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      Anticonvulsant Effect of Diazoxide against Dichlorvos-Induced Seizures in Mice

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          Abstract

          Dichlorvos, a synthetic organophosphate toxin, is used as pesticides. These toxins can be used as pesticides in farming and medicine for the devastation and/or elimination of ectoparasites of animals. Reports have shown that Dichlorvos generate seizure effects in various animals. Potassium channel opener is extensively used for medication of cardiovascular and other diseases. Studies have shown that potassium channel opener has anticonvulsant effects in different animal models. The goal of this study was to evaluate the effect of dizoxide on Dichlorvos-induced seizures in mice. In this research, the animals received different doses of Diazoxide (1, 2.5, 5, 10, and 20 mg/kg b.wt.) intraperitoneally 30 min before intraperitoneal injection of Dichlorvos (50 mg/kg b.w.t). After Dichlorvos injection, latency of clones, severity of seizure, and finally death as the fate were investigated. Results showed that Diazoxide dose-dependently decreased the severity of Dichlorvos-induced seizures, so that Diazoxide at a dose of 5 mg (the lowest, P < 0.05) and 20 mg/kg b.wt. (the highest, P < 0.001) has anticonvulsant effects. Thus, our data suggest that diazoxide as ATP-sensitive potassium channels opener has anticonvulsant activity against dichlorvas-induced seizure.

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          Most cited references32

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          Organophosphate pesticides: biochemistry and clinical toxicology.

          Organophosphate pesticides are used extensively worldwide, and poisoning by these agents, particularly in developing nations, is a serious public health problem. The toxicokinetics and toxicodynamics of organophosphate poisoning vary not only with the route and extent of exposure, but also the chemical structure of the agent. The mechanism of toxicity is the inhibition of acetylcholinesterase, resulting in an accumulation of the neurotransmitter acetylcholine and the continued stimulation of acetylcholine receptors. The standard treatment consists of reactivation of the inhibited acetylcholinesterase with an oxime antidote and reversal of the biochemical effects of acetylcholine with atropine. Patients who receive treatment promptly usually recover from acute toxicity but may suffer from neurologic sequelae.
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            Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure.

            Adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels are activated by various metabolic stresses, including hypoxia. The substantia nigra pars reticulata (SNr), the area with the highest expression of K(ATP) channels in the brain, plays a pivotal role in the control of seizures. Mutant mice lacking the Kir6.2 subunit of K(ATP) channels [knockout (KO) mice] were susceptible to generalized seizures after brief hypoxia. In normal mice, SNr neuron activity was inactivated during hypoxia by the opening of the postsynaptic K(ATP) channels, whereas in KO mice, the activity of these neurons was enhanced. K(ATP) channels exert a depressant effect on SNr neuronal activity during hypoxia and may be involved in the nigral protection mechanism against generalized seizures.
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              Anticholinesterase Toxicity and Oxidative Stress

              Anticholinesterase compounds, organophosphates (OPs) and carbamates (CMs) are commonly used for a variety of purposes in agriculture and in human and veterinary medicine. They exert their toxicity in mammalian system primarily by virtue of acetylcholinesterase (AChE) inhibition at the synapses and neuromuscular junctions, leading into the signs of hypercholinergic preponderance. However, the mechanism(s) involved in brain/muscle damage appear to be linked with alteration in antioxidant and the scavenging system leading to free radical-mediated injury. OPs and CMs cause excessive formation of F2-isoprostanes and F4-neuroprostanes, in vivo biomarkers of lipid peroxidation and generation of reactive oxygen species (ROS), and of citrulline, a marker of NO/NOS and reactive nitrogen species (RNS) generation. In addition, during the course of these excitatory processes and inhibition of AChE, a high rate of ATP consumption, coupled with the inhibition of oxidative phosphorylation, compromise the cell's ability to maintain its energy levels and excessive amounts of ROS and RNS may be generated. Pretreatment with N-methyl D-aspartate (NMDA) receptor antagonist memantine, in combination with atropine sulfate, provides significant protection against inhibition of AChE, increases of ROS/RNS, and depletion of high-energy phosphates induced by DFP/carbofuran. Similar antioxidative effects are observed with a spin trapping agent, phenyl-N-tert-butylnitrone (PBN) or chain breaking antioxidant vitamin E. This review describes the mechanisms involved in anticholinesterase-induced oxidative/nitrosative injury in target organs of OPs/CMs, and protection by various agents.
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                Author and article information

                Journal
                ScientificWorldJournal
                ScientificWorldJournal
                TSWJ
                The Scientific World Journal
                Hindawi Publishing Corporation
                1537-744X
                2013
                17 December 2013
                : 2013
                : 697305
                Affiliations
                1Department of Pharmacology, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord 88514, Iran
                2Department of Biology, Faculty of Sciences, Tehran University, Tehran 14174, Iran
                3Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran 14174, Iran
                Author notes

                Academic Editors: M. W. Jann and S. Ozawa

                Article
                10.1155/2013/697305
                3877645
                e844cb72-b198-4415-86f1-3b14a61fd0a2
                Copyright © 2013 Amin Jazayeri et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 August 2013
                : 15 September 2013
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