Manuj Ahuja

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

Diabetes and Alzheimers 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 Alzheimers 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.

Evaluation of differential cytotoxic effects of the oil spill dispersant Corexit 9500

AIMS The British Petroleum (BP) oil spill has raised several ecological and health concerns. As the first response, BP used a chemical dispersant, Corexit-9500, to disperse the crude oil in the Gulf of Mexico to limit shoreline contamination problems. Nevertheless, portions of this oil/Corexit mixture reached the shoreline and still remain in various Gulf shore environments. The use of Corexit itself has become a significant concern since its impacts on human health and environment is unclear. MAIN METHODS In this study, in vitro cytotoxic effects of Corexit were evaluated using different mammalian cells. KEY FINDINGS Under serum free conditions, the LC50 value for Corexit in BL16/BL6 cell was 16 ppm, in 1321N1 cell was 33 ppm, in H19-7 cell was 70 ppm, in HEK293 was 93 ppm, and in HK-2 cell was 95 ppm. With regard to the mechanisms of cytotoxicity, we hypothesize that Corexit can possibly induce cytotoxicity in mammalian cells by altering the intracellular oxidative balance and inhibiting mitochondrial functions. Corexit induced increased reactive oxygen species and lipid peroxide levels; also, it depleted glutathione content and altered catalase activity in H19-7 cells. In addition, there was mitochondrial complex-I inhibition and increase in the pro-apoptotic factors including caspase-3 and BAX expression. SIGNIFICANCE The experimental results show changes in intracellular oxidative radicals leading to mitochondrial dysfunctions and apoptosis in Corexit treatments, possibly contributing to cell death. Our findings raise concerns about using large volumes of Corexit, a potential environmental toxin, in sensitive ocean environments.

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

AIMS 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. MAIN METHODS The current study investigated the effects of sodium salicylate and/or methamphetamine on oxidative stress, monoamine oxidase, mitochondrial complex I & 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. KEY FINDINGS 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 & 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. SIGNIFICANCE One of the leading causative theories in nigral degeneration associated with movement disorders such as Parkinsons 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.

Elucidating the neurotoxic effects of MDMA and its analogs

AIMS 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. MAIN METHODS 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. KEY FINDINGS 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. SIGNIFICANCE Thus, our study will help in developing effective pharmacological and therapeutic approaches for the treatment of MDMA and MDMA-analog abuse.

Bisphenol A regulation of testicular endocrine function in male rats is affected by diet

There is concern that early-life exposure to bisphenol A (BPA) may alter developmental programming and predispose individuals to obesity and reproductive anomalies. The present study was designed to determine if a high fat diet at sexual maturation moderates testicular toxicity occasioned by exposure to BPA during reproductive development. Therefore, male rats were exposed to BPA by maternal gavage (0, 2.5 or 25 μg/kg body weight/day) from gestational day 12 to postnatal day 21. At weaning, control and BPA-exposed animals were placed on a regular normal fat diet (NFD) until 70 days of age when they were continued on the NFD or were maintained on a high fat diet (HFD) until euthanasia at 98 days. Adult male rats maintained on HFD were generally heavier than NFD animals due to greater energy intake but energy intake per unit body weight gain was similar in all animals. However, perinatal exposure to BPA decreased (P<0.05) serum adiponectin as well as adiponectin and AdipoR2 protein expression levels in Leydig cells. Importantly, the combination of BPA exposure and HFD consumption promoted lipid peroxidation evidenced by elevated serum thiobarbituric acid reactive substances and glutathione concentrations. These findings imply that interaction between BPA and HFD potentially causes testicular dysfunction to a greater degree than would be due to BPA exposure or HFD consumption. Given the relationship that exists between energy homeostasis and reproductive activity, additional studies are warranted to investigate the consequences of BPA-diet interactions on testicular function.

Investigate the Chronic Neurotoxic Effects of Diquat

Chronic exposure to agricultural chemicals (pesticides/herbicides) has been shown to induce neurotoxic effects or results in accumulation of various toxic metabolic by-products. These substances have the relevant ability to cause or increase the risk for neurodegeneration. Diquat is an herbicide that has been extensively used in the United States of America and other parts of the world. Diquat is constantly released into the environment during its use as a contact herbicide. Diquat structurally resembles 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and paraquat. Rotenone, paraquat, maneb and MPTP reproduce features of movement disorders in experimental animal models. Based on the structural similarity to other neurotoxins, chronic exposure of diquat can induce behavioral and neurochemical alterations associated with dopaminergic neurotoxicity. However, in the present study, diquat unlike other neurotoxins (rotenone, 6-hydroxydopamine, MPTP, paraquat and maneb) did not induce dopamine depletion in the mouse striatum. Although, notable exacerbation in motor impairment (swimming score, akinesia and open field) were evident that may be due to the decreased dopamine turnover and mild nigrostriatal neurodegeneration. These data indicate that, despite the apparent structural similarity to other dopaminergic neurotoxins, diquat did not exert severe deleterious effects on dopamine neurons in a manner that is unique to rotenone and MPTP.

Selective inhibition of phosphodiesterase 5 enhances glutamatergic synaptic plasticity and memory in mice

Phosphodiesterases (PDEs) belong to a family of proteins that control metabolism of cyclic nucleotides. Targeting PDE5, for enhancing cellular function, is one of the therapeutic strategies for male erectile dysfunction. We have investigated whether in vivo inhibition of PDE5, which is expressed in several brain regions, will enhance memory and synaptic transmission in the hippocampus of healthy mice. We have found that acute administration of sildenafil, a specific PDE5 inhibitor, enhanced hippocampus‐dependent memory tasks. To elucidate the underlying mechanism in the memory enhancement, effects of sildenafil on long‐term potentiation (LTP) were measured. The level of LTP was significantly elevated, with concomitant increases in basal synaptic transmission, in mice treated with sildenafil (1 mg/kg/day) for 15 days compared to control mice. These results suggest that moderate PDE5 inhibition enhances memory by increasing synaptic plasticity and transmission in the hippocampus. Synapse 67:741–747, 2013.

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

Aims: Inflammation is considered to be one of the crucial pathological factors associated with the development of Alzheimers 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 Alzheimers disease. Main methods: We analyzed amyloid‐beta deposition, oxidative stress, biochemical, neurochemical and immunological markers in a 10 month old (AP&Dgr;E9) mouse model. Memory functions were assessed by behavioral testing followed by measurement of synaptic plasticity via extracellular field recordings. Key findings: 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 AP&Dgr;E9 mice. Interestingly, marked elevations of pro‐inflammatory cytokines in whole brain lysate of AP&Dgr;E9 mice were observed. Flow cytometric analysis revealed a higher frequency of CD4 + IL‐17a and IFN‐&ggr; secreting T‐cells in AP&Dgr;E9 brain, indicating a robust T‐cell infiltration and activation. Behavioral deficits in learning and memory tasks, along with impairment in long‐term potentiation and associated biochemical changes in the expression of glutamatergic receptor subunits were evident. Significance: Thus, this study establishes the role by which oxidative stress, alterations in glutamate and GABA levels and inflammation increases hippocampal and cortical neurotoxicity resulting in the cognitive deficits associated with Alzheimers disease.

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

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.