maneb and Disease-Models--Animal

Parkinson's disease (PD) is a common neurodegenerative disorder largely of idiopathic nature with the exceptions of rare familial forms, and is characterized by both motor and non-motor disturbances. Pathologically, most motor features are the result of a dramatic loss of ventral tier mesencephalic dopaminergic neurons and thus dopamine content at their target sites. Although the exact etiology of the disease remains to be elucidated, it is thought to be multifactorial, with a critical role for environmental factors, such as pesticides, that may act on genetically predisposed individuals. Arising from consideration of the potential environmental triggers of PD, in vivo animal models of the disease utilizing these compounds are increasingly reported in the literature. Here, we review recent advances in the predominant models employing the insecticide Rotenone, the herbicide Paraquat and the fungicide Maneb, discuss their scientific merit and evaluate their relevance in the study of PD pathogenesis.

Topics: Animals; Disease Models, Animal; Environmental Exposure; Humans; Maneb; Paraquat; Parkinson Disease, Secondary; Pesticides; Rotenone

Nonhuman primate models of Parkinson's disease (PD) have been invaluable to our understanding of the human disease and in the advancement of novel therapies for its treatment. In this review, we attempt to give a brief overview of the animal models of PD currently used, with a more comprehensive focus on the advantages and disadvantages presented by their use in the nonhuman primate. In particular, discussion addresses the 6-hydroxydopamine (6-OHDA), 1-methyl-1,2,3,6-tetrahydopyridine (MPTP), rotenone, paraquat, and maneb parkinsonian models. Additionally, the role of primate PD models in the development of novel therapies, such as trophic factor delivery, grafting, and deep brain stimulation, are described. Finally, the contribution of primate PD models to our understanding of the etiology and pathology of human PD is discussed.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Cell Transplantation; Deep Brain Stimulation; Disease Models, Animal; Fungicides, Industrial; Glial Cell Line-Derived Neurotrophic Factor; Herbicides; Humans; Maneb; Nerve Degeneration; Oxidopamine; Paraquat; Parkinson Disease; Pesticides; Primates; Rotenone

Exposure to pesticides may be a risk factor for developing Parkinson's disease (PD). To evaluate the evidence regarding this association in the scientific literature, we examined both analytic epidemiologic studies of PD cases in which exposure to pesticides was queried directly and whole-animal studies for PD-like effects after systemic pesticide exposure. Epidemiologic studies were considered according to study quality parameters, and results were found to be mixed and without consistent exposure-response or pesticide-specific patterns. These epidemiologic studies were limited by a lack of detailed and validated pesticide exposure assessment. In animal studies, no pesticide has yet demonstrated the selective set of clinical and pathologic signs that characterize human PD, particularly at levels relevant to human populations. We conclude that the animal and epidemiologic data reviewed do not provide sufficient evidence to support a causal association between pesticide exposure and PD.

Topics: Animals; Case-Control Studies; Dieldrin; Disease Models, Animal; Fungicides, Industrial; Heptachlor; Humans; Maneb; Occupational Diseases; Occupational Exposure; Paraquat; Parkinson Disease; Permethrin; Pesticides; Pyridazines; Risk Factors

The etiologic basis of Parkinson's disease (PD), the second most common age-related neurodegenerative disorder, is unknown. Recent epidemiological and experimental studies indicate that exposure to environmental agents, including a number of agricultural chemicals, may contribute to the pathogenesis of this disorder. Animal models are important tools in experimental medical science for studying the pathogenesis and therapeutic intervention strategies of human diseases. Since many human disorders do not arise spontaneously in animals, characteristic functional changes have to be mimicked by neurotoxic agents. Recently, agricultural chemicals, when administrated systemically, have been shown to reproduce specific features of PD in rodents, thus opening new routes for the development of animal models for this disorder. In addition to a brief historical overview of the toxin-induced PD models, this study provides a detailed description of exiting models in which Parkinsonism is initiated via the exposure of animals to such agricultural chemicals as rotenone, paraquat, and maneb. Suggested neurotoxicity mechanisms of these chemicals are considered, and the major lessons learned from the analysis of pesticide-induced PD models are discussed.

Topics: Animals; Disease Models, Animal; Fungicides, Industrial; Herbicides; Maneb; Nerve Degeneration; Neurotoxins; Paraquat; Parkinson Disease; Rotenone; Uncoupling Agents

The mechanisms of cognitive impairments in Parkinson's disease (PD) remain unknown. Accumulating evidence revealed that brain neuroinflammatory response mediated by microglial cells contributes to cognitive deficits in neuropathological conditions and macrophage antigen complex-1 (Mac1) is a key factor in controlling microglial activation.. To explore whether Mac1-mediated microglial activation participates in cognitive dysfunction in PD using paraquat and maneb-generated mouse PD model.. Cognitive performance was measured in wild type and Mac1. Genetic deletion of Mac1 significantly ameliorated learning and memory impairments, neuronal damage, synaptic loss and α-synuclein phosphorylation (Ser129) caused by paraquat and maneb in mice. Subsequently, blocking Mac1 activation was found to mitigate paraquat and maneb-elicited microglial NLRP3 inflammasome activation in both in vivo and in vitro. Interestingly, stimulating activation of NOX by phorbol myristate acetate abolished the inhibitory effects of Mac1 blocking peptide RGD on paraquat and maneb-provoked NLRP3 inflammasome activation, indicating a key role of NOX in Mac1-mediated NLRP3 inflammasome activation. Furthermore, NOX1 and NOX2, two members of NOX family, and downstream PAK1 and MAPK pathways were recognized to be essential for NOX to regulate NLRP3 inflammasome activation. Finally, a NLRP3 inflammasome inhibitor glybenclamide abrogated microglial M1 activation, neurodegeneration and phosphorylation (Ser129) of α-synuclein elicited by paraquat and maneb, which were accompanied by improved cognitive capacity in mice.. Mac1 was involved in cognitive dysfunction in a mouse PD model through NOX-NLRP3 inflammasome axis-dependent microglial activation, providing a novel mechanistic basis of cognitive decline in PD.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Dopaminergic Neurons; Inflammasomes; Integrins; Macrophage-1 Antigen; Macrophages; Maneb; Memory Disorders; Mice; Microglia; NADPH Oxidases; NLR Family, Pyrin Domain-Containing 3 Protein; Paraquat; Parkinson Disease

Pesticides exposure can lead to damage of dopaminergic neurons, which are associated with increased risk of Parkinson's disease (PD). However, the etiology of PD remains poorly understood and no therapeutic strategy is available. Previous studies suggested the involvement of NLRP3 inflammasome in the onset of PD. This study was designed to investigate whether glibenclamide, an inhibitor of NLRP3 inflammasome, could offer a reliable protective strategy for PD in a mouse PD model induced by paraquat and maneb. We found that glibenclamide exerted potent neuroprotection against paraquat and maneb-induced upregulation of α-synuclein, dopaminergic neurodegeneration and motor impairment in brain of mice. Mechanistically, glibenclamide treatment blocked NLRP3 inflammasome activation evidenced by reduced expressions of NLRP3, activated caspase-1 and mature interleukin-1β in glibenclamide co-treated mice compared with those in paraquat and maneb group mice. Furthermore, glibenclamide treatment mitigated paraquat and maneb-induced microglial M1 proinflammatory response and nuclear factor-κB activation in mice. Finally, the increased superoxide production, lipid peroxidation, protein levels of NADPH oxidase 2 (NOX2) and inducible nitric oxide synthase (iNOS) induced by paraquat and maneb were all attenuated by glibenclamide. Overall, our findings demonstrated that glibenclamide protected dopaminergic neurons in a mouse PD model induced by combined exposures of paraquat and maneb through suppression of NLRP3 inflammasome activation, microglial M1 polarization and oxidative stress.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Antiparkinson Agents; Disease Models, Animal; Dopaminergic Neurons; Glyburide; Inflammasomes; Lipid Peroxidation; Male; Maneb; Mice, Inbred C57BL; Microglia; Motor Activity; NADPH Oxidase 2; Nerve Degeneration; Neuroprotective Agents; NF-kappa B; Nitric Oxide Synthase Type II; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Paraquat; Parkinsonian Disorders

Mild cognitive impairment in Parkinson's disease (PD-MCI) is considered as a nonmotor clinical symptom in Parkinson's disease (PD). Microglia-mediated inflammation contributes to cognitive function impairment. Poloxamer 188 (P188) is an amphipathic polymer which has cytoprotective effect in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neurons degeneration in PD. But whether P188 could ameliorate cognitive impairment in PD is still illusive. In the present study, we showed in a mouse model that paraquat (10 mg/kg) and maneb (30 mg/kg) (P + M) treatment intraperitoneally twice a week for 6 consecutive weeks resulted in cognitive deficits and synapse loss in hippocampus, together with DA neuron damage in the substantia nigra pars compacta (SNpc). P188 (0.8 g/kg) injection via tail vein 30 min after P + M administration significantly restored DA neuron numbers in SNpc and synapse density in hippocampus, and alleviated P + M-mediated cognitive function impairment in novel object recognition task and morris water maze task (MWM). Pathological synapse loss might be attributed to increased microglial phagocytic activity and cell density, and P188 prevented P + M-induced phagocytic state changes of microglia, such as increase in cell body size and decrease in process length, and upregulated microglia abundance in hippocampus. Consistently, P188 attenuated P + M-mediated increased mRNA levels of microglia proliferation related CSF1r and CSF2ra, microglial engulfment associated CD68, ICAM1, and ICAM2, and pro-inflammatory IL-6, IL-1β, CD11b, and TNF-α in hippocampus. Together, these findings suggest that the biocompatible polymer P188 blunts microglia activation which may promote synaptic loss and exacerbate cognitive function in a mouse model of PD-MCI.

Topics: Animals; Anti-Inflammatory Agents; Behavior, Animal; Cell Proliferation; Cognition; Cognitive Dysfunction; Disease Models, Animal; Dopaminergic Neurons; Hippocampus; Inflammation Mediators; Male; Maneb; Maze Learning; Mice, Inbred C57BL; Microglia; Nerve Degeneration; Paraquat; Parkinsonian Disorders; Pars Compacta; Phagocytosis; Poloxamer; Recognition, Psychology; Synapses

The loss of locus coeruleus noradrenergic (LC/NE) neurons in the brainstem is reported in multiple neurodegenerative disorders, including Parkinson's disease (PD). However, the mechanisms remain unclear. Strong evidence suggested that microglia-mediated neuroinflammation contributes to neurodegeneration in PD. We recently recognized integrin CD11b, the α-chain of macrophage antigen complex-1 (Mac-1, also called CR3), as a key regulator for microglial activation. However, whether CD11b is involved in LC/NE neurodegeneration in PD remains to be investigated.. LC/NE neurodegeneration and microglial activation were compared between wild type (WT) and CD11b KO mice after treated with paraquat and maneb, two pesticides that widely used to create PD model. The role of NLRP3 inflammasome in CD11b-mediated microglial dysfunction and LC/NE neurodegeneration was further explored. LC/NE neurodegeneration, microglial phenotype, and NLRP3 inflammasome activation were determined by using Western blot, immunohistochemistry, and RT-PCR technologies.. Our findings suggested that CD11b mediates LC/NE neurodegeneration through NLRP3 inflammation-dependent microglial proinflammatory activation in a two pesticide-induced mouse PD model, providing a novel insight into the immune pathogenesis of LC/NE neuronal damage in related disorders.

Topics: Adrenergic Neurons; Animals; CD11b Antigen; Disease Models, Animal; Inflammasomes; Locus Coeruleus; Male; Maneb; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Nerve Degeneration; NLR Family, Pyrin Domain-Containing 3 Protein; Paraquat; Parkinsonian Disorders; Pesticides

Topics: Animals; Cognition; Disease Models, Animal; Dopaminergic Neurons; Hippocampus; Learning; Maneb; Memory; Mice, Inbred C57BL; Microglia; Parkinson Disease

Microglia-mediated neuroinflammation is implicated in multiple neurodegenerative disorders, including Parkinson's disease (PD). Hence, the modulatioein of sustained microglial activation may have therapeutic potential. This study is designed to test the neuroprotective efficacy of taurine, a major intracellular free β-amino acid in mammalian tissues, by using paraquat and maneb-induced PD model. Results showed that mice intoxicated with paraquat and maneb displayed progressive dopaminergic neurodegeneration and motor deficits, which was significantly ameliorated by taurine. Taurine also attenuated the aggregation of α-synuclein in paraquat and maneb-intoxicated mice. Mechanistically, taurine suppressed paraquat and maneb-induced microglial activation. Moreover, depletion of microglia abrogated the dopaminergic neuroprotective effects of taurine, revealing the role of microglial activation in taurine-afforded neuroprotection. Subsequently, we found that taurine suppressed paraquat and maneb-induced microglial M1 polarization and gene expression levels of proinflammatory factors. Furthermore, taurine was shown to be able to inhibit the activation of NADPH oxidase (NOX2) by interfering with membrane translocation of cytosolic subunit, p47

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Dopaminergic Neurons; Gait; Gene Expression; Male; Maneb; Mice; Mice, Inbred C57BL; Microglia; NADPH Oxidase 2; NADPH Oxidases; Neuroprotective Agents; NF-kappa B; Paraquat; Parkinson Disease, Secondary; Signal Transduction; Taurine

How genetic variations in the dopamine transporter (DAT) combined with exposure to environmental toxins modulate the risk of Parkinson's disease remains unclear. Using unbiased stereology in DAT knock-down mice (DAT-KD) and wild-type (WT) littermates, we found that decreased DAT caused a loss of tyrosine hydroxylase-positive (dopaminergic) neurons in subregions of the substantia nigra pars compacta at 3-4 days, 5 weeks, and 18 months of age. Both genotypes lost dopaminergic neurons with age and remaining neurons at 11 months were resilient to paraquat/maneb. In 5-week-old mice, the toxins decreased substantia nigra pars compacta dopaminergic neurons in both genotypes but less in DAT-KD. Regional analysis revealed striking differences in the subsets of neurons affected by low DAT, paraquat/maneb, and aging. In particular, we show that a potentially protective effect of low DAT against toxin exposure is not sufficient to reduce death of all nigrostriatal dopaminergic neurons. Thus, different regional vulnerability of nigrostriatal dopaminergic neurons may contribute to an increased risk of developing Parkinson's disease when multiple factors are combined.

Topics: Aging; Animals; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Genetic Variation; Male; Maneb; Mice, Knockout; Mice, Mutant Strains; Paraquat; Parkinson Disease; Pars Compacta; Risk

Topics: Acetophenones; Adrenergic Neurons; Animals; Disease Models, Animal; Enzyme Inhibitors; Locus Coeruleus; Male; Maneb; Mice; Mice, Inbred C57BL; Microglia; NADPH Oxidases; Nerve Degeneration; Neurotoxicity Syndromes; NF-kappa B; Paraquat; Parkinson Disease; Risk Factors

Parkinson's disease (PD) is a debilitating, progressive, neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and motor deficits. Alpha-synuclein-containing aggregates represent a feature of a variety of neurodegenerative disorders, including PD; however, the mechanism that initiates and promotes intraneuronal alpha-synuclein aggregation remains unknown. We hypothesized protein radical formation as an initiating mechanism for alpha-synuclein aggregation. Therefore, we used the highly sensitive immuno-spin trapping technique to investigate protein radical formation as a possible mechanism of alpha-synuclein aggregation as well as to investigate the source of protein radical formation in the midbrains of Maneb- and paraquat-coexposed mice. Coexposure to Maneb and paraquat for 6 weeks resulted in active microgliosis, NADPH oxidase activation, and inducible nitric oxide synthase (iNOS) induction, which culminated in protein radical formation in the midbrains of mice. Results obtained with immuno-spin trapping and immunoprecipitation experiments confirmed formation of alpha-synuclein radicals in dopaminergic neurons of exposed mice. Free radical formation requires NADPH oxidase and iNOS, as indicated by decreased protein radical formation in knockout mice (P47phox(-/-) and iNOS(-/-)) and in mice treated with inhibitors such as FeTPPS (a peroxynitrite decomposition catalyst), 1400 W (an iNOS inhibitor), or apocynin (a NADPH oxidase inhibitor). Concurrence of protein radical formation with dopaminergic neuronal death indicated a link between protein radicals and disease progression. Taken together, these results show for the first time the formation and detection of the alpha-synuclein radical and suggest that NADPH oxidase and iNOS play roles in peroxynitrite-mediated protein radical formation and subsequent neuronal death in the midbrains of Maneb- and paraquat-coexposed mice.

Topics: alpha-Synuclein; Animals; Cyclic N-Oxides; Disease Models, Animal; Dopaminergic Neurons; Injections, Intraperitoneal; Male; Maneb; Mesencephalon; Mice, Inbred C57BL; Microglia; Models, Biological; NADPH Oxidases; Nitric Oxide Synthase Type II; Paraquat; Parkinson Disease; Peroxynitrous Acid; Spin Labels; Substantia Nigra; Tyrosine 3-Monooxygenase

Male infertility is one of the leading causes of social frustration and marginalization, mainly in the developing world. It is attributed to many factors including exposure to agropesticides such as manganese ethylenebis (dithiocarbamate) (maneb), which is one of the most frequently used fungicides in Cameroon. Previous reports support efficiency of some medicinal plants commonly used in Cameroonian folk medicine for the treatment of this disorder.. The present study was aimed at assessing the protective effect of extracts from selected plant species, namely Basella alba L. (Basellaceae) (MEBa) and Carpolobia alba G. Don (Polygalaceae) (AECa), in alleviating the maneb-induced impairment of male reproductive function in Wistar albino rats.. The rats were treated with vehicle, plant extract (MEBa or AECa), maneb and maneb plus plant extract, respectively, and their fertility was assessed. Animals were thereafter sacrificed and organs (liver, kidneys and reproductive organs) were dissected out and weighed. Serum androgens together with alanine aminotransferase, liver glutathione and thiobarbituric acid reactive species (TBARS) were also measured.. From this study, both plant extracts stimulated testosterone and improved fertility. Administration of MEBa plus maneb prevented fertility reduction by maneb and minimized the inhibitory effect of maneb on testosterone levels. AECa also improved fertility of the maneb-exposed rats, though without restoring testosterone levels, and other investigated parameters remained unaffected by different treatments.. These findings emphasized the beneficial effects of B. alba and C. alba extracts on male fertility, and suggest their protective effect against maneb-induced toxicity in male reproductive function.

Topics: Animals; Cameroon; Disease Models, Animal; Fungicides, Industrial; Infertility, Male; Magnoliopsida; Male; Maneb; Medicine, Traditional; Plant Extracts; Polygalaceae; Rats; Rats, Wistar; Testosterone

Current evidence suggests suceptibility of both the substantia nigra and striatum to exposure to components of air pollution. Further, air pollution has been associated with increased risk of PD diagnsosis in humans or PD-like pathology in animals. This study examined whether exposure of mice to concentrated ambient ultrafine particles (CAPS; <100nm diameter) during the first two weeks of life would alter susceptibility to induction of the Parkinson's disease phenyotype (PDP) in a pesticide-based paraquat and maneb (PQ+MB) model during adulthood utilizing i.p. injections of 10mg/kg PQ and 30mg/kg MB 2× per week for 6 weeks. Evidence of CAPS-induced enhancement of the PQ+MB PDP was limited primarily to delayed recovery of locomotor activity 24 post-injection of PQ+MB that could be related to alterations in striatal GABA inhibitory function. Absence of more extensive interactions might also reflect the finding that CAPS and PQ+MB appeared to differentially target the nigrostriatal dopamine and amino acid systems, with CAPS impacting striatum and PQ+MB impacting dopamine-glutamate function in midbrain; both CAPS and PQ+MB elevated glutamate levels in these specific regions, consistent with potential excitotoxicity. These findings demonstrate the ability of postnatal CAPS to produce locomotor dysfunction and dopaminergic and glutamateric changes, independent of PQ+MB, in brain regions involved in the PDP.

Topics: Air Pollutants; Animals; Animals, Newborn; Cell Count; Corpus Striatum; Disease Models, Animal; Drug Combinations; Female; Fungicides, Industrial; Herbicides; Male; Maneb; Mice; Mice, Inbred C57BL; Motor Activity; Nanoparticles; Paraquat; Parkinson Disease; Particulate Matter; Silicones; Substantia Nigra; Tyrosine 3-Monooxygenase

Robust epidemiological data link higher levels of the antioxidant urate to a reduced risk of developing Parkinson׳s disease (PD) and to a slower rate of its progression. Allopurinol, an inhibitor of xanthine oxidoreductase (XOR), blocks the oxidation of xanthine to urate. The present study sought to determine whether lowering levels of urate using allopurinol results in exacerbated neurotoxicity in a dual pesticide mouse model of PD. Although oral allopurinol reduced serum and striatal urate levels 4-fold and 1.3-fold, respectively, it did not alter the multiple motor deficits induced by chronic (7 week) intermittent (biweekly) exposure to intraperitoneal Paraquat (PQ) plus Maneb (MB). However, striatal dopamine content, which was unaffected after either allopurinol or chronic pesticide exposure alone, was significantly reduced by 22% in mice exposed to the combination. Stereological assessment showed that the numbers of dopaminergic nigral neurons were significantly reduced by 29% and the tyrosine hydroxylase (TH) negative neurons unaffected after PQ+MB treatments. This reduction in TH-positive neurons was not affected by allopurinol treatment. Of note, despite the expectation of exacerbated oxidative damage due to the reduction in urate, protein carbonyl levels, a marker of oxidative damage, were actually reduced in the presence of allopurinol. Overall, allopurinol lowered urate levels but did not exacerbate dopaminergic neuron degeneration, findings suggesting that basal levels of urate in mice do not appreciably protect against oxidative damage and neurotoxicity in the PQ+MB model of PD, and/or that allopurinol produces an antioxidant benefit offsetting its detrimental urate-lowering effect.

Topics: Allopurinol; Animals; Corpus Striatum; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Enzyme Inhibitors; Male; Maneb; Mice; Mice, Inbred C57BL; Motor Activity; Paraquat; Parkinson Disease; Pesticides; Uric Acid

The neurodegenerative effects of Parkinson's disease (PD) are marked by a selective loss of dopaminergic (DA) neurons. Epidemiological studies suggest that chronic exposure to the pesticide paraquat may increase the risk for PD and DA cell loss. However, combined exposure with additional fungicide(s) including maneb and/or ziram may be required for pathogenesis. To explore potential pathogenic mechanisms, we have developed a Drosophila model of chronic paraquat exposure. We find that while chronic paraquat exposure alone decreased organismal survival and motor function, combined chronic exposure to both paraquat and maneb was required for DA cell death in the fly. To initiate mechanistic studies of this interaction, we used additional genetic reagents to target the ubiquitin proteasome system, which has been implicated in some rare familial forms of PD and the toxic effects of ziram. Genetic inhibition of E1 ubiquitin ligase, but not the proteasome itself, increased DA cell death in combination with maneb but not paraquat. These studies establish a model for long-term exposure to multiple pesticides, and support the idea that pesticide interactions relevant to PD may involve inhibition of protein ubiquitination.

Topics: Animals; Cell Death; Disease Models, Animal; Dopaminergic Neurons; Drosophila melanogaster; Maneb; Motor Activity; Paraquat; Parkinson Disease, Secondary; Pesticides; Survival Analysis; Ubiquitin-Protein Ligases; Ziram

Parkinson's disease (PD) is a neurodegenerative disorder and these days a lot of emphasis is given on the treatment of this disease using herbal medicines. The present study evaluates the neuroprotective effect of Withania somnifera (Ws) root extract on Parkinsonian mice. The mice were divided into three groups; the first group served as control, the second group was given maneb (MB) and paraquat (PQ) and the last group was administered MB-PQ along with Ws root extract for 3, 6 and 9 weeks. The behavioral studies showed a significant improvement in the motor movement patterns and gripping ability of Ws root extract exposed Parkinsonian mice. Tyrosine hydroxylase (TH) immunostaining was reduced in the substantia nigra of MB-PQ exposed mice, while Ws co-exposure restored TH immunostaining significantly. Additionally, our results also demonstrate generation of oxidative stress in the nigrostriatal region of MB-PQ exposed mice. There was a marked decline in the level of catalase and a simultaneous increase in the level of nitrite and lipid peroxidation in Parkinsonian mice. Thus, the Ws root extract have shown to counteract the pro-oxidants and their associated oxidative stress in the PD model studied here. Our results clearly indicate the usefulness of Ws root extract in providing protection against MB-PQ induced nigrostriatal dopaminergic neurodegeneration and marked improvement in the behavioral, anatomical and the biochemical deformities.

Topics: Animals; Disease Models, Animal; Maneb; Mice; Neuroprotective Agents; Paraquat; Parkinsonian Disorders; Plant Extracts; Plant Roots; Withania

Mitochondrial dysfunction is the foremost perpetrator of the nigrostriatal dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, the roles played by majority of the mitochondrial proteins in PD pathogenesis have not yet been deciphered. The present study investigated the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and combined maneb and paraquat on the mitochondrial proteome of the nigrostriatal tissues in the presence or absence of minocycline, levodopa and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP). The differentially expressed proteins were identified and proteome profiles were correlated with the pathological and biochemical anomalies induced by MPTP and maneb and paraquat. MPTP altered the expression of twelve while combined maneb and paraquat altered the expression of fourteen proteins. Minocycline, levodopa and MnTMPyP, respectively, restored the expression of three, seven and eight proteins in MPTP and seven, eight and eight proteins in maneb- and paraquat-treated groups. Although levodopa and MnTMPyP rescued from MPTP- and maneb- and paraquat-mediated increase in the microglial activation and decrease in manganese-superoxide dismutase expression and complex I activity, dopamine content and number of dopaminergic neurons, minocycline defended mainly against maneb- and paraquat-mediated alterations. The results demonstrate that MPTP and combined maneb and paraquat induce mitochondrial dysfunction and microglial activation and alter the expression of a bunch of mitochondrial proteins leading to the nigrostriatal dopaminergic neurodegeneration and minocycline, levodopa or MnTMPyP variably offset scores of such changes.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Disease Models, Animal; Dopamine; Homeodomain Proteins; Levodopa; Male; Maneb; Metalloporphyrins; Mice; Microglia; Minocycline; Mitochondria; Paraquat; Parkinson Disease, Secondary; Proteome; Stathmin; Superoxide Dismutase

Parkinson's disease (PD) is the second most unconcealed neurodegenerative disorder labelled with motor impairments. Two pesticides, manganese ethylene-1,2-bisdithiocarbamate (maneb) and 1,1'-dimethyl-4,4'-bipyridinium dichloride (paraquat), together, are reported to increase the incidence of PD in humans and Parkinsonism in mice. Conversely, silymarin and melatonin, two naturally occurring antioxidants, rescue from maneb- and paraquat-induced Parkinsonism. The study examined silymarin- and melatonin-mediated changes in the expression of selected genes in maneb- and paraquat-induced Parkinsonism employing mouse discover chips microarrays. The mice were treated intraperitoneally (i.p.), daily, with silymarin (40 mg/kg) or melatonin (30 mg/kg) for 9 weeks along with vehicles. Subsets of animals were also treated with maneb (30 mg/kg; i.p.) and paraquat (10 mg/kg; i.p.), twice a week, for 9 weeks. Whilst the expression of genes in the striatum was determined by microarray, the expression of randomly selected transcripts was validated by quantitative real-time polymerase chain reaction (qRT-PCR). Combined maneb- and paraquat-treatment altered the expression of several genes associated with apoptosis, inflammation, cell cycle, cell-signalling, etc. pathways. Silymarin and melatonin significantly resisted the changes in the expression of a few genes related to apoptosis, inflammation, cell cycle, cell-signalling, etc. The expression patterns of seven randomly selected genes were analyzed by qRT-PCR, which were found to follow the similar trends, as observed with microarray. The results obtained from the study thus demonstrate that despite resemblances, silymarin and melatonin differentially offset maneb- and paraquat-induced changes in transcriptome.

Topics: Animals; Antioxidants; Apoptosis; Cell Cycle; Disease Models, Animal; Gene Expression Regulation; Inflammation; Ion Channels; Male; Maneb; Melatonin; Mice; Mitochondria; Oxidative Stress; Paraquat; Parkinsonian Disorders; Pesticides; Signal Transduction; Silymarin

Parkinson's disease (PD) is a multifactorial disease where environmental factors act on genetically predisposed individuals. Although only 5% of PD manifestations are associated with specific mutations, majority of PD cases are of idiopathic origin, where environment plays a prominent role. Concurrent exposure to Paraquat (PQ) and Maneb (MB) in rural workers increases the risk for PD and exposure of adult mice to MB/PQ results in dopamine fiber loss and decreased locomotor activity. While PD is characterized by neuronal loss in the substantia nigra, we previously showed that accumulation of α-synuclein in the limbic system contributes to neurodegeneration by interfering with adult neurogenesis.. We investigated the effect of pesticides on adult hippocampal neurogenesis in two transgenic models: Line 61, expressing the human wild type SNCA gene and Line LRRK2(G2019S), expressing the human LRRK2 gene with the mutation G2019S. Combined exposure to MB/PQ resulted in significant reduction of neuronal precursors and proliferating cells in non-transgenic animals, and this effect was increased in transgenic mice, in particular for Line 61, suggesting that α-synuclein accumulation and environmental toxins have a synergistic effect. We further investigated the transcription of 84 genes with direct function on neurogenesis. Overexpresion of α-synuclein resulted in the downregulation of 12% of target genes, most of which were functionally related to cell differentiation, while LRRK2 mutation had a minor impact on gene expression. MB/PQ also affected transcription in non-transgenic backgrounds, but when transgenic mice were exposed to the pesticides, profound alterations in gene expression affecting 27% of the studied targets were observed in both transgenic lines. Gene enrichment analysis showed that 1:3 of those genes were under the regulation of FoxF2 and FoxO3A, suggesting a primary role of these proteins in the response to genetic and environmental cues.. We report that adult neurogenesis is highly susceptible to multiple "risk factors" for PD, including α-synuclein accumulation, LRRK2 G2019 mutation and exposure to environmental toxins. We identified specific groups of genes that are responsive to each stressor, while uncovering a novel function for Fox transcription factors in PD.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Gene Expression Regulation; Gene-Environment Interaction; Hippocampus; Humans; Immunohistochemistry; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Maneb; Mice; Mice, Transgenic; Neurogenesis; Paraquat; Parkinson Disease; Pesticides; Protein Serine-Threonine Kinases; Real-Time Polymerase Chain Reaction; Transcription, Genetic

Neostriatum plays an important role in the pathophysiology of Parkinson's disease (PD). However, the changes of sensitivity of dopamine receptors of neostriatal neurons in PD have been less addressed in vivo. In the present study, systemic exposure to paraquat and maneb induced Parkinsonian symptoms and neuronal loss of substantia nigra pars compacta. Using single-unit recording methods, three types of neostriatal neurons were recorded including medium spiny-like neurons, large aspiny-like neurons and fast-spiking interneurons. In the exposed rats, increased firing activity of neostriatal neurons was revealed when compared to control rats. Following D1 receptor agonist, SKF38393 and D2 receptor agonist, LY171555 iontophoretically administrated respectively, effects of increase and decrease in firing activity were both observed in neostriatal neurons. However, stronger inhibitory effects of activating D1 receptors and weaker excitatory effects of activating D2 receptors were found in the exposed rats as compared to controls. It indicated that differential changes of sensitivity of D1 and D2 receptors in Parkinson's disease were related to the modulation of the imbalance between D1-receptor-dependent striatonigral direct pathway and D2-receptor-dependent striatopallidal indirect pathway. Our results illustrate the electrophysiological changes of in vivo neostriatal neurons in Parkinson's disease, thereby providing insight into the regulatory mechanisms of dopamine-mediated physiology.

Topics: Animals; Disease Models, Animal; Electrophysiological Phenomena; Fungicides, Industrial; Herbicides; Male; Maneb; Neocortex; Paraquat; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2

Environmental exposures suspected of contributing to the pathophysiology of Parkinson's disease (PD) include potentially neurotoxic pesticides, which have been linked to an increased risk of PD. Conversely, possible protective factors such as the adenosine antagonist caffeine have been linked to a reduced risk of the disease. Here we assessed whether caffeine alters dopaminergic neuron loss induced by exposure to environmentally relevant pesticides (paraquat and maneb) over 8weeks. The number of nigral neurons positive for tyrosine hydroxylase immunoreactivity (TH+) was assessed using stereological methods and found to be significantly reduced (to 60% of control) by combined pesticide treatment. Caffeine at 20mg/kg significantly reduced TH+ neuron loss (to 85% of the respective control). The results demonstrate the neuroprotective potential of caffeine in a chronic pesticide exposure model of model of PD.

Topics: Animals; Caffeine; Cell Count; Chronic Disease; Disease Models, Animal; Dopamine; Drug Interactions; Fungicides, Industrial; Herbicides; Locomotion; Male; Maneb; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neurons; Neuroprotective Agents; Paraquat; Substantia Nigra

The present study was undertaken to investigate the gene expression patterns of the striatum of control and maneb + paraquat-induced Parkinson's disease (PD) phenotype in mouse to identify the differentially expressed transcripts. The animals were treated with and without maneb (30 mg/kg, i.p.) + paraquat (10 mg/kg, i.p.), twice a week, for 3, 6, and 9 weeks. The RNA was isolated from control and treated mouse striatum and reverse transcribed, and equal quantities of labeled cDNA were mixed and hybridized with mouse 15 k arrays. Comparative transcription patterns showed the time of exposure dependent alteration in the expression of several transcripts associated with various pathways. RT-PCR reconfirmed the differential expression of some energy metabolizing transcripts. The study provides maneb + paraquat-induced differential expression of many transcripts using high-density microarray approach. Few transcripts, which were previously not reported to be associated with neuronal degeneration, were also identified. The results obtained thus suggest that maneb + paraquat induce neurotoxicity in the striatum in a time of exposure dependent manner via multiple pathways and defective energy metabolism could play a critical role.

Topics: Animals; Blotting, Western; Corpus Striatum; Disease Models, Animal; Energy Metabolism; Fungicides, Industrial; Gene Expression Profiling; Herbicides; Male; Maneb; Mice; Oligonucleotide Array Sequence Analysis; Paraquat; Phenotype; RNA, Messenger

Parkinson's disease (PD) is a progressive neurodegenerative disorder contributed by the combination of age, genetic and environmental factors. Several studies have clearly shown increase in the incidences of PD in the rural environments and hypothesized the involvement of pesticides such as paraquat and maneb in neurodegeneration. These studies have prompted researchers to develop paraquat and maneb models to study the effect of co-treatment of maneb and paraquat on neuronal toxicity; however, the mechanism underlying maneb and paraquat co-treatment induced neuronal toxicity has not yet been clearly understood. The involvement of cytochrome P4502E1 and glutathione S-transferases A4-4 enzymes in the detoxification of several pesticides such as atrazine, fenamirol, organophosphorous insecticide parathion, methoxychlor, diethyl dithiocarbamate and paraquat has been known. The contribution of CYP2E1 and GSTA4-4 in neuronal toxicity has also been reported. The present study was therefore undertaken to investigate the mechanism of maneb- and paraquat-induced neurodegeneration by estimating the level of antioxidant defense enzymes in the striatum and measuring the differential expressions of CYP2E1 and GSTA4-4 genes. Animals were treated with and without maneb (30 mg/kg, i.p.) or paraquat (10 mg/kg, i.p.) either alone or in combination in exposure time-dependent manner. A significant increase in catalase, glutathione S-transferase and lipid peroxidation in the striatum was found following 3, 6 and 9 weeks of co-treatment as compared with individual treatment or controls. Individual treatment of maneb or paraquat did not exhibit any significant alteration in CYP2E1 and GSTA4-4 expression up to 6 weeks; however, an augmentation in CYP2E1 and GSTA4-4 expression was observed in the animals exposed to maneb or paraquat for 9 weeks. Augmentation in the expression of CYP2E1 and GSTA4-4 was more pronounced in the animals treated with maneb and paraquat in combination for nine weeks. A significant reduction in the augmented lipid peroxidation in the striatum was observed when the striatum was pre-administered with CYP2E1 inhibitors; however, glutathione pre-administration induced lipid peroxidation. Results obtained from the present investigation suggest the involvement of CYP2E1 and GSTA4-4 in the augmentation of the lipid peroxidation thereby enhancing neurodegeneration.

Topics: Analysis of Variance; Animals; Catalase; Corpus Striatum; Cytochrome P-450 CYP2E1; Disease Models, Animal; Gene Expression; Glutathione Transferase; Herbicides; Lipid Peroxidation; Male; Maneb; Mice; Paraquat; Parkinson Disease; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Superoxide Dismutase; Time Factors

We have previously shown that a single i.p. injection of nitrosomethylurea (NMU) in 3-day-old rats orally treated with the pesticide mancozeb (MZ), the flavonoid quercetin (Q) or in combination (MZ-Q) induces hyperplasia, atypical acinar cell proliferation and carcinoma in situ (CIS) in the pancreas. This work studies the effect of oral administration of phenobarbital (PB) on this model of pancreatic carcinogenesis. The animals were fed on a diet supplemented by MZ or/and Q from the 10th day of pregnancy, thorough lactation and as pups after weaning until being sacrificed at week 24. Saline injection with non-supplemented diet was used for the control group (SAL). The experimental groups were (1) SAL (control), (2) SAL-PB, (3) NMU, (4) NMU-PB, (5) MZ-NMU, (6) MZ-NMU-PB, (7) Q-NMU, (8) Q-NMU-PB, (9) MZ-Q-NMU and (10) MZ-Q-NMU-PB. Acinar cell hyperplasia was found in all groups of NMU-treated rats. Dysplastic foci (DYS) were seen in groups 3-10 at the following percentages: 19, 48, 71, 27, 71, 35, 100 and 30, respectively. CIS were recorded in groups 4 to 10 at percentages: 4, 36, 13, 11, 0, 16, 5, respectively.. Although PB, Q or MZ given alone enhance DYS lesions in NMU-treated rats, the MZ/Q/PB combined treatments may increase (mainly in males) or decrease (mainly in female) the DYS and CIS proportion. Because PB, MZ and Q influence P450 enzymes, we suggest that these enzymes play a role in the carcinogenesis process.

Topics: Alkylating Agents; Animals; Animals, Newborn; Carcinogens; Carcinoma in Situ; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Female; Fungicides, Industrial; Hyperplasia; Maneb; Maternal Exposure; Maternal-Fetal Exchange; Methylnitrosourea; Pancreatic Neoplasms; Phenobarbital; Pregnancy; Quercetin; Rats; Rats, Wistar; Zineb

The goal of this study was to analyze the effects of prenatal exposure to the pesticides paraquat (PQ) and mancozeb (MZ) on the development of synaptic transmission in mouse cerebellar cortex. Pregnant NMRI mice were treated with either saline, 10 mg/kg PQ, 30 mg/kg MZ or the combination of PQ + MZ, between gestational days 12 (E12) and E20. Variation in the levels of amino acid neurotransmitters was determined by HPLC, between postnatal day 1 (P1) and P30. Motor coordination was assessed by locomotor activity evaluation of control and experimental pups at P14, P21 and P30. Significant reductions in the levels of excitatory neurotransmitters, aspartate and glutamate, were observed in PQ-, MZ- or combined PQ + MZ-exposed pups, with respect to control, during peak periods of excitatory innervation of Purkinje cells: between P2-P5 and P11-P15. However, at P30, lower aspartate contents, in contrast with increased glutamate levels, were detected in all experimental groups. During the first two postnatal weeks, delays in GABA and glycine ontogenesis were observed in PQ- and PQ + MZ-exposed pups, whereas notable decrements in GABA and glycine levels were seen in PQ + MZ-exposed animals. Decreased taurine contents were detected at P3 and P11 in PQ- and PQ + MZ-exposed mice. Pups in different experimental groups all showed hyperactivity at P14 and then exhibited reduced locomotor activity at P30. Taken together, our results indicate that prenatal exposure to either PQ or MZ or the combination of both could alter the chronology and magnitude of synaptic transmission in developing mouse cerebellar cortex.

Topics: Animals; Aspartic Acid; Cerebellar Cortex; Disease Models, Animal; Down-Regulation; Female; Fungicides, Industrial; gamma-Aminobutyric Acid; Glutamic Acid; Glycine; Herbicides; Hyperkinesis; Maneb; Mice; Motor Activity; Neural Inhibition; Paraquat; Pregnancy; Prenatal Exposure Delayed Effects; Synaptic Transmission; Zineb

In recent years, several lines of evidence have shown an increase in Parkinson's disease (PD) prevalence in rural environments where pesticides are widely used. Paraquat (PQ--herbicide) and maneb (MB--fungicide) are among the compounds suspected to induce neuronal degeneration and motor deficits characteristics of PD. Here, we investigated the effects of PQ and MB on dopaminergic (DA) neuron-glia cultures and in vivo in young adult rats. In vitro, PQ led to a loss of DA as compared to non-DA neurons and microglial activation in a dose-dependent manner. Addition of MB had no further effect nor did it lead to microglial activation when used alone. In vivo, 2-month old young adult rats were subjected to intraperitoneal injections of vehicle (n = 4), PQ alone (n = 8), or PQ in combination with MB (n = 8) twice a week for 4 weeks and were sacrificed the day following the last injection. Significant loss of nigral DA neurons was observed in both treatment groups, but a significant decrease in striatal DA fibers was not found. Microglial activation was seen in the nigra of rats subjected to PQ with or without MB. Behavioral analyses demonstrated a mixed pattern of motor impairments, which may have been related to early effects of nigral DA neuronal loss or systemic effects associated with MB exposure in addition to PQ. These results indicate that exposure to PQ with or without MB induces neurodegeneration which might occur via an early inflammatory response in young adult animals.

Topics: Age of Onset; Animals; Cells, Cultured; Coculture Techniques; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Encephalitis; Fungicides, Industrial; Gliosis; Herbicides; Male; Maneb; Microglia; Nerve Degeneration; Neurons; Paraquat; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Rats, Wistar; Substantia Nigra

We evaluated the effects of mancozeb (Dithane M4-5), a protective carbamate fungicide, on transplacental carcinogenesis in Swiss albino mice. Mancozeb, a polymeric complex of ethylene bis (dithiocarbamate) manganese with zinc salt, is reported to possess carcinogenic and cocarcinogenic activity in various tumor models. In the present study, pregnant Swiss albino mice were administered mancozeb intraperitoneally on the 14th day of gestation. The first filial generation (F1 progeny) was promoted with a well-known tumor promoter 12-o-tetradecanoyl phorbol-13-acetate (TPA). The results revealed a significantly high tumor incidence (72%) in the F1 progeny of the animals initiated with mancozeb or a well known carcinogen 7,12-dimethyl benzanthracene (DMBA) and promoted with TPA in comparison to animals that were either from mothers given only the vehicle (DMSO) and promoted with TPA in F1 progeny or not promoted with TPA in F1 progeny. No significantly higher tumor incidence was observed in any other experimental groups. These results suggest that mancozeb or its metabolites are capable of crossing the placental barrier and can exert DNA damage and tumor initiating consequences in the fetal cells that, after promotion with TPA, get converted into neoplastic cells.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Disease Models, Animal; Female; Fungicides, Industrial; Male; Maneb; Maternal Exposure; Maternal-Fetal Exchange; Mice; Pregnancy; Prenatal Exposure Delayed Effects; Skin Neoplasms; Tetradecanoylphorbol Acetate; Zineb

The fungicide for corn PF-70 contains 21% of sulphur, 8.4% of mancozeb, and 0.6% of triadimefon . The aim of the study was to determine the effect of the fungicide on the gastric mucosa electrolyte barrier in rats. Mucosa lesion is known to be one of the risk factors of chronic peptic ulcer disease. The experiments were carried out on 80 rats of Wistar strain. The animals were divided into 5 groups--males and females, separately. The fungicide was given for 13 weeks, at the following doses: 100, 400, 1600, and 6400 mg of active substance per 1 kg of fodder. The gastric mucosa electrolyte barrier was examined by determining the transmural electric potential differences (PD) in mucosa before and after treatment with 150 mmlo of hydrochloric acid and 40 mmol of acetylsalicylic acid solutions. No changes in general condition of the animals were observed. An increase in fodder consumption was observed in males receiving the fungicide at doses of 1600 and 6400 mg per 1 kg of fodder. Females exhibited a decrease in body mass after intoxication at concentration of 6400 mg/kg fodder. A decrease in PD was found in all groups intoxicated with the fungicide, irrespective of the animal sex.

Topics: Action Potentials; Animals; Chronic Disease; Disease Models, Animal; Edible Grain; Electric Conductivity; Female; Fungicides, Industrial; Gastric Mucosa; Male; Maneb; Rats; Rats, Inbred Strains; Sulfur; Triazoles; Zineb