Background Epileptogenesis can be defined as the process by which a previously healthy brain develops a tendency toward recurrent electrical activity, occurring in three phases: first as an initial trigger (such as stroke, infections, and traumatic brain injury); followed by the latency period and the onset of spontaneous and recurrent seizures which characterizes epilepsy. Main body The mechanisms that may be involved in epileptogenesis are inflammation, neurogenesis, migration of neurons to different regions of the brain, neural reorganization, and neuroplasticity.In recent years, experimental studies have enabled the discovery of several mechanisms involved in the process of epileptogenesis, mainly neuroinflammation, that involves the activation of glial cells and an increase in specific inflammatory mediators. The lack of an experimental animal model protocol for epileptogenic compounds contributes to the difficulty in understanding disease development and the creation of new drugs. Conclusion To solve these difficulties, a new approach is needed in the development of new AEDs that focus on the process of epileptogenesis and the consolidation of animal models for studies of antiepileptogenic compounds, aiming to reach the clinical phases of the study. Some examples of these compounds are rapamycin, which inhibits mTOR signaling, and losartan, that potentiates the antiepileptogenic effect of some AEDs. Based on this, this review discusses the main mechanisms involved in epileptogenesis, as well as its pharmacological approach.
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, Polybia occidentalis, 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 synthesis of an identical analog 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 ED50 and therapeutic index (TI) 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 Status epilepticus (SE). After determination of 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 across de 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 behavior were not adversely affected, and a potential neuroprotective effect was observed. Occidentalin-1202 can be a potent blocker of 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.
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