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Protective role of glutathione reductase in paraquat induced neurotoxicity.
Chem Biol Interact. 2012 Aug 30; 199(2):74-86.CB

Abstract

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 (O₂·⁻), nitrate (NO₃⁻), malondialdehyde (MDA), superoxide dismutase (SOD), total GSH (tGSH) and its oxidized, disulfide form (GSSG) and glutathione peroxidase (GPx). Results obtained from the intact and the sham operated groups were not statistically different, confirming that invasive i.s. route of administration would not influence the reliability of results. Also, similar pattern of changes were observed between ipsi- and contra- lateral side of examined VBRs, indicating rapid spatial spreading of oxidative stress. Mortality of the animals (10%), within 24h, along with symptoms of Parkinsonism, after awakening from anesthesia for 2-3 h, were observed in the PQ group, only. Increased levels of O₂·⁻, NO₃⁻ and MDA, increased ratio of GSSG/GSH and considerably high activity of GPx were measured at 30 min after the treatment. Cytotoxic effect of PQ was documented by drastic drop of all measured parameters and extremely high peak of the ratio GSSG/GSH at 24th hrs after the PQ i.s. injection. In the GR+PQ group, markedly low activity of GPx and low content of NO₃⁻ (in striatum and cortex) were measured during whole experiment, while increase value was observed only for O₂·⁻, at 7th days. We concluded that oxidative/nitrosative stress and excitotoxicity are the most important events since the early stage of PQ induced neurotoxicity. Based on the ratio GSSG/GSH, the oxidation of GSH to GSSG is probably dominant way of GHS depletion and main reason for reduced antioxidative defense against PQ harmful oxidative effect. The GR pre-treatment resulted in the absence of Parkinson's disease-like symptoms and mortality of the rats. Additionally, oxidative/nitrosative stress did not developed, as well as almost diminished metabolism of the VBRs at 24th hours (as has been documented in the PQ group) did not occurred in the GR+PQ, suggesting a neuroprotective role for the GR in PQ induced neurotoxicity.

Authors+Show Affiliations

Department of Toxicology, Faculty of Pharmacy at the University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia. mirjana.djukic@pharmacy.bg.ac.rsNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22721943

Citation

Djukic, Mirjana M., et al. "Protective Role of Glutathione Reductase in Paraquat Induced Neurotoxicity." Chemico-biological Interactions, vol. 199, no. 2, 2012, pp. 74-86.
Djukic MM, Jovanovic MD, Ninkovic M, et al. Protective role of glutathione reductase in paraquat induced neurotoxicity. Chem Biol Interact. 2012;199(2):74-86.
Djukic, M. M., Jovanovic, M. D., Ninkovic, M., Stevanovic, I., Ilic, K., Curcic, M., & Vekic, J. (2012). Protective role of glutathione reductase in paraquat induced neurotoxicity. Chemico-biological Interactions, 199(2), 74-86. https://doi.org/10.1016/j.cbi.2012.05.008
Djukic MM, et al. Protective Role of Glutathione Reductase in Paraquat Induced Neurotoxicity. Chem Biol Interact. 2012 Aug 30;199(2):74-86. PubMed PMID: 22721943.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protective role of glutathione reductase in paraquat induced neurotoxicity. AU - Djukic,Mirjana M, AU - Jovanovic,Marina D, AU - Ninkovic,Milica, AU - Stevanovic,Ivana, AU - Ilic,Katarina, AU - Curcic,Marijana, AU - Vekic,Jelena, Y1 - 2012/06/18/ PY - 2012/02/06/received PY - 2012/05/19/revised PY - 2012/05/21/accepted PY - 2012/6/23/entrez PY - 2012/6/23/pubmed PY - 2012/11/7/medline SP - 74 EP - 86 JF - Chemico-biological interactions JO - Chem Biol Interact VL - 199 IS - 2 N2 - 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 (O₂·⁻), nitrate (NO₃⁻), malondialdehyde (MDA), superoxide dismutase (SOD), total GSH (tGSH) and its oxidized, disulfide form (GSSG) and glutathione peroxidase (GPx). Results obtained from the intact and the sham operated groups were not statistically different, confirming that invasive i.s. route of administration would not influence the reliability of results. Also, similar pattern of changes were observed between ipsi- and contra- lateral side of examined VBRs, indicating rapid spatial spreading of oxidative stress. Mortality of the animals (10%), within 24h, along with symptoms of Parkinsonism, after awakening from anesthesia for 2-3 h, were observed in the PQ group, only. Increased levels of O₂·⁻, NO₃⁻ and MDA, increased ratio of GSSG/GSH and considerably high activity of GPx were measured at 30 min after the treatment. Cytotoxic effect of PQ was documented by drastic drop of all measured parameters and extremely high peak of the ratio GSSG/GSH at 24th hrs after the PQ i.s. injection. In the GR+PQ group, markedly low activity of GPx and low content of NO₃⁻ (in striatum and cortex) were measured during whole experiment, while increase value was observed only for O₂·⁻, at 7th days. We concluded that oxidative/nitrosative stress and excitotoxicity are the most important events since the early stage of PQ induced neurotoxicity. Based on the ratio GSSG/GSH, the oxidation of GSH to GSSG is probably dominant way of GHS depletion and main reason for reduced antioxidative defense against PQ harmful oxidative effect. The GR pre-treatment resulted in the absence of Parkinson's disease-like symptoms and mortality of the rats. Additionally, oxidative/nitrosative stress did not developed, as well as almost diminished metabolism of the VBRs at 24th hours (as has been documented in the PQ group) did not occurred in the GR+PQ, suggesting a neuroprotective role for the GR in PQ induced neurotoxicity. SN - 1872-7786 UR - https://www.unboundmedicine.com/medline/citation/22721943/Protective_role_of_glutathione_reductase_in_paraquat_induced_neurotoxicity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0009-2797(12)00096-8 DB - PRIME DP - Unbound Medicine ER -