Effect of Nimodipine on Dichlorvos-induced Seizure in Mice

Dichlorvos a synthetic organophosphate poisons are used as insecticide. These toxins can be used insecticides in agriculture and medicine for destruction and /or eradication of ectoparasites of animals. Studies have shown that Dichlorvos creation seizure effects in different animals. Nimodipine, dihydropyridine calcium channel blockers, widely used for treatment of cardiovascular diseases. Studies have shown that the calcium channel blockers are anticonvulsant effects in different animal models. The aim of this study was to determine the effect of Nimodipine on Dichlorvos-induced seizures in mice. In this experiment, the animals were received different doses of Nimodipine (2.5, 5, 10, 20 and 40 mg/ kg b.wt.) intraperitoneally 30 min before intraperitoneal injection of Dichlorvos (50 mg/kg b.wt). After Dichlorvos injection, clonic and tonic seizures, and finally death was the fate was investigated. Results showed that Nimodipine dose dependently reduced the severity of Dichlorvos-induced seizures, so that Nimodipine at dose of 5mg (The lowest, p<0.05) and 40 mg/kg b.wt. (The highest, p<0.001) which had anticonvulsant effects. The anticonvulsant activity of Nimodipine suggests that possibly due to antagonistic effect on voltage-dependent calcium channel. INTRODUCTION models of nerve tissue in a large protective effect [4].


INTRODUCTION
models of nerve tissue in a large protective effect [4].
Epilepsy is one of the major neurological diseases in anticonvulsant effects of some models [5,6], but in all humans and about one percent of the population is animal models of seizures did not show has not involved. It has been shown that epileptic seizure occurs demonstrated these effects [7,8]. Also in rats due to occasional discharges in nerve tissue. It is anticonvulsant effects of calcium channel inhibitors recognized that occasional changes in reversible neuronal shown but seizure agent has not Dichlorvos. Some function, causing brain electrical activity. In some cases, medications such as anticonvulsants phenytoin and the seizure occurs due to the entry of calcium ions into carbamazepine inducing their effect by inhibiting sodium nerve cells and reducing intracellular calcium channels directly and indirectly through preventing the concentration, in some epileptic animal models has flow of calcium from the membranes of neurons and inhibitory effect on seizures. During seizures increased reduction of excessive concentration of intracellular intracellular calcium ion concentration, while extra cellular calcium. Specific drugs used to treat epilepsy are absence calcium concentration decreases [1,2]. Calcium channel seizure kind of like channels as T-type calcium in thalamic antagonists for the treatment of hypertension were neurons are blocked. Reduction of calcium ion produced in the year 1980. Use of these drugs over time concentration of an important goal in development of to treat other diseases was developed, such as treatment neuroprotective and antiepileptic drugs [2,3]. Calcium of angina, supraventricular tachycardia attack, entry into neurons play an important role in creating the hypertrophic cardiomyopathy, pulmonary hypertension seizures and calcium channel inhibitors have different and migraine. Recently have shown that calcium channel effects on health, including cardiovascular diseases, blockers may have anticonvulsant effects in some animal migraine and headaches caused by vascular changes, models. Calcium channel blockers inhibit calcium ion flow nerve regeneration and neuronal regenerative processes through L-type calcium channels sensitive to voltage [3].
[1], So it seems calcium channel inhibitors used to treat It has been shown that calcium channel inhibitors in seizures can be useful. Results of these studies for the They also reported that calcium channel inhibitors on the Statistical Analysis: After testing data as the mean±SEM suggests, therefore likely to Nimodipine reduce expression and to analyze data, ANOVA followed by Dichlorvos-induced seizures. Since no research based on Tukey multiple comparison tests were used. Value of the combined effect of these seizures from Dichlorvos p<0.05 to determine significance between groups was there, in this case study seems necessary. Insecticide use considered. in agriculture and veterinary medicine as strange since World War II and grew during the past 20 years until RESULTS reached its highest rate. While the main consumers of agricultural insecticide industry its uses and application Effect of Twin 80 as solvent, on Dichlorvos-induced for other industries. Most of insecticide residues on the seizures showed that this substance has no significant remaining products and people exposed to low doses of effect on seizures. Therefore the results had not presented chemicals through the foods. Numerous accidents of in graphs and tables have been avoided. Effect of acute insecticide poisoning caused by eating food that different doses of Nimodipine (2.5, 5, 10, 20 and 40 mg/ kg mainly followed during storage or transportation had been b.wt.) on Dichlorvos-induced seizures showed that this infected was created [9]. Including the insecticide, drug dose-dependently reduced the Dichlorvos-induced which are potential toxicity, are organophosphate. One seizures (Graphs 1 and 2).Most anticonvulsant effect of of the organophosphate is Dichlorvos. The aim of Nimodipine on the mortality and severity of seizures with this study was to determine the effect of nimodipine a dose of 40 mg/kg was observed (Graph 3 and Table 1). (calcium channel antagonist) on Dichlorvos-induced seizures.

MATERIALS AND METHODS
Male mice NMRI, weighing between 25-30 grams, maintained at laboratory animals breeding center of Tabriz Islamic Azad University, purchased and were kept under controlled room temperature, light and humidity constant. Animals' were fed food and water ad libitum. All tests were performed between 10-16 hours. Dichlorvos and Nimodipine, both were solved in Twin 80 (5%). Animals Graph 1: Effect of different doses of nimodipine on the were divided randomly and placed in treatment groups starting time of clonic seizures after injection of (each group 10 mice). Nimodipine and Twin 80 were Dichlorvos (second). (Mean±SEM) any forms of administered intraperitoneally with constant volume and graphs are presented. * P<0.05, ** P<0.01 and by weight per animal. To remove the effect of injection *** P<0.001 compared with Dichlorvos group. volume on seizures, all drugs and Twin 80, at 10 ml/kg was set. First, seizures was assessed in animals receiving Dichlorvos and then evaluated the effect of Twin 80 on Dichlorvos-induced seizures with the above injection, 30 minutes before the seizure was determined. 50 mice were given different doses of nimodipine (2.5, 5, 10, 20 and 40 mg/kg) 30 min before the intraperitoneal injection of Dichlorvos. To create seizures, mice received Dichlorvos (50 mg/kg b. wt.) intraperitoneally, and then the animals treated for 120 minutes were recorded by video camera.

DISCUSSION
In this study, Dicholorvos cause clonic and tonic seizures, and ultimately death. After the mice received intraperitoneal dichlorvos, some degree of tremor and excessive activity showed that over time the symptoms became more severe and cause death. In this study, nimodipine dose dependently reduced clonic and tonic seizures and deaths from Dicholorvos. The results showed that the results of different researchers before treatment with calcium channel antagonists, seizure activity creation of different materials down to is in agreement. If nimodipine in preventing tonic convulsions caused by PTZ [1], Aminophyline [5] and pilocarpine [6] have a protective effect, but unlike the above models in all tests anticonvulsant effect has been observed. For example Kainic acid induced seizures, administration of nimodipine before this material could not reduce seizures [4]. In another study showed that nimodipine with values above 80 mg/kg could inhibit tonic seizures from chemicals including PTZ in mice and rats [7, 10], but later showed that high doses of calcium channels blockers cause systemic and cardiac disorders, such as a sharp reduction in coronary blood pressure, decreased movements, imbalance, and headache relief [2,3]. Epilepsy in patients who were resistant to treatment, have reported that nimodipine in an uncontrolled study, seizure frequency is reduced [11], but in another study that two strains were unaware controls, no anticonvulsant effects was observed by nimodipine [12]. Other problems prescription drug, long-term administration of drugs with low prescribed intervals (three to four times a day to several weeks) and side effects include headache and hypotension, pronounced the man was from animal models. However, after 24 and 72 hours of administration of nimodipine, percent of alpha and theta ( ) waves was increased and vice versa percent in delta waves electroencephalogram was reduced [3,12]. Other studies have shown that the anticonvulsant effects of calcium channel blockers, especially nimodipine with other antiepileptic drugs, increases. For example, in mice and rats with concurrent administration of nimodipine with other drugs can be decreased PTZ-induced tonic seizures, seizures resulting from sound and relieve the electroshock [4,8]. Dihydropyridine calcium channels blockers in experimental seizures by ischemia, bicuculine, electrical cortical shocks, nitrous oxide and alcohol withdrawal syndrome is caused due, have anticonvulsant effects [13]. In another study, calcium channel blockers such as verapamil, nifedipine and Flunarizine to prevent of penicillin-induced seizures and electroencephalogram range have changed [13]. Calcium channel inhibitors on seizures induced by N-methyl-D, L-aspartate (NMDLA) and dihydropyridine calcium channel agonist BAY K 8644 have been effective [2,14]. In another study on rats have shown that nimodipine in animal models of seizures, nerve discharge from BAY K 8644 and reduced the decrease in spike-wave EEG [2]. Also have shown that this drug is ischemic brain damage has protective effects [13]. These studies suggest that protective effects of calcium channel antagonists probably due to blocking Ltype calcium channels during seizures. These drugs inhibit voltage-dependent calcium channels in seizures, the increase in intracellular calcium to prevent. Well marked that increased Ca into the cell in the incidence of 2+ certain types of seizures plays a role [1], also marked the loss of calcium outside the cell with reduced flow of calcium from the membranes of neurons for several seconds the discharge of neurons that causes seizures be prevented and the threshold increases [15]. Some of the other antiepileptic drugs such as phenytoin and carbamazepine with a direct effect on neuronal sodium channels act directly or indirectly the flow of calcium 7. Gasior, M., R. Kaminski, T. Burdniak, Z. Kleinrok and ions from the membranes of neurons are inhibited S.J. Czuczwar, 1996. Influence of nicardipine, [2,3]. So it is likely that dihydropyridine calcium channel nimodipine and flunarizine on the anticonvulsant antagonists to act with similar mechanisms. Also have efficacy of antiepileptics against pentylenetetrazol shown that nimodipine may inhibit calcium, sodium, in mice. J. Neural Transmission General Section, chloride, potassium and calcium-dependent glutamate 103: 819-831. channels [2].