Natural product-derived therapies for treating drug-resistant epilepsies: From ethnopharmacology to evidence-based medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Epilepsy is one of the most prevalent neurological human diseases, affecting 1% of the population in all age groups. Despite the availability of over 25 anti-seizure medications (ASMs), which are approved in most industrialized countries, approximately 30% of epilepsy patients still experience seizures that are resistant to these drugs. Since ASMs target only limited number of neurochemical mechanisms, drug-resistant epilepsy (DRE) is not only an unmet medical need, but also a formidable challenge in drug discovery. AIM: In this review, we examine recently approved epilepsy drugs based on natural product (NP) such as cannabidiol (CBD) and rapamycin, as well as NP-based epilepsy drug candidates still in clinical development, such as huperzine A. We also critically evaluate the therapeutic potential of botanical drugs as polytherapy or adjunct therapy specifically for DRE. METHODS: Articles related to ethnopharmacological anti-epileptic medicines and NPs in treating all forms of epilepsy were collected from PubMed and Scopus using keywords related to epilepsy, DRE, herbal medicines, and NPs. The database clinicaltrials.gov was used to find ongoing, terminated and planned clinical trials using herbal medicines or NPs in epilepsy treatment. RESULTS: A comprehensive review on anti-epileptic herbal drugs and natural products from the ethnomedical literature is provided. We discuss the ethnomedical context of recently approved drugs and drug candidates derived from NPs, including CBD, rapamycin, and huperzine A. Recently published studies on natural products with preclinical efficacy in animal models of DRE are summarized. Moreover, we highlight that natural products capable of pharmacologically activating the vagus nerve (VN), such as CBD, may be therapeutically useful to treat DRE. CONCLUSIONS: The review highlights that herbal drugs utilized in traditional medicine offer a valuable source of potential anti-epileptic drug candidates with novel mechanisms of action, and with clinical promise for the treatment of drug-resistant epilepsy (DRE). Moreover, recently developed NP-based anti-seizure medications (ASMs) indicate the translational potential of metabolites of plant, microbial, fungal and animal origin.