Ayanabha Chakraborti

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Journals/Publications

• Shaikh, M. F., Ngadimon, I. W., Chakraborti, A., Abdullah, J. M., & Russo, E. (2023). Editorial: Experimental models of epilepsy and related comorbidities, Volume II. Frontiers in pharmacology, 14, 1182958.
• Sin, R., Sotogaku, N., Ohnishi, Y. N., Shuto, T., Kuroiwa, M., Kawahara, Y., Sugiyama, K., Murakami, Y., Kanai, M., Funakoshi, H., Chakraborti, A., Bibb, J. A., & Nishi, A. (2023). Inhibition of STAT-mediated cytokine responses to chemically-induced colitis prevents inflammation-associated neurobehavioral impairments. Brain, behavior, and immunity, 114, 173-186.
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  Depression can be associated with chronic systemic inflammation, and production of peripheral proinflammatory cytokines and upregulation of the kynurenine pathway have been implicated in pathogenesis of depression. However, the mechanistic bases for these comorbidities are not yet well understood. As tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), which convert tryptophan to kynurenine, are rate-limiting enzymes of the kynurenine pathway, we screened TDO or IDO inhibitors for effects on the production of proinflammatory cytokines in a mouse macrophage cell line. The TDO inhibitor 680C91 attenuated LPS-induced pro-inflammatory cytokines including IL-1β and IL-6. Surprisingly, this effect was TDO-independent, as it occurred even in peritoneal macrophages from TDO knockout mice. Instead, the anti-inflammatory effects of 680C91 were mediated through the suppression of signal transducer and activator of transcription(STAT) signaling. Furthermore, 680C91 suppressed production of proinflammatory cytokines and STAT signaling in an animal model of inflammatory bowel disease. Specifically, 680C91 effectively attenuated acute phase colon cytokine responses in male mice subjected to dextran sulfate sodium (DSS)-induced colitis. Interestingly, this treatment also prevented the development of anxiodepressive-like neurobehaviors in DSS-treated mice during the recovery phase. The ability of 680C91 to prevent anxiodepressive-like behavior in response to chemically-induced colitis appeared to be due to rescue of attenuated dopamine responses in the nucleus accumbens. Thus, inhibition of STAT-mediated, but TDO-independent proinflammatory cytokines in macrophages can prevent inflammation-associated anxiety and depression. Identification of molecular mechanisms involved may facilitate the development of new treatments for gastrointestinal-neuropsychiatric comorbidity.
• Umfress, A., Chakraborti, A., Priya Sudarsana Devi, S., Adams, R., Epstein, D., Massicano, A., Sorace, A., Singh, S., Iqbal Hossian, M., Andrabi, S. A., Crossman, D. K., Kumar, N., Shahid Mukhtar, M., Luo, H., Simpson, C., Abell, K., Stokes, M., Wiederhold, T., Rosen, C., , Lu, H., et al. (2023). Cdk5 mediates rotational force-induced brain injury. Scientific reports, 13(1), 3394.
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  Millions of traumatic brain injuries (TBIs) occur annually. TBIs commonly result from falls, traffic accidents, and sports-related injuries, all of which involve rotational acceleration/deceleration of the brain. During these injuries, the brain endures a multitude of primary insults including compression of brain tissue, damaged vasculature, and diffuse axonal injury. All of these deleterious effects can contribute to secondary brain ischemia, cellular death, and neuroinflammation that progress for weeks, months, and lifetime after injury. While the linear effects of head trauma have been extensively modeled, less is known about how rotational injuries mediate neuronal damage following injury. Here, we developed a new model of repetitive rotational head trauma in rodents and demonstrated acute and prolonged pathological, behavioral, and electrophysiological effects of rotational TBI (rTBI). We identify aberrant Cyclin-dependent kinase 5 (Cdk5) activity as a principal mediator of rTBI. We utilized Cdk5-enriched phosphoproteomics to uncover potential downstream mediators of rTBI and show pharmacological inhibition of Cdk5 reduces the cognitive and pathological consequences of injury. These studies contribute meaningfully to our understanding of the mechanisms of rTBI and how they may be effectively treated.
• Chehade, S. B., Green, G. B., Graham, C. D., Chakraborti, A., Vashai, B., Moon, A., Williams, M. B., Vickers, B., Berryhill, T., Van Der Pol, W., Wilson, L., Powell, M. L., Smith, D. L., Barnes, S., Morrow, C., Mukhtar, M. S., Kennedy, G. D., Bibb, J. A., & Watts, S. A. (2022). A modified standard American diet induces physiological parameters associated with metabolic syndrome in C57BL/6J mice. Frontiers in nutrition, 9, 929446.
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  Investigations into the causative role that western dietary patterns have on obesity and disease pathogenesis have speculated that quality and quantity of dietary fats and/or carbohydrates have a predictive role in the development of these disorders. Standard reference diets such as the AIN-93 rodent diet have historically been used to promote animal health and reduce variation of results across experiments, rather than model modern human dietary habits or nutrition-related pathologies. In rodents high-fat diets (HFDs) became a classic tool to investigate diet-induced obesity (DIO). These murine diets often relied on a single fat source with the most DIO consistent HFDs containing levels of fat up to 45-60% (kcal), higher than the reported human intake of 33-35% (kcal). More recently, researchers are formulating experimental animal (pre-clinical) diets that reflect mean human macro- and micronutrient consumption levels described by the National Health and Nutrition Examination Survey (NHANES). These diets attempt to integrate relevant ingredient sources and levels of nutrients; however, they most often fail to include high-fructose corn syrup (HFCS) as a source of dietary carbohydrate. We have formulated a modified Standard American Diet (mSAD) that incorporates relevant levels and sources of nutrient classes, including dietary HFCS, to assess the basal physiologies associated with mSAD consumption. Mice proffered the mSAD for 15 weeks displayed a phenotype consistent with metabolic syndrome, exhibiting increased adiposity, fasting hyperglycemia with impaired glucose and insulin tolerance. Metabolic alterations were evidenced at the tissue level as crown-like structures (CLS) in adipose tissue and fatty acid deposition in the liver, and targeted 16S rRNA metagenomics revealed microbial compositional shifts between dietary groups. This study suggests diet quality significantly affects metabolic homeostasis, emphasizing the importance of developing relevant pre-clinical diets to investigate chronic diseases highly impacted by western dietary consumption patterns.
• Mickael, M. E., Bhaumik, S., Chakraborti, A., Umfress, A. A., van Groen, T., Macaluso, M., Totenhagen, J., Sorace, A. G., Bibb, J. A., Standaert, D. G., & Basu, R. (2022). RORγt-Expressing Pathogenic CD4 T Cells Cause Brain Inflammation during Chronic Colitis. Journal of immunology (Baltimore, Md. : 1950), 208(8), 2054-2066.
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  Neurobehavioral disorders and brain abnormalities have been extensively reported in both Crohn's disease and ulcerative colitis patients. However, the mechanism causing neuropathological disorders in inflammatory bowel disease patients remains unknown. Studies have linked the Th17 subset of CD4 T cells to brain diseases associated with neuroinflammation and cognitive impairment, including multiple sclerosis, ischemic brain injury, and Alzheimer's disease. To better understand how CD4 T lymphocytes contribute to brain pathology in chronic intestinal inflammation, we investigated the development of brain inflammation in the T cell transfer model of chronic colitis. Our findings demonstrate that CD4 T cells infiltrate the brain of colitic mice in proportional levels to colitis severity. Colitic mice developed hypothalamic astrogliosis that correlated with neurobehavioral disorders. Moreover, the brain-infiltrating CD4 T cells expressed Th17 cell transcription factor retinoic acid-related orphan receptor γt (RORγt) and displayed a pathogenic Th17 cellular phenotype similar to colonic Th17 cells. Adoptive transfer of RORγt-deficient naive CD4 T cells failed to cause brain inflammation and neurobehavioral disorders in recipients, with significantly less brain infiltration of CD4 T cells. The finding is mirrored in chronic dextran sulfate sodium-induced colitis in mice that showed lower frequency of brain-infiltrating CD4 T cells and astrogliosis despite onset of significantly more severe colitis compared with wild-type mice. These findings suggest that pathogenic RORγtCD4 T cells that aggravate colitis migrate preferentially into the brain, contributing to brain inflammation and neurobehavioral disorders, thereby linking colitis severity to neuroinflammation.
• Shaikh, M. F., Chakraborti, A., O'Brien, T. J., & Raymond, A. A. (2022). Editorial: Translational Epilepsy: An Experimental to Clinical Update. Frontiers in neurology, 13, 939559.
• Thomas, R., Hernandez, A., Benavides, D. R., Li, W., Tan, C., Umfress, A., Plattner, F., Chakraborti, A., Pozzo-Miller, L., Taylor, S. S., & Bibb, J. A. (2022). Integrated regulation of PKA by fast and slow neurotransmission in the nucleus accumbens controls plasticity and stress responses. The Journal of biological chemistry, 298(8), 102245.
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  Cortical glutamate and midbrain dopamine neurotransmission converge to mediate striatum-dependent behaviors, while maladaptations in striatal circuitry contribute to mental disorders. However, the crosstalk between glutamate and dopamine signaling has not been entirely elucidated. Here we uncover a molecular mechanism by which glutamatergic and dopaminergic signaling integrate to regulate cAMP-dependent protein kinase (PKA) via phosphorylation of the PKA regulatory subunit, RIIβ. Using a combination of biochemical, pharmacological, neurophysiological, and behavioral approaches, we find that glutamate-dependent reduction in cyclin-dependent kinase 5 (Cdk5)-dependent RIIβ phosphorylation alters the PKA holoenzyme autoinhibitory state to increase PKA signaling in response to dopamine. Furthermore, we show that disruption of RIIβ phosphorylation by Cdk5 enhances cortico-ventral striatal synaptic plasticity. In addition, we demonstrate that acute and chronic stress in rats inversely modulate RIIβ phosphorylation and ventral striatal infusion of a small interfering peptide that selectively targets RIIβ regulation by Cdk5 improves behavioral response to stress. We propose this new signaling mechanism integrating ventral striatal glutamate and dopamine neurotransmission is important to brain function, may contribute to neuropsychiatric conditions, and serves as a possible target for the development of novel therapeutics for stress-related disorders.
• Umfress, A., Singh, S., Ryan, K. J., Chakraborti, A., Plattner, F., Sonawane, Y., Mallareddy, J. R., Acosta, E. P., Natarajan, A., & Bibb, J. A. (2022). Systemic Administration of a Brain Permeable Cdk5 Inhibitor Alters Neurobehavior. Frontiers in pharmacology, 13, 863762.
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  Cyclin-dependent kinase 5 (Cdk5) is a crucial regulator of neuronal signal transduction. Cdk5 activity is implicated in various neuropsychiatric and neurodegenerative conditions such as stress, anxiety, depression, addiction, Alzheimer's disease, and Parkinson's disease. While constitutive Cdk5 knockout is perinatally lethal, conditional knockout mice display resilience to stress-induction, enhanced cognition, neuroprotection from stroke and head trauma, and ameliorated neurodegeneration. Thus, Cdk5 represents a prime target for treatment in a spectrum of neurological and neuropsychiatric conditions. While intracranial infusions or treatment of acutely dissected brain tissue with compounds that inhibit Cdk5 have allowed the study of kinase function and corroborated conditional knockout findings, potent brain-penetrant systemically deliverable Cdk5 inhibitors are extremely limited, and no Cdk5 inhibitor has been approved to treat any neuropsychiatric or degenerative diseases to date. Here, we screened aminopyrazole-based analogs as potential Cdk5 inhibitors and identified a novel analog, 25-106, as a uniquely brain-penetrant anti-Cdk5 drug. We characterize the pharmacokinetic and dynamic responses of 25-106 in mice and functionally validate the effects of Cdk5 inhibition on open field and tail-suspension behaviors. Altogether, 25-106 represents a promising preclinical Cdk5 inhibitor that can be systemically administered with significant potential as a neurological/neuropsychiatric therapeutic.
• Chakraborti, A., Graham, C., Chehade, S., Vashi, B., Umfress, A., Kurup, P., Vickers, B., Chen, H. A., Telange, R., Berryhill, T., Van Der Pol, W., Powell, M., Barnes, S., Morrow, C., Smith, D. L., Mukhtar, M. S., Watts, S., Kennedy, G., & Bibb, J. (2021). High Fructose Corn Syrup-Moderate Fat Diet Potentiates Anxio-Depressive Behavior and Alters Ventral Striatal Neuronal Signaling. Frontiers in neuroscience, 15, 669410.
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  The neurobiological mechanisms that mediate psychiatric comorbidities associated with metabolic disorders such as obesity, metabolic syndrome and diabetes remain obscure. High fructose corn syrup (HFCS) is widely used in beverages and is often included in food products with moderate or high fat content that have been linked to many serious health issues including diabetes and obesity. However, the impact of such foods on the brain has not been fully characterized. Here, we evaluated the effects of long-term consumption of a HFCS-Moderate Fat diet (HFCS-MFD) on behavior, neuronal signal transduction, gut microbiota, and serum metabolomic profile in mice to better understand how its consumption and resulting obesity and metabolic alterations relate to behavioral dysfunction. Mice fed HFCS-MFD for 16 weeks displayed enhanced anxiogenesis, increased behavioral despair, and impaired social interactions. Furthermore, the HFCS-MFD induced gut microbiota dysbiosis and lowered serum levels of serotonin and its tryptophan-based precursors. Importantly, the HFCS-MFD altered neuronal signaling in the ventral striatum including reduced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), increased expression of ΔFosB, increased Cdk5-dependent phosphorylation of DARPP-32, and reduced PKA-dependent phosphorylation of the GluR1 subunit of the AMPA receptor. These findings suggest that HFCS-MFD-induced changes in the gut microbiota and neuroactive metabolites may contribute to maladaptive alterations in ventral striatal function that underlie neurobehavioral impairment. While future studies are essential to further evaluate the interplay between these factors in obesity and metabolic syndrome-associated behavioral comorbidities, these data underscore the important role of peripheral-CNS interactions in diet-induced behavioral and brain function. This study also highlights the clinical need to address neurobehavioral comorbidities associated with obesity and metabolic syndrome.
• Shaikh, M. F., Chakraborti, A., Ravizza, T., O'Brien, T. J., & Abdullah, J. M. (2020). Editorial: Experimental & Clinical Epilepsy and Related Comorbidities. Frontiers in pharmacology, 11, 592448.
• Chakraborti, A., Shaikh, M. F., Vezzani, A., & Abdullah, J. M. (2019). Editorial: Experimental Models of Epilepsy and Related Comorbidities. Frontiers in pharmacology, 10, 179.
• Paudel, Y. N., Shaikh, M. F., Chakraborti, A., Kumari, Y., Aledo-Serrano, ., Aleksovska, K., Alvim, M. K., & Othman, I. (2018). HMGB1: A Common Biomarker and Potential Target for TBI, Neuroinflammation, Epilepsy, and Cognitive Dysfunction. Frontiers in neuroscience, 12, 628.
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  High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein released by glia and neurons upon inflammasome activation and activates receptor for advanced glycation end products (RAGE) and toll-like receptor (TLR) 4 on the target cells. HMGB1/TLR4 axis is a key initiator of neuroinflammation. In recent days, more attention has been paid to HMGB1 due to its contribution in traumatic brain injury (TBI), neuroinflammatory conditions, epileptogenesis, and cognitive impairments and has emerged as a novel target for those conditions. Nevertheless, HMGB1 has not been portrayed as a common prognostic biomarker for these HMGB1 mediated pathologies. The current review discusses the contribution of HMGB1/TLR4/RAGE signaling in several brain injury, neuroinflammation mediated disorders, epileptogenesis and cognitive dysfunctions and in the light of available evidence, argued the possibilities of HMGB1 as a common viable biomarker of the above mentioned neurological dysfunctions. Furthermore, the review also addresses the result of preclinical studies focused on HMGB1 targeted therapy by the HMGB1 antagonist in several ranges of HMGB1 mediated conditions and noted an encouraging result. These findings suggest HMGB1 as a potential candidate to be a common biomarker of TBI, neuroinflammation, epileptogenesis, and cognitive dysfunctions which can be used for early prediction and progression of those neurological diseases. Future study should explore toward the translational implication of HMGB1 which can open the windows of opportunities for the development of innovative therapeutics that could prevent several associated HMGB1 mediated pathologies discussed herein.
• Raber, J., Allen, A. R., Weber, S., Chakraborti, A., Sharma, S., & Fike, J. R. (2016). Effect of behavioral testing on spine density of basal dendrites in the CA1 region of the hippocampus modulated by (56)Fe irradiation. Behavioural brain research, 302, 263-8.
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  A unique feature of the space radiation environment is the presence of high-energy charged particles, including (56)Fe ions, which can present a significant hazard to space flight crews during and following a mission. (56)Fe irradiation-induced cognitive changes often involve alterations in hippocampal function. These alterations might involve changes in spine morphology and density. In addition to irradiation, performing a cognitive task can also affect spine morphology. Therefore, it is often hard to determine whether changes in spine morphology and density are due to an environmental challenge or group differences in performance on cognitive tests. In this study, we tested the hypothesis that the ability of exploratory behavior to increase specific measures of hippocampal spine morphology and density is affected by (56)Fe irradiation. In sham-irradiated mice, exploratory behavior increased basal spine density in the CA1 region of the hippocampus and the enclosed blade of the dentate gyrus. These effects were not seen in irradiated mice. In addition, following exploratory behavior, there was a trend toward a decrease in the percent stubby spines on apical dendrites in the CA3 region of the hippocampus in (56)Fe-irradiated, but not sham-irradiated, mice. Other hippocampal regions and spine measures affected by (56)Fe irradiation showed comparable radiation effects in behaviorally naïve and cognitively tested mice. Thus, the ability of exploratory behavior to alter spine density and morphology in specific hippocampal regions is affected by (56)Fe irradiation.
• Allen, A. R., Raber, J., Chakraborti, A., Sharma, S., & Fike, J. R. (2015). (56)Fe Irradiation Alters Spine Density and Dendritic Complexity in the Mouse Hippocampus. Radiation research, 184(6), 586-94.
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  A unique feature of the space radiation environment is the presence of high-energy charged particles, which can be significantly hazardous to space flight crews who are exposed during a mission. Health risks associated with high-LET radiation exposure include cognitive injury. The pathogenesis of this injury is unknown but may involve modifications to dendritic structure and/or alterations in dendritic spine density and morphology. In this study, 24 two-month-old C57BL6/J male mice were either whole-body irradiated with 0.5 Gy (56)Fe (600 MeV/n; n = 12) or sham irradiated (n = 12). Three months postirradiation animals were tested for locomotor activity and habituation. After behavioral testing, animals were euthanized and the brains were flash frozen. Compared to sham-irradiated mice, irradiated mice moved less when first introduced to the environment, although they did recognize the environment when re-exposed to it one day later. Exposure to (56)Fe radiation significantly compromised the dendritic architecture and reduced spine density throughout the hippocampal tri-synaptic network. To our knowledge, these data represents the first reported evidence that high-LET radiation has deleterious effects on mature neurons associated with hippocampal learning and memory.
• Gulati, K., Chakraborti, A., & Ray, A. (2015). Gender Based Differences in Stress-induced Gastric Ulcer Formation and its Regulation by Nitric Oxide (NO): An Experimental Study. Current pharmaceutical design, 21(23), 3395-401.
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  A variety of physiological and pharmacological factors are known to influence stress responses. Cold restraint stress (CRS) induced gastric ulcerogenesis in both the sexes but such ulceration was found to be markedly higher in male than in female rats. In males, CRS induced significant increases in both ulcer number and ulcer severity; while the females though showed a trend towards increase in both the parameters, the extent of changes was far less than in males. Pre-administration of the NO mimetic, L-Arginine (500 and 1000 mg/kg), prior to CRS, dose dependently decreased ulcer number and severity in male rats. In female rats, L-Arginine also induced a gastric cytoprotective effect during CRS but to a much lesser extent. On the other hand, inhibition of NO synthesis by LNAME (25 and 50 mg/kg) further aggravated such stress ulcerogensis in both males and females, with aggravations being more extensive in males. CRS induced ulcerogenesis was associated with reductions in levels of brain and plasma NOx and GSH levels while MDA levels were elevated in both male and female rats- the magnitude of these changes being higher in males than in females. In female rats, pretreatment with formestane (aromatase inhibitor) but not tamoxifen (estrogen receptor blocker) aggravated stress ulcer formation as compared to vehicle treated CRS exposed rats. Formestane pretreatment also induced greater suppressions in brain NOx and GSH and elevations in brain MDA, as compared to vehicle treated CRS rats. These results indicate that estrogen and its interactions with oxidative stress markers and NO plays a key role in the gender based differences in stress induced gastric ulcerogenesis. It may be speculated that, in males, CRS induces greater reductions in brain NO and enhancement in oxidative injury resulting in greater severity of gastric ulceration. On the other hand, greater resistance of females to ulcerogenic effects of CRS may be due to the protection conferred by estrogen and this effect seems to be related to interactions with brain NO.
• Allen, A. R., Eilertson, K., Chakraborti, A., Sharma, S., Baure, J., Habdank-Kolaczkowski, J., Allen, B., Rosi, S., Raber, J., & Fike, J. R. (2014). Radiation exposure prior to traumatic brain injury induces responses that differ as a function of animal age. International journal of radiation biology, 90(3), 214-23.
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  Uncontrolled radiation exposure due to radiological terrorism, industrial accidents or military circumstances is a continuing threat for the civilian population. Age plays a major role in the susceptibility to radiation; younger children are at higher risk of developing cognitive deterioration when compared to adults. Our objective was to determine if an exposure to radiation affected the vulnerability of the juvenile hippocampus to a subsequent moderate traumatic injury.
• Chakraborti, A., Gulati, K., & Ray, A. (2014). Possible role of nitric oxide (NO) in the regulation of gender related differences in stress induced anxiogenesis in rats. Nitric oxide : biology and chemistry, 43, 74-80.
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  Gender related differences in stress induced neurobehavioral disorders have been reported although the mechanisms involved are not yet clear. The present study investigated the role of nitric oxide, an important biomodulator in the sex related differences in stress induced anxiety like behavior in rats. Restraint stress (RS for 1 h) was used as the experimental stressor and the effects of NO modulators were assessed in the elevated plus maze (EPM) test in both male and female rats. No metabolites (NOx) and asymmetric dimethyl arginine (ADMA) were measured in brain homogenates of these rats for corroborative purposes. RS induced anxiogenesis in both male and female rats and such changes were greater in males as compared to females. The behavioral alterations were associated with enhanced levels of ADMA and reductions in levels of NOx in brain homogenates - the effects being greater in intensity in males as compared to females. Pretreatment with NO precursor L-arginine (500 mg/kg) reversed the RS induced behavioral and biochemical changes, while NO synthase inhibitor L-NAME (50 mg/kg) had opposite effects. Additionally, Formestane (50 mg/kg), an estrogen synthesis blocker, aggravated stress induced anxiogenesis with a corresponding increase in ADMA and decrease in NOx levels in the females. To our knowledge, this is the first report indicating the involvement of ADMA, an endogenous nitric oxide synthase inhibitor in stress induced neurobehavioral changes. Furthermore, it is also evident that nitric oxide and its interactions with estrogens play a crucial modulatory role in the differential anxiogenic response to stress among males and females.
• Chakraborti, A., Allen, A., Allen, B., Rosi, S., & Fike, J. R. (2012). Cranial irradiation alters dendritic spine density and morphology in the hippocampus. PloS one, 7(7), e40844.
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  Therapeutic irradiation of the brain is a common treatment modality for brain tumors, but can lead to impairment of cognitive function. Dendritic spines are sites of excitatory synaptic transmission and changes in spine structure and number are thought to represent a morphological correlate of altered brain functions associated with hippocampal dependent learning and memory. To gain some insight into the temporal and sub region specific cellular changes in the hippocampus following brain irradiation, we investigated the effects of 10 Gy cranial irradiation on dendritic spines in young adult mice. One week or 1 month post irradiation, changes in spine density and morphology in dentate gyrus (DG) granule and CA1 pyramidal neurons were quantified using Golgi staining. Our results showed that in the DG, there were significant reductions in spine density at both 1 week (11.9%) and 1 month (26.9%) after irradiation. In contrast, in the basal dendrites of CA1 pyramidal neurons, irradiation resulted in a significant reduction (18.7%) in spine density only at 1 week post irradiation. Analysis of spine morphology showed that irradiation led to significant decreases in the proportion of mushroom spines at both time points in the DG as well as CA1 basal dendrites. The proportions of stubby spines were significantly increased in both the areas at 1 month post irradiation. Irradiation did not alter spine density in the CA1 apical dendrites, but there were significant changes in the proportion of thin and mushroom spines at both time points post irradiation. Although the mechanisms involved are not clear, these findings are the first to show that brain irradiation of young adult animals leads to alterations in dendritic spine density and morphology in the hippocampus in a time dependent and region specific manner.
• Zou, Y., Corniola, R., Leu, D., Khan, A., Sahbaie, P., Chakraborti, A., Clark, D. J., Fike, J. R., & Huang, T. T. (2012). Extracellular superoxide dismutase is important for hippocampal neurogenesis and preservation of cognitive functions after irradiation. Proceedings of the National Academy of Sciences of the United States of America, 109(52), 21522-7.
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  Cranial irradiation is widely used in cancer therapy, but it often causes cognitive defects in cancer survivors. Oxidative stress is considered a major cause of tissue injury from irradiation. However, in an earlier study mice deficient in the antioxidant enzyme extracellular superoxide dismutase (EC-SOD KO) showed reduced sensitivity to radiation-induced defects in hippocampal functions. To further dissect the role of EC-SOD in neurogenesis and in response to irradiation, we generated a bigenic EC-SOD mouse model (OE mice) that expressed high levels of EC-SOD in mature neurons in an otherwise EC-SOD-deficient environment. EC-SOD deficiency was associated with reduced progenitor cell proliferation in the subgranular zone of dentate gyrus in KO and OE mice. However, high levels of EC-SOD in the granule cell layer supported normal maturation of newborn neurons in OE mice. Following irradiation, wild-type mice showed reduced hippocampal neurogenesis, reduced dendritic spine densities, and defects in cognitive functions. OE and KO mice, on the other hand, were largely unaffected, and the mice performed normally in neurocognitive tests. Although the resulting hippocampal-related functions were similar in OE and KO mice following cranial irradiation, molecular analyses suggested that they may be governed by different mechanisms: whereas neurotrophic factors may influence radiation responses in OE mice, dendritic maintenance may be important in the KO environment. Taken together, our data suggest that EC-SOD plays an important role in all stages of hippocampal neurogenesis and its associated cognitive functions, and that high-level EC-SOD may provide protection against irradiation-related defects in hippocampal functions.
• Chakraborti, A., Gulati, K., & Ray, A. (2011). Involvement of nitric oxide in the protective effects of dehydroepiandrosterone sulphate on stress induced neurobehavioral suppression and brain oxidative injury in rats. European journal of pharmacology, 652(1-3), 55-9.
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  The involvement of nitric oxide (NO) in the effects of dehydroepiandrosterone sulphate (DHEAS) on restraint stress induced neurobehavioral and brain oxidative/nitrosative stress markers was investigated in rats. Exposure of rats to restraint stress suppressed behavioral activity in the elevated plus maze and this was associated with increases in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) and brain NO metabolite (NOx) levels in brain homogenates. Pretreatment with DHEAS (5-40mg/s.c.) reversed the stress induced changes in behavioral and oxidative stress markers and also brain NOx levels. The beneficial effect of DHEAS (40mg/kgs.c.) was blocked by pretreatment with nitric oxide synthase inhibitor, L-NAME (50mg/kgi.p.) while pretreatment of rats with NO-precursor l-Arginine (100mg/kg i.p.) produced potentiation of action of sub effective dose of DHEAS (5mg/kgs.c.). The DHEAS effects were stress specific as these behavioral and biochemical parameters were not much influenced in non-stressed rats. These observations suggest that pretreatment with DHEAS has a protective effect on restraint stress induced alteration of neurobehavioral changes and brain oxidative injury in rats and NO-dependent mechanisms may be involved in this effect.
• Raber, J., Rosi, S., Chakraborti, A., Fishman, K., Dayger, C., Davis, M. J., Villasana, L., & Fike, J. R. (2011). Effects of ⁵⁶Fe-particle cranial radiation on hippocampus-dependent cognition depend on the salience of the environmental stimuli. Radiation research, 176(4), 521-6.
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  Ionizing radiation reduces the numbers of neurons expressing activity-regulated cytoskeleton-associated protein (Arc) in the hippocampal dentate gyrus (DG). It is currently unclear if that change relates to cognitive function. We assessed the effects of 1 Gy of head-only ⁵⁶Fe-particle irradiation on hippocampus-dependent and hippocampus-independent fear conditioning and determined how those changes related to Arc expression within the DG. Irradiated mice that did not receive tone-shock pairings on day 1 showed less freezing in the same context on a second day and a lower fraction of Arc-expressing neurons in the free (lower) blade of the DG than sham-irradiated mice. Those data suggested reduced hippocampus-dependent spatial habituation learning. Changes in Arc expression in the free blade correlated positively with freezing in mice that did not receive tone-shock pairings. However, irradiated mice that did receive tone-shock pairings showed enhanced contextual freezing but a reduced percentage of Arc-expressing neurons in the enclosed (upper) blade. Changes in Arc expression correlated negatively with freezing in mice that received tone-shock pairings. In animals receiving cued fear conditioning, radiation did not affect cognitive performance or the fractions of Arc-expressing neurons. While the relationship between Arc expression and cognitive performance is complex, our data suggest that radiation effects on hippocampus-dependent cognition might depend on the prominence (salience) of environmental stimuli and blade-specific Arc expression.
• Gulati, K., Chakraborti, A., & Ray, A. (2009). Differential role of nitric oxide (NO) in acute and chronic stress induced neurobehavioral modulation and oxidative injury in rats. Pharmacology, biochemistry, and behavior, 92(2), 272-6.
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  The present study evaluated the effects of acute and chronic restraint stress (RS 1 h or 6 h), and their modulation by nitrergic agents on neurobehavioral and oxidative stress markers in rats. Acute RS (1 h or 6 h) reduced open arm entries (OAE) and open arm time (OAT) in the elevated plus maze test - which were attenuated by the NO precursor, L-arginine but not influenced appreciably by the NO synthase inhibitor, L-NAME. These behavioral changes were associated with differential changes in brain NO metabolites (NOx) but consistently reduced GSH and raised MDA levels in comparison to the control group. Following RS 1 h x 10 the neurobehavioral suppression and changes in brain oxidative stress markers were less pronounced as compared to the acute RS (1 h) group indicating adaptation. L-arginine pretreatment facilitated this adaptation to chronic RS (1 h). Interestingly RS 6 h x 10, induced severe behavioral suppression and aggravation of MDA and NOx levels and L-NAME pretreatment tended to protect against these chronic RS induced aggravations. These results suggest that acute and chronic RS induces duration/intensity dependent neurobehavioral and oxidative injury which are under the differential regulatory control of NO.
• Ahmed, R. S., Suke, S. G., Seth, V., Chakraborti, A., Tripathi, A. K., & Banerjee, B. D. (2008). Protective effects of dietary ginger (Zingiber officinales Rosc.) on lindane-induced oxidative stress in rats. Phytotherapy research : PTR, 22(7), 902-6.
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  The protective effect of dietary feeding of Zingiber officinales Rosc. (ginger) against lindane-induced oxidative stress was investigated in male albino rats. Oxidative stress was monitored by estimating the extent of lipid peroxidation, activities of the oxygen free radical (OFR) scavenging enzymes superoxide dismutase (SOD) and catalase (CAT) and the status of the glutathione redox cycle antioxidants. Lindane administration (30 mg/kg bw orally for 4 weeks) was associated with enhanced lipid peroxidation and compromised antioxidant defenses in rats fed a normal diet. Concomitant dietary feeding of ginger (1%w/w) significantly attenuated lindane-induced lipid peroxidation, accompanied by modulation of OFR scavenging enzymes as well as reduced glutathione (GSH) and the GSH dependent enzymes glutathione peroxidase (Gpx), glutathione reductase (GR) and glutathione-S-transferase (GST) in these rats. These findings suggest that a diet containing naturally occurring compounds is effective in exerting protective effects by modulating oxidative stress.
• Chakraborti, A., Gulati, K., & Ray, A. (2008). Age related differences in stress-induced neurobehavioral responses in rats: modulation by antioxidants and nitrergic agents. Behavioural brain research, 194(1), 86-91.
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  The effect of restraint stress (RS) on neurobehavioral and brain oxidative/nitrosative stress markers and their modulation by antioxidants and nitrergic agents were evaluated in young (2 months) and old (16 months) male Wistar rats. Exposure to RS, induced anxiogenesis when tested in the elevated plus maze (EPM) and open field (OF) tests and such changes were greater in the old as compared to the young rats. These behavioral alterations were associated with enhanced levels of malondialdehyde (MDA) and reductions in glutathione (GSH), catalase (CAT) and nitric oxide metabolites (NOx) levels in brain homogenates-the effects being greater in intensity in the old as compared to the young animals. Pretreatment with antioxidants, alpha-tocopherol (25 and 50mg/kg) and N-acetylcysteine (100 and 200mg/kg) consistently reversed the RS-induced behavioral and biochemical alterations in both young and old rats. Similar attenuations of RS-induced changes were seen after pretreatment with NO precursor L-arginine (500 and 1000mg/kg) while the NO synthase inhibitor N-nitro L-arginine methyl ester (L-NAME) (50 and 100mg/kg) tended to aggravate the effects of RS in both age groups of rats. The results suggest that susceptibility to stress-induced neurobehavioral alterations may increase with age and interactions of reactive oxygen species (ROS) and nitric oxide in the central nervous system may exert a regulatory influence in such age dependent responses to stress.
• Oberoi, S., Ahmed, R. S., Suke, S. G., Bhattacharya, S. N., Chakraborti, A., & Banerjee, B. D. (2007). Comparative effect of topical application of lindane and permethrin on oxidative stress parameters in adult scabies patients. Clinical biochemistry, 40(16-17), 1321-4.
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  The insecticides lindane and permethrin are commonly used for treatment of scabies. Animal studies have shown the presence of insecticide induced oxidative stress. Hence, this study was undertaken to assess and compare the effects of topical application of lindane and permethrin on oxidative stress parameters in scabies patients.