to the development of optimal cell therapies for neural disorders.
- Madhavan, L., Daley, B. F., Paumier, K. L., & Collier, T. J. (2009). Transplantation of subventricular zone neural precursors induces an endogenous precursor cell response in a rat model of Parkinson's disease. The Journal of comparative neurology, 515(1), 102-15.More infoRealistically, future stem cell therapies for neurological conditions including Parkinson's disease (PD) will most probably entail combination treatment strategies, involving both the stimulation of endogenous cells and transplantation. Therefore, this study investigates these two modes of neural precursor cell (NPC) therapy in concert in order to determine their interrelationships in a rat PD model. Human placental alkaline phosphatase (hPAP)-labeled NPCs were transplanted unilaterally into host rats which were subsequently infused ipsilaterally with 6-hydroxydopamine (6-OHDA). The reaction of host NPCs to the transplantation and 6-OHDA was tracked by bromodeoxyuridine (BrdU) labeling. Two weeks after transplantation, in animals transplanted with NPCs we found evidence of elevated host subventricular zone NPC proliferation, neurogenesis, and migration to the graft site. In these animals, we also observed a significant preservation of striatal tyrosine hydroxylase (TH) expression and substantia nigra TH cell number. We have seen no evidence that neuroprotection is a product of dopamine neuron replacement by NPC-derived cells. Rather, the NPCs expressed glial cell line-derived neurotrophic factor (GDNF), sonic hedgehog (Shh), and stromal cell-derived factor 1 alpha (SDF1alpha), providing a molecular basis for the observed neuroprotection and endogenous NPC response to transplantation. In summary, our data suggests plausible synergy between exogenous and endogenous NPC actions, and that NPC implantation before the 6-OHDA insult can create a host microenvironment conducive to stimulation of endogenous NPCs and protection of mature nigral neurons.
- Madhavan, L., Ourednik, V., & Ourednik, J. (2008). Neural stem/progenitor cells initiate the formation of cellular networks that provide neuroprotection by growth factor-modulated antioxidant expression. Stem cells (Dayton, Ohio), 26(1), 254-65.More infoRecent studies indicate that transplanted neural stem/progenitor cells (NSPs) can interact with the environment of the central nervous system and stimulate protection and regeneration of host cells exposed to oxidative stress. Here, a set of animals grafted with NSPs and treated with 3-nitropropionic acid (3-NP) exhibited reduced behavioral symptoms and less severe damage of striatal cytoarchitecture than sham transplanted controls including better survival of neurons. Sites of tissue sparing correlated with the distribution pattern of donor cells in the host brain. To investigate the cellular and molecular bases of this phenomenon, we treated cocultures of NSPs and primary neural cell cultures with 3-NP to induce oxidative stress and to study NSP-dependent activation of antioxidant mechanisms and cell survival. Proactive presence of NSPs significantly improved cell viability by interfering with production of free radicals and increasing the expression of neuroprotective factors. This process was accompanied by elevated expression of ciliary neurotrophic factor (CNTF) and vascular endothelial growth factor (VEGF) in a network of NSPs and local astrocytes. Intriguingly, both in vitro and in vivo, enhanced growth factor secretion stimulated a robust upregulation of the antioxidant enzyme superoxide dismutase 2 (SOD2) in neurons and resulted in their improved survival. Our findings thus reveal a so far unrecognized mechanism of interaction between NSPs and surrounding cells accompanying neuroprotection: through mutual, NSP-triggered stimulation of growth factor production and activation of antioxidant mechanisms, cellular networks may shield the local environment from the arriving impact of oxidative stress.
- Madhavan, L., Ourednik, V., & Ourednik, J. (2006). Increased "vigilance" of antioxidant mechanisms in neural stem cells potentiates their capability to resist oxidative stress. Stem cells (Dayton, Ohio), 24(9), 2110-9.More infoAlthough the potential value of transplanted and endogenous neural stem cells (NSCs) for the treatment of the impaired central nervous system (CNS) has widely been accepted, almost nothing is known about their sensitivity to the hostile microenvironment in comparison to surrounding, more mature cell populations. Since many neuropathological insults are accompanied by oxidative stress, this report compared the alertness of antioxidant defense mechanisms and cell survival in NSCs and postmitotic neural cells (PNCs). Both primary and immortalized cells were analyzed. At steady state, NSCs distinguished themselves in their basal mitochondrial metabolism from PNCs by their lower reactive oxygen species (ROS) levels and higher expression of the key antioxidant enzymes uncoupling protein 2 (UCP2) and glutathione peroxidase (GPx). Following exposure to the mitochondrial toxin 3-nitropropionic acid, PNC cultures were marked by rapidly decreasing mitochondrial activity and increasing ROS content, both entailing complete cell loss. NSCs, in contrast, reacted by fast upregulation of UCP2, GPx, and superoxide dismutase 2 and successfully recovered from an initial deterioration. This recovery could be abolished by specific antioxidant inhibition. Similar differences between NSCs and PNCs regarding redox control efficiency were detected in both primary and immortalized cells. Our first in vivo data from the subventricular stem cell niche of the adult mouse forebrain corroborated the above observations and revealed strong baseline expression of UCP2 and GPx in the resident, proliferating NSCs. Thus, an increased "vigilance" of antioxidant mechanisms might represent an innate characteristic of NSCs, which not only defines their cell fate, but also helps them to encounter oxidative stress in diseased CNS.
- Madhavan, L., Ourednik, V., & Ourednik, J. (2005). Grafted neural stem cells shield the host environment from oxidative stress. Annals of the New York Academy of Sciences, 1049, 185-8.More infoHere, we present our preliminary data showing that neural stem cells (NSCs) can prevent the degeneration of striatal neurons when transplanted into the CNS prior to intoxication with 3-nitropropionic acid (3-NP). In the adult CNS, the number of NSCs, a major source of neural cell populations and plasticity-modulating factors, is relatively low if compared to that of the developing brain. This, together with the adult growth-inhibitory environment, limits its regenerative capacity. Our recent observation has shown that grafted NSCs may rescue/protect neurons in the chronically impaired mesostriatal system. On the basis of this study and because we were also intrigued by our recent observations regarding the rescue/protective role of NSCs in vitro, we decided to test the hypothesis that grafted NSCs can also be deposited preventively in the CNS (and perhaps join the pool of endogenous NSCs of the intact host brain) for later buffering and maintenance of homeostasis when the host is exposed to oxidative stress.
- Madhavan, L., Freed, W. J., Anantharam, V., & Kanthasamy, A. G. (2003). 5-hydroxytryptamine 1A receptor activation protects against N-methyl-D-aspartate-induced apoptotic cell death in striatal and mesencephalic cultures. The Journal of pharmacology and experimental therapeutics, 304(3), 913-23.More infoApoptosis and glutamate-mediated excitotoxicity may play a role in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we investigated whether stimulation of the 5-hydroxytryptamine 1A (5-HT1A) receptor attenuates N-methyl-D-aspartate- (NMDA) and 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptotic cell death in cell culture models. A brief exposure (20 min) of M213-2O striatal cells to NMDA and glutamate produced a delayed increase in caspase-3 activity and DNA fragmentation in a dose- and time-dependent manner. NMDA-induced caspase-3 activity and DNA fragmentation were almost completely blocked by the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and (R)-5-fluoro-8 hydroxy-2-(dipropylamino)-tetralin (R-UH-301). Additionally, the protective effects of 8-OH-DPAT and R-UH-301 on NMDA-induced caspase-3 activation and apoptosis were reversed by pretreatment with the 5-HT1A antagonists N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635) and S-UH-301, respectively. Similarly, dose- and time-dependent increases in caspase-3 activity and DNA fragmentation were observed in rat primary mesencephalic neurons after a brief exposure to NMDA and glutamate. Caspase-3 activation and DNA fragmentation in primary mesencephalic neurons were almost completely inhibited by 8-OH-DPAT. This neuroprotective effect of 8-OH-DPAT was reversed by WAY 100635. Additionally, 8-OH-DPAT blocked tyrosine hydroxylase (TH)-positive cell death after NMDA exposure and also almost completely attenuated the NMDA-induced Ca(2+) influx in primary mesencephalic cultures. Furthermore, 8-OH-DPAT and R-UH-301 blocked apoptotic cell death in the primary mesencephalic neurons that were exposed to the Parkinsonian toxin MPP(+). Together, these results suggest that 5-HT1A receptor stimulation may be a promising pharmacological approach in the development of neuroprotective agents for PD.
- Madhavan, L. (2017, April). Growth, Morphology, Mitochondrial And Autophagic Alterations In Sporadic Parkinson’s Disease Fibroblasts. American Society for Neural Therapy and Repair conference.
- Madhavan, L. (2017, March). Rejuvenating The Aging Brain By Improving Stem Cell Function. Arizona Biomedical Research Comission conference.
- Madhavan, L. (2016, April). A critical middle-age period and a role for Nrf2 in the decline in neural stem cell function with age. American Society for Neural Therapy and Repair conference.
- Madhavan, L. (2016, November). Targeting the Nrf2 pathway to improve neural stem cell function with age. Society for Neuroscience meeting, San Diego.
- Corenblum, M. J., Ray, S., Remley, Q. W., Zhang, D. D., Min, L., Harder, B., Barnes, C. A., & Madhavan, L. (2015, January 6-8). Nrf2 regulates neural stem cell function during aging, Keap1/Nrf2 pathway in health and disease. Biochemical Society focused conference on the ‘Keap1/Nrf2 pathway in health and disease’, Cambridge UK.
- Madhavan, L. (2017, January). Autophagic Alterations In Dermal Fibroblasts From Individuals With Idiopathic Parkinson’s Disease. UBRP conference at UA.
- Madhavan, L. (2017, January). Effects Of Nrf2 Loss On The Regenerative Function Of Neural Stem Cells In The Developing Hippocampus Of Newborn Mice. UBRP conference at UA.
- Madhavan, L. (2017, January). Nrf2 Expression And Its Effects On Hippocampal Neural Stem Cells. UBRP conference at UA.
- Madhavan, L. (2017, November). Enhanced Nrf2 Expression Improves Neural Stem Cell Function During A Critical Aging Period. Society for Neuroscience meeting, Washington DC.
- Madhavan, L. (2016, January). Effects of age-related systemic alterations on subventricular zone neural stem and progenitor cells. UBRP conference at UA.
- Madhavan, L. (2016, January). In Vitro and In Vivo Characterization and Magnetic Resonance Imaging of Molday Ion Rhodamine B labeled Neural Stem Cells. UBRP conference at UA.
- Madhavan, L. (2016, January). Modeling Parkinson’s Disease in Patient-Specific Human Dermal Fibroblasts. UBRP conference at UA.
- Madhavan, L. (2016, November). An analysis of Nrf2 expression and its effects on aging hippocampal neural stem cell function. Society for Neuroscience meeting, San Diego.
- Madhavan, L. (2016, November). Modeling Parkinson's disease using patient-derived primary dermal fibroblasts. Society for Neuroscience meeting, San Diego.
- Flores, A. J., Corenblum, M. J., Curiel, C. N., Sherman, S. J., & Madhavan, L. (2015, May 14). In vitro morphologic and spatial dynamics of primary skin fibroblasts from idiopathic Parkinson’s disease patients. ADC Annual Conference, Phoenix. Phoenix AZ.
- Flores, A. J., Corenblum, M. J., Curiel, C. N., Sherman, S. J., & Madhavan, L. (2015, Spring). Analysis of morphology, autophagy, and alpha-synuclein expression in primary skin fibroblasts from Parkinson’s disease patients. Society for Neuroscience meeting, Chicago. Chicago, IL.
- Madhavan, L., Corenblum, M. J., Ray, S., Remley, Q. W., Long, M., Harder, B., Zhang, D. D., & Barnes, C. A. (2015, Spring). A role for Nrf2 in neural stem cell function during aging. Society for Neuroscience meeting, Chicago.
- Madhavan, L., Remley, Q. W., & Corenblum, M. J. (2015, January 24). A Heat Induced Antigen Retrieval Method to Improve Detection of Neural Stem and Progenitor Cells in Prefixed Frozen mouse tissues. UBRP conference at UA.
- Ray, S., Corenblum, M. J., Remley, Q. W., Zhang, D. D., Min, L., Harder, B., & Madhavan, L. (2015, January 24). Characterizing NSC’s in Nrf2 -/- Knockout Mice. UBRP conference at UA.
- Umashankar, A., Corenblum, M. J., Yoshimaru, E., Trouard, T. P., & Madhavan, L. (2015, January 24). Effects of the MR Sensitive Iron Oxide Nanoparticle Molday ION Rhodamine B on Neural Stem Cell Viability and Behavior. UBRP conference at UA.