maneb and Parkinsonian-Disorders

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 pathological features of Parkinson's disease (PD) include an abnormal accumulation of α-synuclein in the surviving dopaminergic neurons. Though PD is multifactorial, several epidemiological reports show an increased incidence of PD with co-exposure to pesticides such as Maneb and paraquat (MP). In pesticide-related PD, mitochondrial dysfunction and α-synuclein oligomers have been strongly implicated, but the link between the two has not yet been understood. Similarly, the biological effects of α-synuclein or its radical chemistry in PD is largely unknown. Mitochondrial dysfunction during PD pathogenesis leads to release of cytochrome c in the cytosol. Once in the cytosol, cytochrome c has one of two fates: It either binds to apaf1 and initiates apoptosis or can act as a peroxidase. We hypothesized that as a peroxidase, cytochrome c leaked out from mitochondria can form radicals on α-synuclein and initiate its oligomerization.. Samples from controls, and MP co-exposed wild-type and α-synuclein knockout mice were studied using immuno-spin trapping, confocal microscopy, immunohistochemistry, and microarray experiments.. Experiments with MP co-exposed mice showed cytochrome c release in cytosol and its co-localization with α-synuclein. Subsequently, we used immuno-spin trapping method to detect the formation of α-synuclein radical in samples from an in vitro reaction mixture consisting of cytochrome c, α-synuclein, and hydrogen peroxide. These experiments indicated that cytochrome c plays a role in α-synuclein radical formation and oligomerization. Experiments with MP co-exposed α-synuclein knockout mice, in which cytochrome c-α synuclein co-localization and interaction cannot occur, mice showed diminished protein radical formation and neuronal death, compared to wild-type MP co-exposed mice. Microarray data from MP co-exposed wild-type and α-synuclein knockout mice further showed that the absence of α-synuclein per se or its co-localization with cytochrome c confers protection from MP co-exposure, as several important pathways were unaffected in α-synuclein knockout mice.. Altogether, these results show that peroxidase activity of cytochrome c contributes to α-synuclein radical formation and oligomerization, and that α-synuclein, through its co-localization with cytochrome c or on its own, affects several biological pathways which contribute to increased neuronal death in an MP-induced model of PD.

Topics: alpha-Synuclein; Animals; Cell Death; Cytochromes c; Free Radicals; Immunohistochemistry; Male; Maneb; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Neurons; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Paraquat; Parkinsonian Disorders; Pesticides

Paraquat (PQ) and maneb (MB) are potential risk factors for Parkinson's disease. However, their impact on non-motor disorders, monoamine neurotransmission and basal ganglia function is not clearly determined. Here we investigated the effects of combined treatment with PQ/MB on motor behavior, anxiety and "depressive-like" disorders, tissue content of monoamines, and subthalamic nucleus (STN) neuronal activity. Male Sprague-Dawley rats were intoxicated by PQ (10 mg/kg) and MB (30 mg/kg) twice a week. Two weeks later, the majority of animals (group 1, 16/26) showed a severe loss of body weight with tremor and respiratory distress and others (group 2, 6/26) showed only tremor. Animals of group 2 received PQ/MB during four weeks before developing weight loss. A last group (group 3, 4/26) was insensitive to PQ/MB after 6 weeks of injections. Groups 1 and 2 displayed a failure of motor activity and motor coordination. Group 3 showed slight motor deficits only after the last injection of PQ/MB. Moreover, PQ/MB induced anxiety and "depressive-like" behaviors in animals of groups 2 and 3. Biochemical analysis showed that PQ/MB reduced striatal dopamine (DA) tissue content paralleled by changes in the activity of STN neurons without changing the content of norepinephrine and serotonin in the cortex. Our data provide evidence that individuals are not equally sensitive to PQ/MB and show that the motor deficits in vulnerable animals, are not only a result of DA neuron degeneration, but may also be a consequence of peripheral disabilities. Nevertheless, the parkinsonian-like non-motor impairments may be a direct consequence of the bilateral DA depletion.

Topics: Animals; Anxiety Disorders; Central Nervous System Agents; Corpus Striatum; Depressive Disorder; Dopamine; Male; Maneb; Motor Activity; Neurons; Norepinephrine; Paraquat; Parkinsonian Disorders; Rats, Sprague-Dawley; Serotonin; Subthalamic Nucleus

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

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

SNCA and MAPT genes and environmental factors are important risk factors of Parkinson's disease [PD], the second-most common neurodegenerative disease. The agrichemicals maneb and paraquat selectively target dopaminergic neurons, leading to parkinsonism, through ill-defined mechanisms. In the current studies we have analyzed the ability of maneb and paraquat, separately and together, to induce synucleinopathy and tauopathy in wild type mice. Maneb was ineffective in increasing α-synuclein [α-Syn] or p-Tau levels. By contrast, paraquat treatment of mice resulted in robust accumulation of α-Syn and hyperphosphorylation of Tau in striata, through activation of p-GSK-3β, a major Tau kinase. Co-treatment with maneb did not enhance the effects of paraquat. Increased hyperacetylation of α-tubulin was observed in paraquat-treated mice, suggesting cytoskeleton remodeling. Paraquat, but not maneb, inhibited soluble proteasomal activity on a peptide substrate but this was not associated with a decreased expression of 26S proteasome subunits. Both paraquat and maneb treatments increased levels of the autophagy inhibitor, mammalian target of rapamycin, mTOR, suggesting impaired axonal autophagy, despite increases in certain autophagic proteins, such as beclin 1 and Agt12. Autophagic flux was also impaired, as ratios of LC3 II to LC3 I were reduced in treated animals. Increased mTOR was also observed in postmortem human PD striata, where there was a reduction in the LC3 II to LC3 I ratio. Heat shock proteins were either increased or unchanged upon paraquat-treatment suggesting that chaperone-mediated autophagy is not hampered by the agrichemicals. These studies provide novel insight into the mechanisms of action of these agrichemicals, which indicate that paraquat is much more toxic than maneb, via its inhibitory effects on proteasomes and autophagy, which lead to accumulation of α-Syn and p-Tau.

Topics: alpha-Synuclein; Animals; Autophagy; Case-Control Studies; Corpus Striatum; Down-Regulation; Fungicides, Industrial; Herbicides; Humans; Male; Maneb; Mice; Mice, Inbred C57BL; Paraquat; Parkinsonian Disorders; Proteasome Endopeptidase Complex; Signal Transduction; Tauopathies

A strong association between polymorphisms of the cytochrome P450 (CYP/Cyp) 2D6 gene and risk to Parkinson's disease (PD) is well established. The present study investigated the neuroprotective potential of Cyp2d22, a mouse ortholog of human CYP2D6, in maneb- and paraquat-induced parkinsonism and the mechanisms involved therein along with the effects of resveratrol on various parameters associated with Cyp2d22-mediated neuroprotection. The animals were treated intraperitoneally with resveratrol (10mg/kg, daily) and paraquat (10mg/kg) alone or in combination with maneb (30 mg/kg), twice a week, for 9 weeks, along with their respective controls. The subsets of animals were also treated intraperitoneally with a Cyp2d22 inhibitor, ketoconazole (100mg/kg, daily). Maneb and paraquat reduced Cyp2d22 and vesicular monoamine transporter type 2 (VMAT-2) expressions, the number of tyrosine hydroxylase-positive cells, and dopamine content and increased paraquat accumulation in the nigrostriatal tissues, oxidative stress, microglial activation, neuroinflammation, and apoptosis. Cyp2d22 inhibitor significantly exacerbated all these neurodegenerative indexes. Resveratrol cotreatment, partially but significantly, ameliorated the neurodegenerative changes by altering Cyp2d22 expression and paraquat accumulation. The results obtained in the study demonstrate that Cyp2d22 offers neuroprotection in maneb- and paraquat-induced dopaminergic neurodegeneration and resveratrol enhances its neuroprotective credentials by influencing Cyp2d22 expression and paraquat accumulation.

Topics: Animals; Blotting, Western; Chromatography, High Pressure Liquid; Corpus Striatum; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Dopamine; Fungicides, Industrial; Herbicides; Male; Maneb; Mice; Neuroprotective Agents; Paraquat; Parkinsonian Disorders; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes

Topics: Fungicides, Industrial; Humans; Male; Maneb; Middle Aged; Parkinsonian Disorders; Zineb

To investigate the effects of exposure of paraquat and maneb on the behavior, the morphology and electrical activity of the Substantia nigra and striatum, and to discuss the relationship between this two pesticides and Parkinson's disease.. 37 rats were divided randomly into 3 groups: control group (n = 11), paraquat (10 mg/kg) group (n = 13) and combinative group of paraquat (10 mg/kg) and maneb (30 mg/kg) (n = 13), and were exposed twice a week for 6 weeks by intraperitoneal injection. The behavior of animals in the declined-plane, the vertical-grid and the open-field test were observed. The morphology of substantia nigral neurons were investigated by HE pathology. The spontaneous discharge of striatum neurons were recorded after exposure.. Compared to the control group and the pre-exposure group, both the numbers of animals sliding down from the declined-plane and the latency of rats' moving on the vertical-grid significantly increased, and the animals' autonomic movement decreased significantly (P < 0.05, P < 0.001). After the combinative exposure, the neurons of the Substantial nigra pars compacta (SNPc) were progressively impaired, the cell density of the paraquat group [(82.17 ± 12.91) n/mm(2)] and the combined group [(41.15 ± 6.44) n/mm(2)] were lower than that in control group (143.10 ± 20.85 n/mm(2)] (P < 0.01). In the paraquat group (5.97 ± 7.30 Hz) and the combined group [(6.95 ± 9.87) Hz], the average discharge rates of the striatum neurons were increased significantly compared to the control group [(1.78 ± 5.05) Hz] (P < 0.01). The bursting discharge was increased significantly in the combined group (22.3%) compared to the control group (9.8%) and the paraquat group (5.6%) (P < 0.05, P < 0.01).. The co-exposure of paraquat and maneb could induce similar symptoms to Parkinsonism syndrome of rats such as rigidity, moving reduction and etc, and the combined exposure had a certain enhanced effect compared to alone paraquat exposure. The combinative exposure of paraquat and maneb could cause neural loss in SNPc and it is involved with the enhanced electrophysiological activity in striatum. The synergy toxicity of paraquat and maneb in nigrostriatal system is related to Parkinson's disease.

Topics: Animals; Corpus Striatum; Male; Maneb; Paraquat; Parkinsonian Disorders; Pesticides; Rats; Rats, Sprague-Dawley; Substantia Nigra

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

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

The absence of any compelling basis for a heritable basis of idiopathic Parkinson's disease (PD) has focused attention on environmental exposures as causative agents. While the herbicide paraquat has repeatedly been implicated, its impact on dopamine systems following systemic exposures is equivocal. The restricted focus on paraquat also ignores the extensive geographical overlap of its use with other agrichemicals known to adversely impact dopamine systems, including ethylenebisdithiocarbamate fungicides such as maneb. The present study sought to determine whether combined exposures to paraquat and maneb would produce additive effects and support a multiple-hit environmental contribution to PD. C57BL/6 mice were exposed to either paraquat (5-10 mg/kg) or maneb (15-30 mg/kg) i.p. alone or in combination once a week for 4 weeks. Sustained decreases in motor activity immediately following injections were consistently observed only with combined exposures, with activity levels returning to control values 24 h later. Concurrently, levels of dopamine and metabolites and dopamine turnover were increased immediately post-injection only by combined exposures, and returned to control levels or below within 48 h. Reductions in tyrosine hydroxylase immunoreactivity, measured 3 days after the last injection, resulted only from combined exposure and were detected in dorsal striatum, but not in the nucleus accumbens. The fact that combined exposures resulted in potentiated effects that appear to target nigrostriatal dopamine systems suggests that these combinations may be important environmental risk factors for Parkinsonism. These findings also raise questions about the adequacy of current risk assessment guidelines for these chemicals which are based on effect levels derived from exposures to single agents.

Topics: Animals; Body Weight; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Environmental Exposure; Lung; Male; Maneb; Mice; Mice, Inbred C57BL; Motor Activity; Neostriatum; Neural Pathways; Neurons; Paraquat; Parkinsonian Disorders; Risk Factors; Substantia Nigra; Time Factors; Tyrosine 3-Monooxygenase