Avaliação do efeito do composto MPMT-OX sobre neurotransmissão e comportamento convulsivo em Caenorhabditis elegans

Abstract

Epilepsy is characterized as an increased predisposition of the brain to generate recurrent seizures, which represent the effects of abnormal, excessive and hypersynchronous electrical discharges of cortical neurons. Currently, 65 million people in the world have epilepsy. However, 33% of the patients are refractory to the available treatments, making necessary the search for new drugs. Oxadiazois are heterocyclic compounds which the general formula C2H2ON2. The 1,3,4-oxadiazole isomer is one of the most known and studied, presenting a wide range of biological activities, such as antibacterial, antiviral, antifungal and anticonvulsant. In this work the effect of 2-[(4-methoxyphenylselenyl)methylthio]-5-phenyl-1,3,4-oxadiazole (MPMT-OX) on the cholinergic and GABAergic signaling in the nematode Caenorhabditis elegans was tested. The nematodes were exposed to 0, 5, 15 and 50 μM MPMT-OX from the L1 stage to young adults. The obtained results indicate that chronic exposure to MPMT-OX increased GABAergic signaling due to the regulation of unc-25 and unc-47 genes responsible for the synthesis and release of GABA in the synaptic cleft, respectively. The increase in inhibitory signaling attenuated the paralysis induced by pentylenetetrazol (PTZ) and aldicarb, drugs that promote hyperexcitation in neuromuscular junction. MPMT-OX increased the locomotor activity of nematodes with mutations in the unc-30, unc-46 and unc-49 genes (involved in the release and response to GABA). MPMT-OX also increased latency time to the onset of PTZ-induced seizure behavior and assisted in the recovery of the locomotor activity of these nematodes after exposure to PTZ. These data suggest that MPMT-OX represents a promising pharmacological agent in the treatment of conditions where the GABAergic system could be involved.