Browsing by Author "Manindra Nath Tiwari"

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A current review of cypermethrin-induced neurotoxicity and nigrostriatal dopaminergic neurodegeneration
(2012) Anand Kumar Singh; Manindra Nath Tiwari; Om Prakash; Mahendra Pratap Singh
Cypermethrin, a class II pyrethroid pesticide, is used to control insects in the household and agricultural fields. Despite beneficial roles, its uncontrolled and repetitive applications lead to unintended effects in non-target organisms. Cypermethrin crosses the blood-brain barrier and induces neurotoxicity and motor deficits. Cypermethrin prolongs the opening of sodium channel, a major site of its action, leading to hyper-excitation of the central nervous system. In addition to sodium channel, cypermethrin modulates chloride, voltage-gated calcium and potassium channels, alters the activity of glutamate and acetylcholine receptors and adenosine triphosphatases and induces DNA damage and oxidative stress in the neuronal cells. Cypermethrin also modulates the level of neurotransmitters, including gamma-aminobutyric acid and dopamine. It is one of the most commonly used pesticides in neurotoxicology research not only because of its variable responses depending upon the doses, time and routes of exposure and strain, age, gender and species of animals used across multiple studies but also owing to its ability to induce the nigrostriatal dopaminergic neurodegeneration. This article describes the effect of acute, chronic, developmental and adulthood exposures to cypermethrin in experimental animals. The article sheds light on cypermethrin-induced changes in the central nervous system, including its contribution in the onset of specific features, which are associated with the nigrostriatal dopaminergic neurodegeneration. Resemblances and dissimilarities of cypermethrin-induced nigrostriatal dopaminergic neurodegeneration with sporadic and chemicals-induced disease models along with its advantages and pitfalls are also discussed. © 2012 Bentham Science Publishers.
Cypermethrin alters the expression profile of mrnas in the adult rat striatum: A putative mechanism of postnatal pre-exposure followed by adulthood re-exposure-enhanced neurodegeneration
(2012) Manindra Nath Tiwari; Anand Kumar Singh; Sonal Agrawal; Satya Prakash Gupta; Anurag Jyoti; Rishi Shanker; Om Prakash; Mahendra Pratap Singh
Abstract This study was undertaken to investigate the effect of cypermethrin on the expression patterns of mRNAs in the striatum of adulthood alone and postnatal pre-exposed followed by adulthood re-exposed rats using discover chips rat microarrays. The expression patterns of V-akt murine thymoma viral oncogene homolog 1, B-cell lymphoma 2 (BCL-2), BCL-2-associated X protein, caspase 1, caspase 9, death-associated protein 3 and interleukin-1β were validated by the qRT-PCR. The expressions of inducible nitric oxide synthase (iNOS) and major histocompatibility complex (MHC) II were assessed immunohistochemically; however, tumour protein p53 and cytochrome c (mitochondrial and cytosolic) expressions were checked at protein level by western blotting. Cypermethrin differentially regulated 65 transcripts at one or the other stage of exposure and 21 transcripts exhibited more pronounced alterations in the postnatal pre-exposed and adulthood re-challenged rats. The results of qRT-PCR were in accordance with the microarray observations and the expressions of iNOS, p53 and cytosolic cytochrome c and MHC II positivity were increased while the level of mitochondrial cytochrome c was reduced in adulthood treated animals. The effects were more pronounced in the postnatal pre-exposed followed by adulthood re-exposed rats. The results obtained thus suggest that multiple pathways are involved in the neurodegeneration as well as in enhancing the vulnerability of neurons in cypermethrin pre-exposed postnatal animals upon re-exposure during adulthood. ©Springer Science+Business Media, LLC 2012.
Effects of cypermethrin on monoamine transporters, xenobiotic metabolizing enzymes and lipid peroxidation in the rat nigrostriatal system
(2010) Manindra Nath Tiwari; Anand Kumar Singh; Israr Ahmad; Ghanshyam Upadhyay; Dhirendra Singh; Devendra Kumar Patel; Chetna Singh; Om Prakash; Mahendra Pratap Singh
Long-term exposure to cypermethrin induces the nigrostriatal dopaminergic neurodegeneration in adult rats and its pre-exposure in the critical periods of brain development enhances the susceptibility during adulthood. Monoamine transporters, xenobiotic metabolizing enzymes and oxidative stress play critical roles in the nigrostriatal dopaminergic neurodegeneration. The study was undertaken to investigate the effects of cypermethrin on DAT, VMAT 2, CYP2E1, GST Ya, GST Yc and GSTA4-4 expressions, CYP2E1 and GST activities and lipid peroxidation in the nigrostriatal system of adult rats with/without post-natal exposure to cypermethrin. Cypermethrin reduced VMAT 2 and increased CYP2E1 expressions without causing significant change in DAT. Although GSTA4-4 mRNA expression and lipid peroxidation were increased, no significant changes were observed in GST Ya and GST Yc expressions and total GST activity. The results obtained demonstrate that long-term exposure to cypermethrin modulates VMAT 2, CYP2E1, GSTA4-4 expressions and lipid peroxidation, which could contribute to the nigrostriatal dopaminergic neurodegeneration. © 2010 Informa UK, Ltd.
Involvement of multiple molecular events in pyrogallol-induced hepatotoxicity and silymarin-mediated protection: Evidence from gene expression profiles
(2010) Ghanshyam Upadhyay; Manindra Nath Tiwari; Om Prakash; Anurag Jyoti; Rishi Shanker; Mahendra Pratap Singh
In this study, the involvement of various molecular events in pyrogallol-mediated hepatotoxicity was deciphered by differential mRNA transcription profiles of control and pyrogallol treated mice liver. The modulatory effects of silymarin on pyrogallol-induced differentially expressed transcripts were also looked into. Swiss albino mice were treated with or without pyrogallol. In some set of experiments, mice were also treated with silymarin 2. h prior to pyrogallol. Total RNA was isolated from liver and polyadenylated RNA was reverse-transcribed into Cye 3 or Cye 5 labelled cDNA. Equal amounts of labelled cDNA from two different groups were mixed and hybridized with mouse 15. k array. The hybridized arrays were scanned, analyzed and the expression level of each transcript was calculated. The differential expression was validated by quantitative real time polymerase chain reaction. Comparative transcription pattern showed an alteration in the expression of 183 transcripts (150 up-regulated and 33 down-regulated) associated with oxidative stress, cell cycle, cytoskeletal network, cell-cell adhesion, extra-cellular matrix, inflammation, apoptosis, cell-signaling and intermediary metabolism in pyrogallol-exposed liver and silymarin pre-treatment modulated the expression of many of these transcripts. Results obtained thus suggest that pyrogallol induces multiple molecular events leading to hepatotoxicity and silymarin effectively counteracts pyrogallol-mediated alterations. © 2010 Elsevier Ltd.
Long term exposure to cypermethrin induces nigrostriatal dopaminergic neurodegeneration in adult rats: Postnatal exposure enhances the susceptibility during adulthood
(2012) Anand Kumar Singh; Manindra Nath Tiwari; Ghanshyam Upadhyay; Devendra Kumar Patel; Dhirendra Singh; Om Prakash; Mahendra Pratap Singh
The study aimed to investigate the effects of cypermethrin on biochemical, histopathological, and motor behavioral indices of the nigrostriatal dopaminergic system in adult rats treated with or without cypermethrin (1/10 adult dose) during postnatal days 5-19. Spontaneous locomotor activity (SLA) and rotarod tests were performed to assess motor behavior. Levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum, and tyrosine hydroxylase (TH) immunoreactivity and 4',6-diamidino-2-phenylindole (DAPI)/Fluoro-Jade B staining in the substantia nigra were measured to assess dopaminergic neurodegeneration. Postnatal treated animals did not exhibit significant changes in any measured parameters. The significant reduction in the time of stay on rotarod, spontaneous locomotor activity, dopamine, 3,4-dihydroxyphenylacetic acid, and tyrosine hydroxylase immunoreactivity while an increase in homovanillic acid level and Fluoro-Jade B-positive cells were observed in cypermethrin treated adult rats. These changes were more pronounced in the animals treated with cypermethrin during postnatal days followed by adulthood compared with adulthood alone. The results obtained thus demonstrate that exposure to cypermethrin during adulthood induces dopaminergic neurodegeneration in rats and postnatal exposure enhances the susceptibility of animals to dopaminergic neurodegeneration if rechallenged during adulthood. © 2012 Elsevier Inc.
Nigrostriatal proteomics of cypermethrin-induced dopaminergic neurodegeneration: Microglial activation-dependent and -independent regulations
(2011) Anand Kumar Singh; Manindra Nath Tiwari; Anubhuti Dixit; Ghanshyam Upadhyay; Devendra Kumar Patel; Dhirendra Singh; Om Prakash; Mahendra Pratap Singh
The study aimed to identify the differentially expressed nigrostriatal proteins in cypermethrin-induced neurodegeneration and to investigate the role of microglial activation therein. Proteomic approaches were used to identify the differentially expressed proteins. Microglial activation, tyrosine hydroxylase immunoreactivity (TH-IR), dopamine content, and neurobehavioral changes were measured according to the standard procedures. The expressions of a-internexin intermediate filament (α-IIF), ATP synthase D chain (ATP-SD), heat shock protein (Hsp)-70, truncated connexin-47, Hsp-60, mitogen-activated protein kinaseactivated kinase-5, nicotinamide adenine dinucleotide dehydrogenase 24k chain precursor, platelet-activating factor acetyl hydrolase 1b-α2 (PAF-AH 1b-α2), and synaptosomal-associated protein-25 (SNAP-25) were altered in the substantia nigra and nicotinamide adenine dinucleotide- specific isocitrate dehydrogenase, phosphatidylethanolamine-binding protein-1, prohibitin, protein disulfide isomerase-endoplasmic reticulum 60 protease, stathmin, and ubiquitin-conjugating enzyme in the striatum along with motor impairment, decreased dopamine and TH-IR, and increased microglial activation after cypermethrin exposure. Minocycline restored α-IIF, ATP-SD chain, truncated connexin-47, Hsp-60, PAF-AH 1b-α2, stathmin and SNAP-25 expressions, motor impairment, dopamine, TH-IR, and microglial activation. The results suggest that cypermethrin produces microglial activation-dependent and -independent changes in the expression patterns of the nigrostriatal proteins leading to dopaminergic neurodegeneration. © The Author 2011. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.