The role of oxidative stress in paraquat-induced neurotoxicity in rats: protection by non peptidyl superoxide dismutase mimetic (original) (raw)
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The pesticide paraquat (PQ) was found to be a suitable xenobiotic to model Parkinson's disease. The reactive oxygen species (ROS) production was suggested to be the main cause of PQ toxicity but very few evidences were found for its generation in the brain in vivo after ip administration. We compared the effects of PQ-induced ROS generation between the brain structures and the peripheral tissues using two different hydroxyl radical generation markers. Repeated but not single ip PQ administration increased the levels of ROS in the striatal homogenates but, when measured in the extracellular microdialysis filtrate, no change was observed. The increased dopamine release was detected in the striatum after the fourth PQ administration and its basal levels were decreased. A single treatment with the pesticide did not influence ROS production in the lungs or kidneys but repeated intoxication decreased its levels. These results suggest that repeated, systemic administration of a low dose of PQ triggers intracellular ROS formation in the brain and can cause slowly progressing degenerative processes , without the toxic effects in the peripheral tissues.
Protective role of glutathione reductase in paraquat induced neurotoxicity
Chemico-Biological Interactions, 2012
Paraquat (PQ), a widely used herbicide is a well-known free radical producing agent. The mechanistic pathways of PQ neurotoxicity were examined by assessing oxidative/nitrosative stress markers. Focus was on the role of glutathione (GSH) cycle and to examine whether the pre-treatment with enzyme glutathione reductase (GR) could protect the vulnerable brain regions (VBRs) against harmful oxidative effect of PQ. The study was conducted on Wistar rats, randomly divided in five groups: intact-control group, (n = 8) and four experimental groups (n = 24). All tested compounds were administered intrastriatally (i.s.) in one single dose. The following parameters of oxidative status were measured in the striatum, hippocampus and cortex, at 30 min, 24 h and 7 days post treatment: superoxide anion radical (O 2 ÅÀ ), nitrate (NO 3 À ), malondialdehyde (MDA), superoxide dismutase (SOD), total GSH (tGSH) and its oxidized, disulfide form (GSSG) and glutathione peroxidase (GPx).
BMC Neuroscience, 2009
Background Parkinson's disease, for which currently there is no cure, develops as a result of progressive loss of dopamine neurons in the brain; thus, identification of any potential therapeutic intervention for disease management is of a great importance. Results Here we report that prophylactic application of water-soluble formulation of coenzyme Q10 could effectively offset the effects of environmental neurotoxin paraquat, believed to be a contributing factor in the development of familial PD. In this study we utilized a model of paraquat-induced dopaminergic neurodegeneration in adult rats that received three weekly intra-peritoneal injections of the herbicide paraquat. Histological and biochemical analyses of rat brains revealed increased levels of oxidative stress markers and a loss of approximately 65% of dopamine neurons in the substantia nigra region. The paraquat-exposed rats also displayed impaired balancing skills on a slowly rotating drum (rotorod) evidenced by thei...
Toxicological Sciences, 2010
Paraquat (PQ) is a well-known herbicide that exerts its effects by elevating intracellular levels of superoxide. It has been previously demonstrated that oxidative and nitrosative stress participate to PQ-induced cell death. Here, we document that PQ increases the levels of nitric oxide (NO) in rat mesencephalic cells and causes nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to activate the NO/GAPDH/Siah cell death cascade. PQ exposure increases expression of the p300/CREBbinding protein (p300/CBP) and phosphorylation of p53 at Ser 15, which stimulates p53-dependent transactivation through increased binding with p300. Although this cascade could be inhibited by preincubation with the monoamine oxidase B inhibitor deprenyl, cell death was not prevented. Pretreatment of cells with the neuronal nitric oxide synthase inhibitor 7-nitroindazole efficiently prevented the activation of the GAPDH/NO/Siah cell death cascade, thereby protecting cells against PQ-induced toxicity. The results suggest that PQ induces this novel cell death cascade in rat mesencephalic cells, but inhibition of the pathway does not impede cell death because of an oxidative burst generated by the pesticide.
Maneb and paraquat-mediated neurotoxicity: involvement of peroxiredoxin/thioredoxin system
2011
Epidemiological and in vivo studies have demonstrated that exposure to the pesticides paraquat (PQ) and maneb (MB) increase the risk of developing Parkinson's disease (PD) and cause dopaminergic cell loss, respectively. PQ is a well-recognized cause of oxidative toxicity; therefore, the purpose of this study was to determine if MB potentiates oxidative stress caused by PQ, thus providing a mechanism for enhanced neurotoxicity by the combination. The results show that PQ alone at a moderately toxic dose (20-30% cell death in 24 h) caused increased reactive oxygen species (ROS) generation, oxidation of mitochondrial thioredoxin-2 and peroxiredoxin-3, lesser oxidation of cytoplasmic thioredoxin-1 and peroxiredoxin-1, and no oxidation of cellular GSH/GSSG. In contrast, MB alone at a similar toxic dose resulted in no ROS generation, no oxidation of thioredoxin and peroxiredoxin, and an increase in cellular GSH after 24 h. Together, MB increased GSH and inhibited ROS production and thioredoxin/ peroxiredoxin oxidation observed with PQ alone, yet resulted in more extensive (> 50%) cell death. MB treatment resulted in increased abundance of nuclear Nrf2 and mRNA for phase II enzymes under the control of Nrf2, indicating activation of cell protective responses. The results show that MB potentiation of PQ neurotoxicity does not occur by enhancing oxidative stress and suggests that increased toxicity occurs by a combination of divergent mechanisms, perhaps involving alkylation by MB and oxidation by PQ.
The role of nitric oxide in paraquat-induced oxidative stress in rat striatum
Annals of agricultural and environmental medicine : AAEM, 2007
The role of nitric oxide (NO) in paraquat (PQ)-induced neurotoxicity is still not fully understood. In this study we used NG-nitro-L-arginine methyl ester (L-NAME), a non-selective nitric oxide synthase (NOS) inhibitor, in order to examine the effects of NO, reactive oxygen species (ROS) generation and lipid peroxidation (LPO) development during PQ-mediated neurotoxicity. Oxidative stress development in the striatum of Wistar rats intrastriatally (i.s.) poisoned with PQ (and in some cases pre-treated with L-NAME) was investigated by measuring superoxide anion (O2.-), malondialdehyde (MDA) and nitrate (NO3-), 30 min, 24 hours and 7 days after treatment. L-NAME pre-treatment provided the possibility to distinguish the role of ROS from reactive nitrogen species (RNS) in oxidative stress development induced by PQ. Our results confirm the involvement of NO in PQ-mediated neurotoxicity and reduced LPO by L-NAME pre-treatment implying that the latter has a protective role.
Paraquat and maneb induced neurotoxicity
Proceedings of the Western Pharmacology Society, 2007
Parkinson's disease is a progressive neurological disorder associated with selective degeneration of nigrostriatal dopaminergic neurons. It is the most common of the neurodegenerative movement disorders, affecting approximately 1% of the population over age 65. Though the exact cause of the neurodegeneration is unknown, it has been shown that environmental factors can contribute to the onset of Parkinson's disease. Parkinsonian symptoms are seen following exposure to the herbicide paraquat, and the fungicide maneb. Furthermore, evidence clearly shows that neurodegeneration develops in environments where workers are co-exposed to paraquat and maneb. These neurotoxins cause a pesticide-induced loss of dopaminergic neurons, inducing a Parkinsonian phenotype. The specific mechanisms by which these environmental neurotoxins affect the nigral dopaminergic neurons are unknown. This gap in mechanistic understanding raises a need for further examination of their cytotoxic effects. De...
Toxicology and Applied Pharmacology, 1996
in Hong Kong; subjects who had previously used herbicides Effects of paraquat on the substantia nigra of the male Wistar and pesticides had a 3.6-fold increased risk of developing rats were studied pharmacologically by a intracerebral injection PD (Ho et al., 1989). of paraquat. The neurochemical, morphological, and behavioral The discovery that the clinical, biochemical, and pathochanges observed after a unilateral intranigral injection of paralogic feathers of PD can be caused by the chemical 1-methylquat (1-5 mg) were as follows: (1) neurochemically, paraquat 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suggests that a caused dose-dependent depletion of dopamine in the ipsilateral similar neurotoxin may cause PD (Langston et al., 1983; striatum starting 2 weeks after treatment; this effect was long