O monoterpeno hidroxicitronelal como potencial agente antiepiléptico e neuroprotetor : um estudo in sílico e in vivo

Abstract

Epilepsy is a chronic brain disorder that affects approximately 70 million people worldwide and is characterized by recurrent and spontaneous epileptic seizures. Current treatment focuses on reducing the frequency and intensity of seizures but does not provide a cure. Furthermore, due to the toxicity and high rate of refractoriness to the available medications, there is an urgent need for new drugs that are both effective and possess better safety profiles. In the literature, monoterpenes already show preliminary evidence of antiepileptic activity. Thus, the aim of this work is to evaluate the antiepileptic and neuroprotective effects of hydroxycitronellal through in silico and in vivo methodologies. To this end, molecular docking studies were conducted to assess its potential chemical interaction with key targets involved in epilepsy. Additionally, the compound’s acute oral toxicity and its LD50 were evaluated using OECD protocol no. 423 in male Swiss albino mice (25–30 g). Subsequently, to assess the possible antiepileptic and neuroprotective effects of the compound, the rodents were subjected to an acute seizure model induced by pentylenetetrazole and to the chemical kindling model. As for the results, the in silico study showed that hydroxycitronellal may interact with important pharmacological targets related to epilepsy, such as the GABAA receptor, the channels NMDA, Nav 1.6 and Cav 1.2, and the SV2A protein. The in vivo study demonstrated that the compound is not toxic when administered acutely and orally and that it exhibits antiepileptic and neuroprotective effects at doses of 200, 100, 50, 25, and 12.5 mg.kg-1. Among these, the 100 mg.kg-1 dose was identified as the most effective under the experimental conditions evaluated, while the 6.25 mg.kg-1 dose was determined as the threshold for loss of antiepileptic effect. Furthermore, the compound was able to increase the levels of reduced glutathione in the hippocampus of the animals. In the kindling model, the compound delayed epileptogenesis, increasing the latency to the first seizure and to death. Histological analysis revealed neuronal protection and a reduction in glial nodules compared to the control group. Therefore, based on this study, hydroxycitronellal emerges as a promising antiepileptic drug candidate; however, further studies are necessary to elucidate its potential pharmacological mechanism of action.