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Manuj Ahuja

Auburn University, Harrison School of Pharmacy, Graduate Student

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Throughout my career, I have been majorly interested in studying neurodegenerative disorders affecting various physiological functions of central nervous system (CNS). The inducers of these neurodegenerative disorders include genetic mutations and various environmental toxicants, which makes it much more complex disease systems to study. I am always inspired and intrigued by the unanswered complex questions of underlying pathophysiological mechanisms of various neurodegenerative disorders especially Parkinson’s disease and Alzheimer’s disease. My long-term goal is to utilize this mechanistic knowledge to develop effective novel therapeutic interventions for Parkinson's disease and other neurodegenerative disorders. Currently, I am working closely with the group that employs both genetic and toxicant induced cell culture and mouse models of Parkinson's disease, patient derived iPS cells and postmortem tissues.

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ATHANASIOS ELLINOUDIS

Walter Kutschera

Bernhard Weninger

Universität zu Köln

National Research Institute for Cultural Properties, Tokyo

Yoshihiro Nishiaki

The University of Tokyo

Vincent Ollivier

Aix-Marseille University

Razi University of Kermanshah, Iran

BUSHRA M A J E E D ISSA

Ghader Ebrahimi

Mehdi/Mahdi kazempour

TABRIZ ISLAMIC ART UNIVERSITY

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Papers by Manuj Ahuja

Probable Mechanisms of Doxorubicin Antitumor Activity Enhancement by Ginsenoside Rh2

Molecules, 2022

Ginsenoside Rh2 increases the efficacy of doxorubicin (DOX) treatment in murine models of solid a... more Ginsenoside Rh2 increases the efficacy of doxorubicin (DOX) treatment in murine models of solid and ascites Ehrlich’s adenocarcinoma. In a solid tumor model (treatment commencing 7 days after inoculation), DOX + Rh2 co-treatment was significantly more efficacious than DOX alone. If treatment was started 24 h after inoculation, the inhibition of tumor growth of a solid tumor for the DOX + Rh2 co-treatment group was complete. Furthermore, survival in the ascites model was dramatically higher for the DOX + Rh2 co-treatment group than for DOX alone. Mechanisms underlying the combined DOX and Rh2 effects were studied in primary Ehrlich’s adenocarcinoma-derived cells and healthy mice’s splenocytes. Despite the previously established Rh2 pro-oxidant activity, DOX + Rh2 co-treatment revealed no increase in ROS compared to DOX treatment alone. However, DOX + Rh2 treatment was more effective in suppressing Ehrlich adenocarcinoma cell adhesion than either treatment alone. We hypothesize that t...

Centella asiatica, an Ayurvedic Medicinal Plant, Prevents the Major Neurodegenerative and Neurotoxic Mechanisms Associated with Cognitive Impairment

Medicinal and Aromatic Plants of the World, 2017

Ayurveda is one of the ancient traditional healthcare systems that originated in India. A number ... more Ayurveda is one of the ancient traditional healthcare systems that originated in India. A number of herbal-based medicinal preparations have been used for the treatment of health disorders associated with the nervous system. According to Alzheimer’s disease Facts and Figures, millions of people around the world are suffering with cognitive impairment. Cognitive ailments and diseases are a group of disorders associated with mental health. The cognitive disorders mainly comprise of acute and chronic or reversible or irreversible conditions such as amnesia, delirium, and various types of dementia. These disorders primarily cause deficits in cognitive tasks associated with awareness, insight, knowledge, memory, and problem-solving skills. Alzheimer’s disease is the most common type of dementia. It is a chronic neurodegenerative disorder that occurs due to excessive protein deposition inside and outside the neuron, oxidative stress, apoptosis, mitochondrial dysfunction, inflammation, and excitotoxicity. These neurotoxic mechanisms cause synaptic disturbance, alteration of neurotransmission leading to neurodegeneration. Centella asiatica is a well-known medicinal herb used in Ayurveda to improve cognitive functions since ancient times. In this article, we review the therapeutic potential of Centella asiatica in relation to its neuroprotective properties.

Identification of a potent Nrf2 displacement activator among aspirin-containing prodrugs

Neurochemistry International, 2021

Aspirin is a desired leaving group in prodrugs aimed at treatment of neurodegeneration and other ... more Aspirin is a desired leaving group in prodrugs aimed at treatment of neurodegeneration and other conditions. A library of aspirin derivatives of various scaffolds potentially activating Nrf2 has been tested in Neh2-luc reporter assay which screens for direct Nrf2 protein stabilizers working via disruption of Nrf2-Keap1 interaction. Most aspirin prodrugs had a pro-alkylating or pro-oxidant motif in the structure and, therefore, were toxic at high concentrations. However, among the active compounds, we identified a molecule resembling a well-known Nrf2 displacement activator, bis-1,4-(4-methoxybenzenesulfonamidyl) naphthalene (NMBSA). The direct comparison of the newly identified compound with NMBSA and its improved analog in the reporter assay showed no quenching with N-acetyl cysteine, thus pointing to Nrf2 stabilization mechanism without cysteine alkylation. The potency of the newly identified compound in the reporter assay was much stronger than NMBSA, despite its inhibitory action in the commercial fluorescence polarization assay was observed only in the millimolar range. Molecular docking predicted that mono-deacetylation of the novel prodrug should generate a potent displacement activator. The time-course of reporter activation with the novel prodrug had a pronounced lag-period pointing to a plausible intracellular transformation leading to an active product. Treatment of the novel prodrug with blood plasma or cell lysate demonstrated stepwise deacetylation as judge by liquid chromatography-mass spectrometry (LC-MS). Hence, the esterase-catalyzed hydrolysis of the prodrug liberates only acetyl groups from aspirin moiety and generates a potent Nrf2 activator. The discovered mechanism of prodrug activation makes the newly identified compound a promising lead for future optimization studies.

Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue

Frontiers in Aging Neuroscience, 2021

The Keap1-Nrf2 signaling axis is a validated and promising target for cellular defense and surviv... more The Keap1-Nrf2 signaling axis is a validated and promising target for cellular defense and survival pathways. This minireview discusses the potential off-target effects and their impact on future drug development originating from Keap1-targeting small molecules that function as displacement activators of the redox-sensitive transcription factor Nrf2. We argue that small-molecule displacement activators, similarly to electrophiles, will release both Nrf2 and other Keap1 client proteins from the ubiquitin ligase complex. This non-specificity is likely unavoidable and may result in off-target effects during Nrf2 activation by targeting Keap1. The small molecule displacement activators may also target Kelch domains in proteins other than Keap1, causing additional off-target effects unless designed to ensure specificity for the Kelch domain only in Keap1. A potentially promising and alternative therapeutic approach to overcome this non-specificity emerging from targeting Keap1 is to inhi...

The molecular chaperone sigma 1 receptor mediates rescue of retinal cone photoreceptor cells via modulation of NRF2

Free Radical Biology and Medicine, 2019

Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic targ... more Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic target for retinal degenerative disease. Earlier studies showed that activation of Sig1R via the highaffinity ligand (+)-pentazocine ((+)-PTZ) induced profound rescue of cone photoreceptor cells in the rd10 mouse model of retinitis pigmentosa; however the mechanism of rescue is unknown.

Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy

Human molecular genetics, Jan 15, 2018

Impaired glucose metabolism, decreased levels of thiamine and its phosphate esters, and reduced a... more Impaired glucose metabolism, decreased levels of thiamine and its phosphate esters, and reduced activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase occur in Alzheimer's disease (AD). Thiamine deficiency exacerbates amyloid beta (Aβ) deposition, tau hyperphosphorylation and oxidative stress. Benfotiamine (BFT) rescued cognitive deficits and reduced Aβ burden in amyloid precursor protein (APP)/PS1 mice. In this study, we examined whether BFT confers neuroprotection against tau phosphorylation and the generation of neurofibrillary tangles (NFTs) in the P301S mouse model of tauopathy. Chronic dietary treatment with BFT increased lifespan, improved behavior, reduced glycated tau, decreased NFTs and prevented death of motor neurons. BFT administration significantly ameliorated mitochondrial dysfunction and attenuated oxidative damage and inflammation. We found that BFT and its metabolites (but not thiamine) trigge...

Hsp90 Co-chaperone p23 contributes to dopaminergic mitochondrial stress via stabilization of PHD2: Implications for Parkinson's disease

Neurotoxicology, 2018

The heat shock factor 90 (hsp90) complex has long been associated with neuropathological phenotyp... more The heat shock factor 90 (hsp90) complex has long been associated with neuropathological phenotypes linked to Parkinson's disease (PD) and its inhibition is neuroprotective in disease models. Hsp90 is conventionally believed to act by suppressing induction of hsp70. Here, we report a novel hsp70-independent mechanism by which Hsp90 may also contribute to PD-associated neuropathology. We previously reported that inhibition of the enzyme prolyl hydroxylase domain 2 (PHD2) in conjunction with increases in hypoxia-inducible factor 1 alpha (HIF1α) results in protection of vulnerable dopaminergic substantia nigra pars compacta (DAergic SNpc) neurons in in vitro and in vivo models of PD. We discovered an increased interaction between PHD2 and the p23:Hsp90 chaperone complex in response to mitochondrial stress elicited by the mitochondrial neurotoxin 1-methyl-4-phenylpyridine (MPP) within cultured DAergic cells. Genetic p23 knockdown was found to result in decreases in steady-state PHD2...

L-ascorbic acid: A true substrate for HIF prolyl hydroxylase?

Biochimie, 2018

L-Ascorbate (L-Asc), but not D-isoascorbate (D-Asc) and N-acetylcysteine (NAC) suppress HIF1 ODD-... more L-Ascorbate (L-Asc), but not D-isoascorbate (D-Asc) and N-acetylcysteine (NAC) suppress HIF1 ODD-luc reporter activation induced by various inhibitors of HIF prolyl hydroxylase (PHD). The efficiency of suppression by L-Asc was sensitive to the nature of HIF PHD inhibitor chosen for reporter activation. In particular, the inhibitors developed to compete with alpha-ketoglutarate (αKG), were less sensitive to suppression by the physiological range of L-Asc (40-100 μM) than those having a strong iron chelation motif. Challenging those HIF activators in the reporter system with D-Asc demonstrated that the D-isomer, despite exhibiting the same reducing potency with respect to ferric iron, had almost no effect compared to L-Asc. Similarly, no effect on reporter activation was observed with cell-permeable reducing agent NAC up to 1 mM. Docking of L-Asc and D-Asc acid into the HIF PHD2 crystal structure showed interference of Tyr310 with respect to D-Asc. This suggests that L-Asc is not mere...

Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors

ACS chemical neuroscience, Jan 17, 2018

Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, an... more Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer's and Parkinson's diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2. Two superior tripartite agents, ING-6 and ING-66, showed neuroprotection against various cellular insults, associated with stabilization of both Nrf2 and HIF-1, and expression of their respective target genes in vitro and in vivo. Discovery of the innate ability of phenylhydroxamate HDAC inhibitors to activate Nrf2 and HIF provides a novel rou...

Immunological alteration & toxic molecular inductions leading to cognitive impairment & neurotoxicity in transgenic mouse model of Alzheimer's disease

Life sciences, Jan 15, 2017

Inflammation is considered to be one of the crucial pathological factors associated with the deve... more Inflammation is considered to be one of the crucial pathological factors associated with the development of Alzheimer's disease, although supportive experimental evidence remains undiscovered. Therefore, the current study was carried out to better understand and establish the pathophysiological involvement of chronic inflammation in a double transgenic mouse model of Alzheimer's disease. We analyzed amyloid-beta deposition, oxidative stress, biochemical, neurochemical and immunological markers in a 10month old (APΔE9) mouse model. Memory functions were assessed by behavioral testing followed by measurement of synaptic plasticity via extracellular field recordings. Substantial increases in amyloid-beta levels, beta-secretase activity, and oxidative stress, along with significant neurochemical alterations in glutamate and GABA levels were detected in the brain of APΔE9 mice. Interestingly, marked elevations of pro-inflammatory cytokines in whole brain lysate of APΔE9 mice were...

Benzylpiperazine: “A messy drug”

Drug and Alcohol Dependence, 2016

Designer drugs are synthetic structural analogues/congeners of controlled substances with slightl... more Designer drugs are synthetic structural analogues/congeners of controlled substances with slightly modified chemical structures intended to mimic the pharmacological effects of known drugs of abuse so as to evade drug classification. Benzylpiperazine (BZP), a piperazine derivative, elevates synaptic dopamine and serotonin levels producing stimulatory and hallucinogenic effects, respectively, similar to the well-known drug of abuse, methylenedioxymethamphetamine (MDMA). Furthermore, BZP augments the release of norepinephrine by inhibiting presynaptic autoreceptors, therefore, BZP is a "messy drug" due to its multifaceted regulation of synaptic monoamine neurotransmitters. Initially, pharmaceutical companies used BZP as a therapeutic drug for the treatment of various disease states, but due to its contraindications and abuse potential it was withdrawn from the market. BZP imparts predominately sympathomimetic effects accompanied by serious cardiovascular implications. Addictive properties of BZP include behavioral sensitization, cross sensitization, conditioned place preference and repeated self-administration. Additional testing of piperazine derived drugs is needed due to a scarcity of toxicological data and widely abuse worldwide.

Crosstalk between Nrf2 signaling and mitochondrial function in Parkinson's disease

Molecular and Cellular Neuroscience, 2019

Search for a definitive cure for neurodegenerative disorders like Parkinson's disease (PD) has me... more Search for a definitive cure for neurodegenerative disorders like Parkinson's disease (PD) has met with little success. Mitochondrial dysfunction and elevated oxidative stress precede characteristic loss of dopamine-producing neurons from the midbrain in PD. The majority of PD cases are classified as sporadic (sPD) with an unknown etiology, whereas mutations in a handful of genes cause monogenic form called familial (fPD). Both sPD and fPD is characterized by proteinopathy and mitochondrial dysfunction leading to increased oxidative stress. These pathophysiological mechanisms create a vicious cycle feeding into each other, ultimately tipping the neurons to its demise. Effect of iron accumulation and dopamine oxidation adds an additional dimension to mitochondrial oxidative stress and apoptotic pathways affected. Nrf2 is a redox-sensitive transcription factor which regulates basal as well as inducible expression of antioxidant enzymes and proteins involved in xenobiotic detoxicfication. Recent advances, however, shows a multifacted role for Nrf2 in the regulation of genes connected with inflammatory response, metabolic pathways, protein homeostasis, iron management, and mitochondrial bioenergetics. Here we review the role of mitochondria and oxidative stress in the PD etiology and the potential crosstalk between Nrf2 signaling and mitochondrial function in PD. We also make a case for the development of therapeutics that safely activates Nrf2 pathway in halting the progression of neurodegeneration in PD patients.

Distinct Nrf2 Signaling Mechanisms of Fumaric Acid Esters and Their Role in Neuroprotection against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Experimental Parkinson's-Like Disease

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 8, 2016

A promising approach to neurotherapeutics involves activating the nuclear-factor-E2-related facto... more A promising approach to neurotherapeutics involves activating the nuclear-factor-E2-related factor 2 (Nrf2)/antioxidant response element signaling, which regulates expression of antioxidant, anti-inflammatory, and cytoprotective genes. Tecfidera, a putative Nrf2 activator, is an oral formulation of dimethylfumarate (DMF) used to treat multiple sclerosis. We compared the effects of DMF and its bioactive metabolite monomethylfumarate (MMF) on Nrf2 signaling and their ability to block 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental Parkinson's disease (PD). We show that in vitro DMF and MMF activate the Nrf2 pathway via S-alkylation of the Nrf2 inhibitor Keap1 and by causing nuclear exit of the Nrf2 repressor Bach1. Nrf2 activation by DMF but not MMF was associated with depletion of glutathione, decreased cell viability, and inhibition of mitochondrial oxygen consumption and glycolysis rates in a dose-dependent manner, whereas MMF increased these activities...

Methamphetamine-induced dopaminergic toxicity prevented owing to the neuroprotective effects of salicylic acid

Life Sciences, 2016

Methamphetamine (Schedule-II drug, U.S. Drug Enforcement Administration) is one of the most abuse... more Methamphetamine (Schedule-II drug, U.S. Drug Enforcement Administration) is one of the most abused illicit drug following cocaine, marijuana, and heroin in the USA. There are numerous health impairments and substantial economic burden caused by methamphetamine abuse. Salicylic acid, potent anti-inflammatory drug and a known neuroprotectant has shown to protect against toxicity-induced by other dopaminergic neurotoxins. Hence, in this study we investigated the neuroprotective effects of salicylic acid against methamphetamine-induced toxicity in mice. The current study investigated the effects of sodium salicylate and/or methamphetamine on oxidative stress, monoamine oxidase, mitochondrial complex I &amp;amp;amp;amp;amp; IV activities using spectrophotometric and fluorimetric methods. Behavioral analysis evaluated the effect on movement disorders-induced by methamphetamine. Monoaminergic neurotransmitter levels were evaluated using high pressure liquid chromatography-electrochemical detection. Methamphetamine caused significant generation of reactive oxygen species and decreased complex-I activity leading to dopamine depletion. Striatal dopamine depletion led to significant behavioral changes associated with movement disorders. Sodium salicylate (50 &amp;amp;amp;amp;amp; 100mg/kg) significantly scavenged reactive oxygen species, blocked mitochondrial dysfunction and exhibited neuroprotection against methamphetamine-induced neurotoxicity. In addition, sodium salicylate significantly blocked methamphetamine-induced behavioral changes related to movement abnormalities. One of the leading causative theories in nigral degeneration associated with movement disorders such as Parkinson&amp;amp;amp;amp;#39;s disease is exposure to stimulants, drugs of abuse, insecticide and pesticides. These neurotoxic substances can induce dopaminergic neuronal insult by oxidative stress, apoptosis, mitochondrial dysfunction and inflammation. Salicylic acid due to its antioxidant and anti-inflammatory effects could provide neuroprotection against the stimulants or drugs of abuse.

Anti-oxidative and DNA protecting effects of flavonoids-rich Scutellaria lateriflora

by Manuj Ahuja and Madhukar Lohani

Natural Product Communications, Oct 1, 2013

Scutellaria lateriflora (American skullcap), a native plant of North America, has been used by Am... more Scutellaria lateriflora (American skullcap), a native plant of North America, has been used by Americans and Europeans as a nerve tonic for more than 200 years. In vivo studies have shown anxiolytic activity ofS. lateriflora in animals and humans. However, the neuroprotective mechanisms ofS. lateriflora are not fully understood. Oxidative stress plays a vital role in the neurodegenerative and neuropsychiatric diseases such as anxiety, Alzheimer's disease, depression, and Parkinson's disease. Bioactive compounds present in various medicinal plants neutralize or scavenge toxic free radicals and thus suppress oxidative stress. Therefore, the objective of this study was to investigate the antioxidant effects of S. lateriflora. The antioxidant potential of aqueous or ethanolic extracts of S. lateriflora was determined in mouse brain tissue using various biochemical assays. Protective effects of S. lateriflora against oxidative stress induced DNA fragmentation was determined using plasmid DNA. The ethanolic and aqueous extracts scavenged the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals. The ethanolic extract reduced tert-butyl peroxide-induced reactive oxygen species (ROS) and lipid peroxides in the mouse brain homogenates. Furthermore, the ethanolic extract of S. lateriflora protected hydrogen peroxide-UV induced cleavage of supercoiled plasmid DNA. In conclusion, S. lateriflora exhibited significant antioxidant effects. The current findings posit S. lateriflora as one of the potential experimental herbal drugs that should be screened for its therapeutic potential against various oxidative stress associated mental disorders.

Anti-oxidative and DNA protecting effects of flavonoids-rich Scutellaria lateriflora

Natural product communications, 2013

Scutellaria lateriflora (American skullcap), a native plant of North America, has been used by Am... more Scutellaria lateriflora (American skullcap), a native plant of North America, has been used by Americans and Europeans as a nerve tonic for more than 200 years. In vivo studies have shown anxiolytic activity ofS. lateriflora in animals and humans. However, the neuroprotective mechanisms ofS. lateriflora are not fully understood. Oxidative stress plays a vital role in the neurodegenerative and neuropsychiatric diseases such as anxiety, Alzheimer's disease, depression, and Parkinson's disease. Bioactive compounds present in various medicinal plants neutralize or scavenge toxic free radicals and thus suppress oxidative stress. Therefore, the objective of this study was to investigate the antioxidant effects of S. lateriflora. The antioxidant potential of aqueous or ethanolic extracts of S. lateriflora was determined in mouse brain tissue using various biochemical assays. Protective effects of S. lateriflora against oxidative stress induced DNA fragmentation was determined using...

Neuroscience 2011,Nov. 12-16, 2011, Washington, DC

http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=2828ecee-c877-4630-8b24-Changes in cor... more http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=2828ecee-c877-4630-8b24-Changes in cortisol levels serve as a reliable indicator of stimulus response. Cortisol is the most potent glucocorticoid produced and secreted by the adrenal cortex in response to activation of HPA-axis. We investigated intra-individual cortisol responses under single and mixed sex groupings during a cognitive task. Our efforts were driven by an interest in connecting the long standing debate over co-education vs. single sex education with a consideration of physiological processes. The assumptions of cognitive sciences that mental events are structured informational manipulations of physical systems in the brain served as the theoretical foundation for this study. Thus, if the sex of the partner is relevant to a response, the intra-individual cortisol differences should be evidenced among varying sex groupings. If there are no differences, researchers cannot empirically state that sex rises to the l...

Investigation of an organism`s endocrine response to the presence of opposite sex individuals using cortisol as a bio-marker

Humans frequently compete with members of their own sex to gain reproductive access to opposite-s... more Humans frequently compete with members of their own sex to gain reproductive access to opposite-sex partners. Competition is often accompanied by adaptive changes in basic physiological processes, endocrine system in particular. We investigated organism`s cortisol response to the presence of opposite sex individuals in educational settings. Working from the assumption of evolutionary psychology that behavior depends on underlying psychological mechanisms and notion that all intrasexual interactions serve reproductive purposes to some degree,we predicted that presence of opposite sex individuals will elicit a physiological response that help to gain reproductive access to opposite-sex partners. 5 males and 4 females were exposed to mixed and single sex environs while completing a jigsaw puzzle. Saliva samples were extracted to establish individual cortisol base line prior to introduction of mental tasks and after 30 minutes in the task in each environ. ELISA kit was used to assess fr...

Elucidating the neurotoxic effects of MDMA and its analogs

Life Sciences, 2014

There is a rapid increase in the use of methylenedioxymethamphetamine (MDMA) and its structural c... more There is a rapid increase in the use of methylenedioxymethamphetamine (MDMA) and its structural congeners/analogs globally. MDMA and MDMA-analogs have been synthesized illegally in furtive dwellings and are abused due to its addictive potential. Furthermore, MDMA and MDMA-analogs have shown to have induced several adverse effects. Hence, understanding the mechanisms mediating this neurotoxic insult of MDMA-analogs is of immense importance for the public health in the world. We synthesized and investigated the neurotoxic effects of MDMA and its analogs [4-methylenedioxyamphetamine (MDA), 2, 6-methylenedioxyamphetamine (MDMA), and N-ethyl-3, 4-methylenedioxyamphetamine (MDEA)]. The stimulatory or the dopaminergic agonist effects of MDMA and MDMA-analogs were elucidated using the established 6-hydroxydopamine lesioned animal model. Additionally, we also investigated the neurotoxic mechanisms of MDMA and MDMA-analogs on mitochondrial complex-I activity and reactive oxygen species generation. MDMA and MDMA-analogs exhibited stimulatory activity as compared to amphetamines and also induced several behavioral changes in the rodents. MDMA and MDMA-analogs enhanced the reactive oxygen generation and inhibited mitochondrial complex-I activity which can lead to neurodegeneration. Hence the mechanism of neurotoxicity, MDMA and MDMA-analogs can enhance the release of monoamines, alter the monoaminergic neurotransmission, and augment oxidative stress and mitochondrial abnormalities leading to neurotoxicity. Thus, our study will help in developing effective pharmacological and therapeutic approaches for the treatment of MDMA and MDMA-analog abuse.

Central activation of PPAR-gamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression

by Manuj Ahuja and I. Patanwala

Neurobiology of Aging, 2014

Diabetes and Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Diabetes and Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease share pathologic links toward cognitive deficits. Pharmacologic agonist of the nuclear receptor, peroxisomal proliferator-activating receptor gamma (PPARγ), that is, rosiglitazone (rosi), are insulin sensitizing agents that improve memory in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. However, direct molecular signaling targets that improve memory by PPARγ in the hippocampus have not been investigated. We compared outcomes from oral versus intracerebroventricular (ICV) administration of rosi on memory and changes in synaptic plasticity in type 2 diabetic (db/db) mice. Db/db mice treated with rosi (ICV) showed significant improvement in memory, long-term potentiation, and post-tetanic potentiation but did not improve peripheral insulin sensitivity. Gene and protein analysis revealed increased brain-derived neurotrophic factor (BDNF) in db/db mice treated with rosi (ICV). Transcriptional activation of exon IX as determined by luciferase assays confirmed PPARγ regulation of BDNF promoter activity. Transient transfection of constitutively active PPARγ plasmid in hippocampal neuronal cells induced increased BDNF, AMPA, and NMDA receptors expression and spine formation. Findings from the present study implicate a novel PPARγ-BDNF molecular signaling mechanism as a potential therapeutic target for cognitive impairment.

Probable Mechanisms of Doxorubicin Antitumor Activity Enhancement by Ginsenoside Rh2

Molecules, 2022

Ginsenoside Rh2 increases the efficacy of doxorubicin (DOX) treatment in murine models of solid a... more Ginsenoside Rh2 increases the efficacy of doxorubicin (DOX) treatment in murine models of solid and ascites Ehrlich’s adenocarcinoma. In a solid tumor model (treatment commencing 7 days after inoculation), DOX + Rh2 co-treatment was significantly more efficacious than DOX alone. If treatment was started 24 h after inoculation, the inhibition of tumor growth of a solid tumor for the DOX + Rh2 co-treatment group was complete. Furthermore, survival in the ascites model was dramatically higher for the DOX + Rh2 co-treatment group than for DOX alone. Mechanisms underlying the combined DOX and Rh2 effects were studied in primary Ehrlich’s adenocarcinoma-derived cells and healthy mice’s splenocytes. Despite the previously established Rh2 pro-oxidant activity, DOX + Rh2 co-treatment revealed no increase in ROS compared to DOX treatment alone. However, DOX + Rh2 treatment was more effective in suppressing Ehrlich adenocarcinoma cell adhesion than either treatment alone. We hypothesize that t...

Centella asiatica, an Ayurvedic Medicinal Plant, Prevents the Major Neurodegenerative and Neurotoxic Mechanisms Associated with Cognitive Impairment

Medicinal and Aromatic Plants of the World, 2017

Ayurveda is one of the ancient traditional healthcare systems that originated in India. A number ... more Ayurveda is one of the ancient traditional healthcare systems that originated in India. A number of herbal-based medicinal preparations have been used for the treatment of health disorders associated with the nervous system. According to Alzheimer’s disease Facts and Figures, millions of people around the world are suffering with cognitive impairment. Cognitive ailments and diseases are a group of disorders associated with mental health. The cognitive disorders mainly comprise of acute and chronic or reversible or irreversible conditions such as amnesia, delirium, and various types of dementia. These disorders primarily cause deficits in cognitive tasks associated with awareness, insight, knowledge, memory, and problem-solving skills. Alzheimer’s disease is the most common type of dementia. It is a chronic neurodegenerative disorder that occurs due to excessive protein deposition inside and outside the neuron, oxidative stress, apoptosis, mitochondrial dysfunction, inflammation, and excitotoxicity. These neurotoxic mechanisms cause synaptic disturbance, alteration of neurotransmission leading to neurodegeneration. Centella asiatica is a well-known medicinal herb used in Ayurveda to improve cognitive functions since ancient times. In this article, we review the therapeutic potential of Centella asiatica in relation to its neuroprotective properties.

Identification of a potent Nrf2 displacement activator among aspirin-containing prodrugs

Neurochemistry International, 2021

Aspirin is a desired leaving group in prodrugs aimed at treatment of neurodegeneration and other ... more Aspirin is a desired leaving group in prodrugs aimed at treatment of neurodegeneration and other conditions. A library of aspirin derivatives of various scaffolds potentially activating Nrf2 has been tested in Neh2-luc reporter assay which screens for direct Nrf2 protein stabilizers working via disruption of Nrf2-Keap1 interaction. Most aspirin prodrugs had a pro-alkylating or pro-oxidant motif in the structure and, therefore, were toxic at high concentrations. However, among the active compounds, we identified a molecule resembling a well-known Nrf2 displacement activator, bis-1,4-(4-methoxybenzenesulfonamidyl) naphthalene (NMBSA). The direct comparison of the newly identified compound with NMBSA and its improved analog in the reporter assay showed no quenching with N-acetyl cysteine, thus pointing to Nrf2 stabilization mechanism without cysteine alkylation. The potency of the newly identified compound in the reporter assay was much stronger than NMBSA, despite its inhibitory action in the commercial fluorescence polarization assay was observed only in the millimolar range. Molecular docking predicted that mono-deacetylation of the novel prodrug should generate a potent displacement activator. The time-course of reporter activation with the novel prodrug had a pronounced lag-period pointing to a plausible intracellular transformation leading to an active product. Treatment of the novel prodrug with blood plasma or cell lysate demonstrated stepwise deacetylation as judge by liquid chromatography-mass spectrometry (LC-MS). Hence, the esterase-catalyzed hydrolysis of the prodrug liberates only acetyl groups from aspirin moiety and generates a potent Nrf2 activator. The discovered mechanism of prodrug activation makes the newly identified compound a promising lead for future optimization studies.

Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue

Frontiers in Aging Neuroscience, 2021

The Keap1-Nrf2 signaling axis is a validated and promising target for cellular defense and surviv... more The Keap1-Nrf2 signaling axis is a validated and promising target for cellular defense and survival pathways. This minireview discusses the potential off-target effects and their impact on future drug development originating from Keap1-targeting small molecules that function as displacement activators of the redox-sensitive transcription factor Nrf2. We argue that small-molecule displacement activators, similarly to electrophiles, will release both Nrf2 and other Keap1 client proteins from the ubiquitin ligase complex. This non-specificity is likely unavoidable and may result in off-target effects during Nrf2 activation by targeting Keap1. The small molecule displacement activators may also target Kelch domains in proteins other than Keap1, causing additional off-target effects unless designed to ensure specificity for the Kelch domain only in Keap1. A potentially promising and alternative therapeutic approach to overcome this non-specificity emerging from targeting Keap1 is to inhi...

The molecular chaperone sigma 1 receptor mediates rescue of retinal cone photoreceptor cells via modulation of NRF2

Free Radical Biology and Medicine, 2019

Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic targ... more Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic target for retinal degenerative disease. Earlier studies showed that activation of Sig1R via the highaffinity ligand (+)-pentazocine ((+)-PTZ) induced profound rescue of cone photoreceptor cells in the rd10 mouse model of retinitis pigmentosa; however the mechanism of rescue is unknown.

Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy

Human molecular genetics, Jan 15, 2018

Impaired glucose metabolism, decreased levels of thiamine and its phosphate esters, and reduced a... more Impaired glucose metabolism, decreased levels of thiamine and its phosphate esters, and reduced activity of thiamine-dependent enzymes, such as pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase occur in Alzheimer's disease (AD). Thiamine deficiency exacerbates amyloid beta (Aβ) deposition, tau hyperphosphorylation and oxidative stress. Benfotiamine (BFT) rescued cognitive deficits and reduced Aβ burden in amyloid precursor protein (APP)/PS1 mice. In this study, we examined whether BFT confers neuroprotection against tau phosphorylation and the generation of neurofibrillary tangles (NFTs) in the P301S mouse model of tauopathy. Chronic dietary treatment with BFT increased lifespan, improved behavior, reduced glycated tau, decreased NFTs and prevented death of motor neurons. BFT administration significantly ameliorated mitochondrial dysfunction and attenuated oxidative damage and inflammation. We found that BFT and its metabolites (but not thiamine) trigge...

Hsp90 Co-chaperone p23 contributes to dopaminergic mitochondrial stress via stabilization of PHD2: Implications for Parkinson's disease

Neurotoxicology, 2018

The heat shock factor 90 (hsp90) complex has long been associated with neuropathological phenotyp... more The heat shock factor 90 (hsp90) complex has long been associated with neuropathological phenotypes linked to Parkinson's disease (PD) and its inhibition is neuroprotective in disease models. Hsp90 is conventionally believed to act by suppressing induction of hsp70. Here, we report a novel hsp70-independent mechanism by which Hsp90 may also contribute to PD-associated neuropathology. We previously reported that inhibition of the enzyme prolyl hydroxylase domain 2 (PHD2) in conjunction with increases in hypoxia-inducible factor 1 alpha (HIF1α) results in protection of vulnerable dopaminergic substantia nigra pars compacta (DAergic SNpc) neurons in in vitro and in vivo models of PD. We discovered an increased interaction between PHD2 and the p23:Hsp90 chaperone complex in response to mitochondrial stress elicited by the mitochondrial neurotoxin 1-methyl-4-phenylpyridine (MPP) within cultured DAergic cells. Genetic p23 knockdown was found to result in decreases in steady-state PHD2...

L-ascorbic acid: A true substrate for HIF prolyl hydroxylase?

Biochimie, 2018

L-Ascorbate (L-Asc), but not D-isoascorbate (D-Asc) and N-acetylcysteine (NAC) suppress HIF1 ODD-... more L-Ascorbate (L-Asc), but not D-isoascorbate (D-Asc) and N-acetylcysteine (NAC) suppress HIF1 ODD-luc reporter activation induced by various inhibitors of HIF prolyl hydroxylase (PHD). The efficiency of suppression by L-Asc was sensitive to the nature of HIF PHD inhibitor chosen for reporter activation. In particular, the inhibitors developed to compete with alpha-ketoglutarate (αKG), were less sensitive to suppression by the physiological range of L-Asc (40-100 μM) than those having a strong iron chelation motif. Challenging those HIF activators in the reporter system with D-Asc demonstrated that the D-isomer, despite exhibiting the same reducing potency with respect to ferric iron, had almost no effect compared to L-Asc. Similarly, no effect on reporter activation was observed with cell-permeable reducing agent NAC up to 1 mM. Docking of L-Asc and D-Asc acid into the HIF PHD2 crystal structure showed interference of Tyr310 with respect to D-Asc. This suggests that L-Asc is not mere...

Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors

ACS chemical neuroscience, Jan 17, 2018

Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, an... more Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer's and Parkinson's diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2. Two superior tripartite agents, ING-6 and ING-66, showed neuroprotection against various cellular insults, associated with stabilization of both Nrf2 and HIF-1, and expression of their respective target genes in vitro and in vivo. Discovery of the innate ability of phenylhydroxamate HDAC inhibitors to activate Nrf2 and HIF provides a novel rou...

Immunological alteration & toxic molecular inductions leading to cognitive impairment & neurotoxicity in transgenic mouse model of Alzheimer's disease

Life sciences, Jan 15, 2017

Inflammation is considered to be one of the crucial pathological factors associated with the deve... more Inflammation is considered to be one of the crucial pathological factors associated with the development of Alzheimer's disease, although supportive experimental evidence remains undiscovered. Therefore, the current study was carried out to better understand and establish the pathophysiological involvement of chronic inflammation in a double transgenic mouse model of Alzheimer's disease. We analyzed amyloid-beta deposition, oxidative stress, biochemical, neurochemical and immunological markers in a 10month old (APΔE9) mouse model. Memory functions were assessed by behavioral testing followed by measurement of synaptic plasticity via extracellular field recordings. Substantial increases in amyloid-beta levels, beta-secretase activity, and oxidative stress, along with significant neurochemical alterations in glutamate and GABA levels were detected in the brain of APΔE9 mice. Interestingly, marked elevations of pro-inflammatory cytokines in whole brain lysate of APΔE9 mice were...

Benzylpiperazine: “A messy drug”

Drug and Alcohol Dependence, 2016

Designer drugs are synthetic structural analogues/congeners of controlled substances with slightl... more Designer drugs are synthetic structural analogues/congeners of controlled substances with slightly modified chemical structures intended to mimic the pharmacological effects of known drugs of abuse so as to evade drug classification. Benzylpiperazine (BZP), a piperazine derivative, elevates synaptic dopamine and serotonin levels producing stimulatory and hallucinogenic effects, respectively, similar to the well-known drug of abuse, methylenedioxymethamphetamine (MDMA). Furthermore, BZP augments the release of norepinephrine by inhibiting presynaptic autoreceptors, therefore, BZP is a "messy drug" due to its multifaceted regulation of synaptic monoamine neurotransmitters. Initially, pharmaceutical companies used BZP as a therapeutic drug for the treatment of various disease states, but due to its contraindications and abuse potential it was withdrawn from the market. BZP imparts predominately sympathomimetic effects accompanied by serious cardiovascular implications. Addictive properties of BZP include behavioral sensitization, cross sensitization, conditioned place preference and repeated self-administration. Additional testing of piperazine derived drugs is needed due to a scarcity of toxicological data and widely abuse worldwide.

Crosstalk between Nrf2 signaling and mitochondrial function in Parkinson's disease

Molecular and Cellular Neuroscience, 2019

Search for a definitive cure for neurodegenerative disorders like Parkinson's disease (PD) has me... more Search for a definitive cure for neurodegenerative disorders like Parkinson's disease (PD) has met with little success. Mitochondrial dysfunction and elevated oxidative stress precede characteristic loss of dopamine-producing neurons from the midbrain in PD. The majority of PD cases are classified as sporadic (sPD) with an unknown etiology, whereas mutations in a handful of genes cause monogenic form called familial (fPD). Both sPD and fPD is characterized by proteinopathy and mitochondrial dysfunction leading to increased oxidative stress. These pathophysiological mechanisms create a vicious cycle feeding into each other, ultimately tipping the neurons to its demise. Effect of iron accumulation and dopamine oxidation adds an additional dimension to mitochondrial oxidative stress and apoptotic pathways affected. Nrf2 is a redox-sensitive transcription factor which regulates basal as well as inducible expression of antioxidant enzymes and proteins involved in xenobiotic detoxicfication. Recent advances, however, shows a multifacted role for Nrf2 in the regulation of genes connected with inflammatory response, metabolic pathways, protein homeostasis, iron management, and mitochondrial bioenergetics. Here we review the role of mitochondria and oxidative stress in the PD etiology and the potential crosstalk between Nrf2 signaling and mitochondrial function in PD. We also make a case for the development of therapeutics that safely activates Nrf2 pathway in halting the progression of neurodegeneration in PD patients.

Distinct Nrf2 Signaling Mechanisms of Fumaric Acid Esters and Their Role in Neuroprotection against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Experimental Parkinson's-Like Disease

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 8, 2016

A promising approach to neurotherapeutics involves activating the nuclear-factor-E2-related facto... more A promising approach to neurotherapeutics involves activating the nuclear-factor-E2-related factor 2 (Nrf2)/antioxidant response element signaling, which regulates expression of antioxidant, anti-inflammatory, and cytoprotective genes. Tecfidera, a putative Nrf2 activator, is an oral formulation of dimethylfumarate (DMF) used to treat multiple sclerosis. We compared the effects of DMF and its bioactive metabolite monomethylfumarate (MMF) on Nrf2 signaling and their ability to block 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental Parkinson's disease (PD). We show that in vitro DMF and MMF activate the Nrf2 pathway via S-alkylation of the Nrf2 inhibitor Keap1 and by causing nuclear exit of the Nrf2 repressor Bach1. Nrf2 activation by DMF but not MMF was associated with depletion of glutathione, decreased cell viability, and inhibition of mitochondrial oxygen consumption and glycolysis rates in a dose-dependent manner, whereas MMF increased these activities...

Methamphetamine-induced dopaminergic toxicity prevented owing to the neuroprotective effects of salicylic acid

Life Sciences, 2016

Methamphetamine (Schedule-II drug, U.S. Drug Enforcement Administration) is one of the most abuse... more Methamphetamine (Schedule-II drug, U.S. Drug Enforcement Administration) is one of the most abused illicit drug following cocaine, marijuana, and heroin in the USA. There are numerous health impairments and substantial economic burden caused by methamphetamine abuse. Salicylic acid, potent anti-inflammatory drug and a known neuroprotectant has shown to protect against toxicity-induced by other dopaminergic neurotoxins. Hence, in this study we investigated the neuroprotective effects of salicylic acid against methamphetamine-induced toxicity in mice. The current study investigated the effects of sodium salicylate and/or methamphetamine on oxidative stress, monoamine oxidase, mitochondrial complex I &amp;amp;amp;amp;amp; IV activities using spectrophotometric and fluorimetric methods. Behavioral analysis evaluated the effect on movement disorders-induced by methamphetamine. Monoaminergic neurotransmitter levels were evaluated using high pressure liquid chromatography-electrochemical detection. Methamphetamine caused significant generation of reactive oxygen species and decreased complex-I activity leading to dopamine depletion. Striatal dopamine depletion led to significant behavioral changes associated with movement disorders. Sodium salicylate (50 &amp;amp;amp;amp;amp; 100mg/kg) significantly scavenged reactive oxygen species, blocked mitochondrial dysfunction and exhibited neuroprotection against methamphetamine-induced neurotoxicity. In addition, sodium salicylate significantly blocked methamphetamine-induced behavioral changes related to movement abnormalities. One of the leading causative theories in nigral degeneration associated with movement disorders such as Parkinson&amp;amp;amp;amp;#39;s disease is exposure to stimulants, drugs of abuse, insecticide and pesticides. These neurotoxic substances can induce dopaminergic neuronal insult by oxidative stress, apoptosis, mitochondrial dysfunction and inflammation. Salicylic acid due to its antioxidant and anti-inflammatory effects could provide neuroprotection against the stimulants or drugs of abuse.

Anti-oxidative and DNA protecting effects of flavonoids-rich Scutellaria lateriflora

by Manuj Ahuja and Madhukar Lohani

Natural Product Communications, Oct 1, 2013

Scutellaria lateriflora (American skullcap), a native plant of North America, has been used by Am... more Scutellaria lateriflora (American skullcap), a native plant of North America, has been used by Americans and Europeans as a nerve tonic for more than 200 years. In vivo studies have shown anxiolytic activity ofS. lateriflora in animals and humans. However, the neuroprotective mechanisms ofS. lateriflora are not fully understood. Oxidative stress plays a vital role in the neurodegenerative and neuropsychiatric diseases such as anxiety, Alzheimer's disease, depression, and Parkinson's disease. Bioactive compounds present in various medicinal plants neutralize or scavenge toxic free radicals and thus suppress oxidative stress. Therefore, the objective of this study was to investigate the antioxidant effects of S. lateriflora. The antioxidant potential of aqueous or ethanolic extracts of S. lateriflora was determined in mouse brain tissue using various biochemical assays. Protective effects of S. lateriflora against oxidative stress induced DNA fragmentation was determined using plasmid DNA. The ethanolic and aqueous extracts scavenged the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals. The ethanolic extract reduced tert-butyl peroxide-induced reactive oxygen species (ROS) and lipid peroxides in the mouse brain homogenates. Furthermore, the ethanolic extract of S. lateriflora protected hydrogen peroxide-UV induced cleavage of supercoiled plasmid DNA. In conclusion, S. lateriflora exhibited significant antioxidant effects. The current findings posit S. lateriflora as one of the potential experimental herbal drugs that should be screened for its therapeutic potential against various oxidative stress associated mental disorders.

Anti-oxidative and DNA protecting effects of flavonoids-rich Scutellaria lateriflora

Natural product communications, 2013

Scutellaria lateriflora (American skullcap), a native plant of North America, has been used by Am... more Scutellaria lateriflora (American skullcap), a native plant of North America, has been used by Americans and Europeans as a nerve tonic for more than 200 years. In vivo studies have shown anxiolytic activity ofS. lateriflora in animals and humans. However, the neuroprotective mechanisms ofS. lateriflora are not fully understood. Oxidative stress plays a vital role in the neurodegenerative and neuropsychiatric diseases such as anxiety, Alzheimer's disease, depression, and Parkinson's disease. Bioactive compounds present in various medicinal plants neutralize or scavenge toxic free radicals and thus suppress oxidative stress. Therefore, the objective of this study was to investigate the antioxidant effects of S. lateriflora. The antioxidant potential of aqueous or ethanolic extracts of S. lateriflora was determined in mouse brain tissue using various biochemical assays. Protective effects of S. lateriflora against oxidative stress induced DNA fragmentation was determined using...

Neuroscience 2011,Nov. 12-16, 2011, Washington, DC

http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=2828ecee-c877-4630-8b24-Changes in cor... more http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=2828ecee-c877-4630-8b24-Changes in cortisol levels serve as a reliable indicator of stimulus response. Cortisol is the most potent glucocorticoid produced and secreted by the adrenal cortex in response to activation of HPA-axis. We investigated intra-individual cortisol responses under single and mixed sex groupings during a cognitive task. Our efforts were driven by an interest in connecting the long standing debate over co-education vs. single sex education with a consideration of physiological processes. The assumptions of cognitive sciences that mental events are structured informational manipulations of physical systems in the brain served as the theoretical foundation for this study. Thus, if the sex of the partner is relevant to a response, the intra-individual cortisol differences should be evidenced among varying sex groupings. If there are no differences, researchers cannot empirically state that sex rises to the l...

Investigation of an organism`s endocrine response to the presence of opposite sex individuals using cortisol as a bio-marker

Humans frequently compete with members of their own sex to gain reproductive access to opposite-s... more Humans frequently compete with members of their own sex to gain reproductive access to opposite-sex partners. Competition is often accompanied by adaptive changes in basic physiological processes, endocrine system in particular. We investigated organism`s cortisol response to the presence of opposite sex individuals in educational settings. Working from the assumption of evolutionary psychology that behavior depends on underlying psychological mechanisms and notion that all intrasexual interactions serve reproductive purposes to some degree,we predicted that presence of opposite sex individuals will elicit a physiological response that help to gain reproductive access to opposite-sex partners. 5 males and 4 females were exposed to mixed and single sex environs while completing a jigsaw puzzle. Saliva samples were extracted to establish individual cortisol base line prior to introduction of mental tasks and after 30 minutes in the task in each environ. ELISA kit was used to assess fr...

Elucidating the neurotoxic effects of MDMA and its analogs

Life Sciences, 2014

There is a rapid increase in the use of methylenedioxymethamphetamine (MDMA) and its structural c... more There is a rapid increase in the use of methylenedioxymethamphetamine (MDMA) and its structural congeners/analogs globally. MDMA and MDMA-analogs have been synthesized illegally in furtive dwellings and are abused due to its addictive potential. Furthermore, MDMA and MDMA-analogs have shown to have induced several adverse effects. Hence, understanding the mechanisms mediating this neurotoxic insult of MDMA-analogs is of immense importance for the public health in the world. We synthesized and investigated the neurotoxic effects of MDMA and its analogs [4-methylenedioxyamphetamine (MDA), 2, 6-methylenedioxyamphetamine (MDMA), and N-ethyl-3, 4-methylenedioxyamphetamine (MDEA)]. The stimulatory or the dopaminergic agonist effects of MDMA and MDMA-analogs were elucidated using the established 6-hydroxydopamine lesioned animal model. Additionally, we also investigated the neurotoxic mechanisms of MDMA and MDMA-analogs on mitochondrial complex-I activity and reactive oxygen species generation. MDMA and MDMA-analogs exhibited stimulatory activity as compared to amphetamines and also induced several behavioral changes in the rodents. MDMA and MDMA-analogs enhanced the reactive oxygen generation and inhibited mitochondrial complex-I activity which can lead to neurodegeneration. Hence the mechanism of neurotoxicity, MDMA and MDMA-analogs can enhance the release of monoamines, alter the monoaminergic neurotransmission, and augment oxidative stress and mitochondrial abnormalities leading to neurotoxicity. Thus, our study will help in developing effective pharmacological and therapeutic approaches for the treatment of MDMA and MDMA-analog abuse.

Central activation of PPAR-gamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression

by Manuj Ahuja and I. Patanwala

Neurobiology of Aging, 2014

Diabetes and Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Diabetes and Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease share pathologic links toward cognitive deficits. Pharmacologic agonist of the nuclear receptor, peroxisomal proliferator-activating receptor gamma (PPARγ), that is, rosiglitazone (rosi), are insulin sensitizing agents that improve memory in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. However, direct molecular signaling targets that improve memory by PPARγ in the hippocampus have not been investigated. We compared outcomes from oral versus intracerebroventricular (ICV) administration of rosi on memory and changes in synaptic plasticity in type 2 diabetic (db/db) mice. Db/db mice treated with rosi (ICV) showed significant improvement in memory, long-term potentiation, and post-tetanic potentiation but did not improve peripheral insulin sensitivity. Gene and protein analysis revealed increased brain-derived neurotrophic factor (BDNF) in db/db mice treated with rosi (ICV). Transcriptional activation of exon IX as determined by luciferase assays confirmed PPARγ regulation of BDNF promoter activity. Transient transfection of constitutively active PPARγ plasmid in hippocampal neuronal cells induced increased BDNF, AMPA, and NMDA receptors expression and spine formation. Findings from the present study implicate a novel PPARγ-BDNF molecular signaling mechanism as a potential therapeutic target for cognitive impairment.