maneb and Nerve-Degeneration

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

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

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

The activation of NADPH oxidase contributes to dopaminergic neurodegeneration induced by paraquat and maneb, two concurrently used pesticides in agriculture. However, the mechanisms remain unclear. Ferroptosis, a recently recognized form of regulated cell death, has been implicated in the pathogenesis of multiple neurodegenerative diseases. This study is designed to investigate whether ferroptosis is involved in NADPH oxidase-regulated dopaminergic neurotoxicity. In vitro study showed that paraquat and maneb exposure induced ferroptosis in SHSY5Y dopaminergic cells, which was associated with activation of NADPH oxidase. Inhibition of NADPH oxidase by apocynin or diphenyleneiodonium (DPI), two widely used NADPH oxidase inhibitors mitigated paraquat and maneb-induced ferroptotic cell death. Consistently, stimulating activation of NADPH oxidase by phorbol myristate acetate (PMA) or supplementation of H

Topics: Animals; Cell Line, Tumor; Dopaminergic Neurons; Ferroptosis; Fungicides, Industrial; Herbicides; Humans; Male; Maneb; Mice; Mice, Inbred C57BL; NADPH Oxidases; Nerve Degeneration; Paraquat; Random Allocation

The pesticide mancozeb (mz) is recognized as a potent inducer of oxidative stress due to its ability to catalyze the production of reactive oxygen species plus inhibiting mitochondrial respiration thus becoming an environmental risk for neurodegenerative diseases. Despite numerous toxicological studies on mz have been directed to mammals, attention on marine fish is still lacking. Thus, it was our intention to evaluate neurobehavioral activities of ornate wrasses (Thalassoma pavo) exposed to 0.2mg/l of mz after a preliminary screening test (0.07-0.3mg/l). Treated fish exhibited an evident (p<0.001) latency to reach T-maze arms (>1000%) while exploratory attitudes (total arm entries) diminished (-50%; p<0.05) versus controls during spontaneous exploration tests. Moreover, they showed evident enhancements (+111%) of immobility in the cylinder test. Contextually, strong (-88%; p<0.01) reductions of permanence in light zone of the Light/Dark apparatus along with diminished crossings (-65%) were also detected. Conversely, wrasses displayed evident enhancements (160%) of risk assessment consisting of fast entries in the dark side of this apparatus. From a molecular point of view, a notable activation (p<0.005) of the brain transcription factor pCREB occurred during mz-exposure. Similarly, in situ hybridization supplied increased HSP90 mRNAs in most brain areas such as the lateral part of the dorsal telencephalon (Dl; +68%) and valvula of the cerebellum (VCe; +35%) that also revealed evident argyrophilic signals. Overall, these first indications suggest a possible protective role of the early biomarkers pCREB and HSP90 against fish toxicity.

Topics: Animals; Behavior, Animal; Brain; Cyclic AMP Response Element-Binding Protein; Exploratory Behavior; Female; Fish Proteins; Fishes; Fungicides, Industrial; HSP90 Heat-Shock Proteins; Maneb; Motor Activity; Nerve Degeneration; Neurotoxicity Syndromes; Reaction Time; Time Factors; Water Pollutants, Chemical; Zineb

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

Manganese-containing fungicides like Mancozeb have been associated with neurodegenerative conditions like Parkinson's disease. We examined the behavioral damage and differential neuronal vulnerability resulting from Mancozeb exposure using Caenorhabditis elegans, an important mid-trophic level soil organism that is also a powerful model for studying mechanisms of environmental pollutant-induced neurodegenerative disease. The dopamine-mediated swim to crawl locomotory transition behavior is exquisitely vulnerable to Mancozeb, with functional impairment preceding markers of neuronal structural damage. The damage is partially rescued in mutants lacking the divalent metal transporter, SMF-1, demonstrating that some, but not all, of the damage is mediated by manganese. Increasing concentrations of Mancozeb recruit additional behavioral dysfunction, notably serotonin-mediated egg-laying behavior, but without evident serotonergic neuronal structural damage. Thus, measurements of behavioral dysfunction are a sensitive early marker of fungicide toxicity that could be exploited to examine further mechanisms of neuron damage and possible therapeutic interventions. These results also provide important insight into the consequences of fungicide use on the ecological behavior of nematodes.

Topics: Animals; Behavior, Animal; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cation Transport Proteins; Dopamine; Dose-Response Relationship, Drug; Environmental Pollutants; Fungicides, Industrial; Locomotion; Maneb; Mechanotransduction, Cellular; Mutation; Nerve Degeneration; Neurons; Oviposition; Serotonin; Touch; Zineb

Previous studies demonstrate a positive correlation between pesticide usage and Parkinson's disease (PD), which preferentially targets dopaminergic (DAergic) neurons. In order to examine the potential relationship between two common pesticides and specific neurodegeneration, we chronically (24 h) or acutely (30 min) exposed two Caenorhabditis elegans (C. elegans) strains to varying concentrations (LC(25), LC(50) or LC(75)) of TouchDown(®) (TD) as percent active ingredient (glyphosate), or Mancozeb(®) (MZ) as percent active ingredient (manganese/zinc ethylene-bis-dithiocarbamate). Furthermore, to more precisely model environmental exposure, worms were also exposed to TD for 30 min, followed by 30-min incubation with varying MZ concentrations. Previous data from out lab suggested general neuronal degeneration using the worm strain NW1229 (pan-neuronal//green fluorescent protein (GFP) construct). To determine whether distinct neuronal groups were preferentially affected, we specifically used EG1285 (GABAergic neurons//GFP construct) and BZ555 (DAergic neurons//GFP construct) worms to verify GABAergic and DAergic neurodegeneration, respectively. Results indicated a statistically significant decrease, when compared to controls (CN), in number of green pixels associated with GABAergic neurons in both chronic (*P < 0.05) and acute (*P < 0.05) treatment paradigms. Analysis of the BZ555 worms indicated a statistically significant decrease (*P < 0.05) in number of green pixels associated with DAergic neurons in both treatment paradigms (chronic and acute) when compared to CN. Taken together, our data suggest that exposure to TD and/or MZ promotes neurodegeneration in both GABAergic and DAergic neurons in the model organism C. elegans.

Topics: Animals; Animals, Genetically Modified; Caenorhabditis elegans; Dopaminergic Neurons; Dose-Response Relationship, Drug; Drug Interactions; Fungicides, Industrial; GABAergic Neurons; Glycine; Glyphosate; Green Fluorescent Proteins; Interneurons; Maneb; Motor Neurons; Nerve Degeneration; Organophosphorus Compounds; Pesticides; Zineb

Epidemiological evidence suggests positive correlations between pesticide usage and the incidence of Parkinson's disease (PD). To further explore this relationship, we used wild type (N2) Caenorhabditis elegans (C. elegans) to test the following hypothesis: Exposure to a glyphosate-containing herbicide (TD) and/or a manganese/zinc ethylene-bis-dithiocarbamate-containing fungicide (MZ) may lead to neurotoxicity. We exposed N2 worms to varying concentrations of TD or MZ for 30 min (acute) or 24h (chronic). To replicate agricultural usage, a third population was exposed to TD (acute) followed by MZ (acute). For acute TD exposure, the LC(50)=8.0% (r(2)=0.6890), while the chronic LC(50)=5.7% (r(2)=0.9433). Acute MZ exposure led to an LC(50)=0.22% (r(2)=0.5093), and chronic LC(50)=0.50% (r(2)=0.9733). The combined treatment for TD+MZ yielded an LC(50)=12.5% (r(2)=0.6367). Further studies in NW1229 worms, a pan-neuronally green fluorescent protein (GFP) tagged strain, indicated a statistically significant (p<0.05) and dose-dependent reduction in green pixel number in neurons of treated worms following each paradigm. This reduction of pixel number was accompanied by visual neurodegeneration in photomicrographs. For the dual treatment, Bliss analysis suggested synergistic interactions. Taken together, these data suggest neuronal degeneration occurs in C. elegans following treatment with environmentally relevant concentrations of TD or MZ.

Topics: Analysis of Variance; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Dose-Response Relationship, Drug; Drug Synergism; Fungicides, Industrial; Glycine; Glyphosate; Green Fluorescent Proteins; Herbicides; Lethal Dose 50; Maneb; Microscopy, Fluorescence; Nerve Degeneration; Neurons; Time Factors; Zineb

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

We investigated the effects of combined systemic exposure to the herbicide paraquat (PQ) and the fungicide maneb (MB) in 6-month-old rats, an animal model of Parkinson's disease resulting from environmental toxin exposure. Following two doses of PQ (10 mg/kg) and MB (30 mg/kg), 52% of animals developed fatal lung injury. Examination of the remaining animals showed degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta 6 weeks, but not 4 weeks, following PQ/MB. In contrast, microglial activation was observed at 4 weeks, but had abated by 6 weeks. Compared with our previous findings in younger rats, these results suggest increased susceptibility of older animals to lung and brain toxicity from PQ/MB exposure. Microglial activation preceded, and therefore likely contributed to, DA neurodegeneration. Further, electron microscopy revealed an abnormal appearance of the Golgi apparatus at 4 weeks that was confirmed using double immunostaining for tyrosine hydroxylase and Golgi. This suggests that PQ/MB causes protein processing dysfunction in nigral DA neurons that may be either a direct effect of PQ/MB or the result of microglial activation.

Topics: Aging; Animals; Cell Death; Dopamine; Drug Administration Schedule; Drug Combinations; Male; Maneb; Microglia; Nerve Degeneration; Neurons; Paraquat; Rats; Rats, Sprague-Dawley; Time Factors

The neuroprotective effects of Polygonum multiflorum extract (PME) and its two fractions, ethanol-soluble PME (PME-I) and -insoluble PME (PME-II), on the degeneration of nigrostriatal dopaminergic neurons induced by a combination of paraquat and maneb (PQMB) were investigated in male C57BL/6 mice. The mice were treated twice a week for 6 weeks with intraperitoneal injections of PQMB. This combination caused a reduction of spontaneous locomotor activity, motor incoordination, and declines of dopamine level in the striatum and tyrosine hydroxylase-positive neurons in the substantia nigra. Administration of PME and PME-I once daily for 47 days during 6 weeks of PQMB treatment and last 8 days after PQMB significantly attenuated the impairment of behavioral performance and the decrease in striatal dopamine level and substantia nigral tyrosine hydroxylase-positive neurons in the PQMB-treated animals, whereas the administration of PME-II had no effect on these behavioral, neurochemical and histological indices. The present findings suggest that PME has a beneficial influence on parkinsonism induced by PQMB and that the effects of PME are attributable to some substance(s) included in the ethanol-soluble fraction of PME (PME-I).

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antiparkinson Agents; Chromatography, High Pressure Liquid; Dopamine; Fungicides, Industrial; Herbicides; Immunohistochemistry; Levodopa; Male; Maneb; Mice; Mice, Inbred C57BL; Motor Activity; Neostriatum; Nerve Degeneration; Neuroprotective Agents; Paraquat; Parkinson Disease, Secondary; Phytotherapy; Plant Roots; Polygonum; Substantia Nigra; Tyrosine 3-Monooxygenase

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