Estudo dos efeitos neuroprotetores da trimetazidina no modelo de convulsão induzida por pilocarpina em camundongos

Abstract

Epilepsy is a neurological disease that affects approximately 1% of the population worldwide. Currently, the conventional antiepileptic drugs available promote seizure control and improvement of only about 75-80% of patients. The biggest limitation to the prolonged use of these agents is related to numerous adverse effects they present. Therefore, the development of new antiepileptic drugs with better efficacy and fewer adverse effects is of paramount importance for medical research. Calcium ions play an important role in the genesis of seizures. Trimetazidine used in the treatment of ischemic diseases preserves the operation of ionic pumps and transmembrane flux of calcium, sodium and potassium while maintaining cellular homeostasis. The literature has shown that trimetazidine anti-inflammatory and antioxidant properties in several experimental animal models. Many studies have shown that trimetazidine had a protective effect on ischemic injury not only in the heart but also in the brain, lung, kidney, intestine and liver. The present work aims to study the effects of trimetazidine alone or associated with phenobarbital on seizure model induced by pilocarpine and determine their effects on neurodegeneration involved in the pathophysiology of this disease. The animals (adult male Swiss mice, 20-30g) were injected with trimetazidine (5, 10 and 20 mg / kg, ip), phenobarbital (10 and 30 mg / kg, ip), clonazepam (0.5 mg / kg ip) or saline - 0.9% NaCl ip for seven days. 60 minutes after the last injection of vehicle or drug under study was administered at a dose pilocarpine 400 mg / kg, ip or 320 mg / kg, i.p. after the animals were subjected to behavioral tests and were then sacrificed and their brains dissected for neurochemical analysis performance. TMZ administration reduced the number of deaths at all doses tested, but the highest dose (20 mg / kg) showed better effect, increased the latency of seizures in 41% (11.76 ± 0.75) compared to control ( 8.36 ± 0.41) led to absence seizures in 10% of animals, reduced the occurrence of status epilepticus in 10% and 29% of animals protected from death. There was an increase of MDA concentration in the hippocampus of animals treated with pilocarpine (Control = 98.8 ± 5.5, 336.5 ± 25.2 = PILO), this effect was partially reversed by pretreatment with the TMZ Doses of 10 and 20 mg / kg (TMZ5 = 284.6 ± 19.7; TMZ10 = 171.3 ± 20.1; TMZ20 = 175.3 ± 20.1). The combination of TMZ at the lowest dose (5 mg / kg) with anticonvulsant dose of sub-PHE (10 mg / kg) caused a reduction in the levels of MDA by 48% (TMZ5 FEN10 + = 174.6 ± 23.0) when compared with the control group. Similar results were observed with the determination of the concentrations of nitrite / nitrate. Also, the TMZ was able to reverse the changes produced by pilocarpine in the levels of glutamate and GABA. The results of this study suggest that trimetazidine possesses anticonvulsant activity in the model of pilocarpine-induced seizures in mice, possibly due to its modulatory action on calcium channels