Two decades of research towards a potential first anti-epileptic drug

• Published in: Seizure (London, England) England), 2021-08, Vol.90, p.99-109
• Main Authors: Benassi, Simone Kastropil, Alves, Julieta Goncalves Silva Macedo, Guidoreni, Cristiane Gorgatti, Massant, Cristina Gonçalves, Queiroz, Claudio M, Garrido-Sanabria, Emilio, Loduca, Rafael Duarte de Souza, Susemihl, Maria Alice, Paiva, Wellingson Silva, de Andrade, Almir Ferreira, Teixeira, Manoel Jacobsen, Andrade, Joaquina Queiroz, Garzon, Eliana, Foresti, Maira Licia, Mello, Luiz E
• Format: Article
• Language: English
• Subjects: Biperiden; Epileptogenesis; Post-traumatic epilepsy; Scopolamine; Seizure; Status epilepticus
• ISSN: 1059-1311; 1532-2688
• DOI: 10.1016/j.seizure.2021.02.031

•Permanent or temporary blockade of the cholinergic system alters epileptogenesis.•Effects of cholinergic antagonist in different models of epilepsy.•Selective M1 cholinergic antagonist positively modify epileptogenesis.•Safety and feasibility study of biperiden to prevent post-traumatic epilepsy. The basic mechanisms by which brain insults, such as trauma, stroke or status epilepticus produce epilepsy are not completely understood, and effective preventive measures and treatment are still not available in the clinical setting. Over the last 2 decades we have conducted several studies with animal models of epilepsy (rodents and non-human primates) and demonstrated that drugs that modify neuronal plastic processes, such as anticholinergic agents (e.g., antimuscarinic compounds), if administered soon after brain injury and over a period of 10–20 days, have the potential to modify the natural course of post-traumatic epilepsy. To that end treatment with scopolamine showed promising results as a candidate agent in both the pilocarpine and kainate models. We then showed that biperiden, yet another cholinergic antagonist acting in the muscarinic receptor, that is widely used to treat Parkinson's disease, also decreased the incidence and intensity of spontaneous epileptic seizures, delaying their appearance in the pilocarpine model of epilepsy. In other words, biperiden showed to be a potential candidate to be further investigated as an antiepileptogenic agent. Accordingly, we tested the safety of biperiden in a small group of patients (as a small phase II safety assessment) and confirmed its safety in the context of traumatic brain injury (TBI). Now, we provide information on our ongoing project to evaluate the efficacy of biperiden in preventing the development of epilepsy in patients that suffered TBI, in a double blind, randomized, placebo-controlled trial.