Mortari Márcia Renata, Cunha Alexandra O S, Dos Anjos Lilian C, Amaral Henrique O, Quintanilha Maria Varela Torres, Gelfuso Erica A, Homem-de-Mello Mauricio, de Almeida Hugo, Rego Solange, Maigret Bernard, Lopes Norberto P, Dos Santos Wagner F
Neuropharmacology Laboratory, Department of Physiological Sciences, Institute of Biological Sciences, University of Brasília, Brasília 71910-900, Brazil.
Neurobiology and Venoms Laboratory, Department of Biology, Faculty of Philosophy, Sciences and Literature of Ribeirão Preto, University of São Paulo, São Paulo 14040-900, Brazil.
Brain Commun. 2023 Feb 17;5(1):fcad016. doi: 10.1093/braincomms/fcad016. eCollection 2023.
The ability of venom-derived peptides to disrupt physiological processes in mammals provides an exciting source for pharmacological development. Our research group has identified a new class of neuroactive peptides from the venom of a Brazilian social wasp, , with the potential pharmacological profile to treat epilepsies. The study was divided into five phases: Phase 1 concerned the extraction, isolation and purification of Occidentalin-1202(n) from the crude venom, followed by the synthesis of an identical analogue peptide, named Occidentalin-1202(s). In Phase 2, we described the effects of both peptides in two acute models of epilepsy-kainic acid and pentylenetetrazole-induced model of seizures-and measured estimated ED and therapeutic index values, electroencephalographic studies and C-fos evaluation. Phase 3 was a compilation of advanced tests performed with Occidentalin-1202(s) only, reporting histopathological features and its performance in the pilocarpine-induced . After the determination of the antiepileptic activity of Occidentalin-1202(s), Phase 4 consisted of evaluating its potential adverse effects, after chronic administration, on motor coordination (Rotarod) and cognitive impairment (Morris water maze) tests. Finally, in Phase 5, we proposed a mechanism of action using computational models with kainate receptors. The new peptide was able to cross the blood-brain barrier and showed potent antiseizure effects in acute (kainic acid and pentylenetetrazole) and chronic (temporal lobe epilepsy model induced by pilocarpine) models. Motor and cognitive behaviour were not adversely affected, and a potential neuroprotective effect was observed. Occidentalin-1202 can be a potent blocker of the kainate receptor, as assessed by computational analysis, preventing glutamate and kainic acid from binding to the receptor's active site. Occidentalin-1202 is a peptide with promising applicability to treat epilepsy and can be considered an interesting drug model for the development of new medicines.
源自毒液的肽破坏哺乳动物生理过程的能力为药理学发展提供了一个令人兴奋的来源。我们的研究小组从一种巴西群居黄蜂的毒液中鉴定出了一类新的神经活性肽，具有治疗癫痫的潜在药理学特性。该研究分为五个阶段：第一阶段涉及从粗毒液中提取、分离和纯化西方毒素-1202(n)，随后合成一种相同的类似肽，命名为西方毒素-1202(s)。在第二阶段，我们描述了这两种肽在两种癫痫急性模型——海藻酸和戊四氮诱导的癫痫发作模型中的作用，并测量了估计的半数有效剂量（ED）和治疗指数值、脑电图研究以及C-fos评估。第三阶段仅对西方毒素-1202(s)进行了一系列高级测试，报告了组织病理学特征及其在毛果芸香碱诱导的癫痫模型中的表现。在确定了西方毒素-1202(s)的抗癫痫活性后，第四阶段包括评估其在长期给药后对运动协调（转棒试验）和认知障碍（莫里斯水迷宫试验）的潜在不良影响。最后，在第五阶段，我们使用与海人酸受体相关的计算模型提出了一种作用机制。这种新肽能够穿过血脑屏障，并且在急性（海藻酸和戊四氮）和慢性（毛果芸香碱诱导的颞叶癫痫模型）模型中显示出强大的抗癫痫作用。运动和认知行为未受到不利影响，并且观察到了潜在的神经保护作用。通过计算分析评估，西方毒素-1202可能是海人酸受体的有效阻滞剂，可防止谷氨酸和海藻酸与受体的活性位点结合。西方毒素-1202是一种具有治疗癫痫前景的肽，可被视为开发新药的一个有趣的药物模型。
