ABSTRACT
Indole alkaloids are the main bioactive molecules of the Gelsemium genus plants. Diverse reports have shown the beneficial actions of Gelsemium alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, Gelsemium alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of Gelsemium alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABAA receptors (GABAARs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between Gelsemium alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC50 of 31.5 ± 1.7 and 40.6 ± 8.2 µM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABAARs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major Gelsemium indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.
Subject(s)
Alkaloids , Gelsemium , Animals , Gelsemium/chemistry , Alkaloids/chemistry , Plant Extracts/chemistry , Indole Alkaloids/chemistry , gamma-Aminobutyric Acid , Mammals/metabolismABSTRACT
A COVID-19 é uma doença multifatorial infecciosa causada pela SARS-COV-2, cepa advinda de uma ampla família de vírus, que podem causar desde um resfriado comum até doenças mais graves, como síndrome respiratória aguda grave (SRAG). Reportada primariamente em Wuang, na China, no ano de 2019, esta doença foi declarada pandemia pela Organização Mundial de Saúde (OMS) no ano seguinte. A manifestação da doença pode variar de pessoas assintomáticas, a casos leves, moderados e graves. Por na época ser uma doença com alta transmissibilidade, virulência e mortalidade, as organizações de saúde se esforçaram para criar o mais rápido possível vacinas para evitar as formas mais graves desta patologia. Em contrapartida, os praticantes da homeopatia hahnemanniana focaram em pesquisar medicamentos homeopáticos para curar e prevenir, por meio do "gênio epidêmico", ou seja, conforme o conjunto de sinais e sintomas peculiares à doença coletiva. Diversos medicamentos foram considerados para prevenir e tratar a COVID-19, com resultados positivos em sua maioria. No entanto, há ainda a necessidade de realizar estudos com uma qualidade metodológica mais rigorosa para se obter evidências científicas melhores.
COVID-19 is a multifactorial infectious disease caused by SARS-CoV-2, a strain derived from a broad family of viruses that can cause anything from the common cold to more severe diseases, such as severe acute respiratory syndrome (SARS). Initially reported in Wuhan, China, in 2019, this disease was declared a pandemic by the World Health Organisation (WHO) the following year. The manifestation of the disease can vary from asymptomatic individuals to mild, moderate, and severe cases. At the time, as it was a disease with high transmissibility, virulence, and mortality, health organisations made efforts to create vaccines as quickly as possible to prevent the more severe forms of this pathology. In contrast, practitioners of Hahnemannian homeopathy focused on researching homeopathic remedies to cure and prevent it through the "epidemic genius", which means according to the set of peculiar signs and symptoms of the collective disease. Various remedies were considered to prevent and treat COVID-19, with mostly positive results. However, there is still a need to conduct studies with more rigorous methodological quality to obtain better scientific evidence.