Computer-Aided Identification of Anticonvulsant Effect of Natural Nonnutritive Sweeteners Stevioside and Rebaudioside A.

Steviol glycosides are natural constituents of Stevia rebaudiana (Bert.) Bert. (Asteraceae) that have recently gained worldwide approval as nonnutritive sweeteners by the Joint Food and Agriculture Organization/World Organization Expert Committee on Food Additives. Cheminformatic tools suggested that the aglycone steviol and several of its phase I metabolites were predicted as potential anticonvulsant agents effective in the seizure animal model maximal electroshock seizure (MES) test. Thus, aqueous infusion from S. rebaudiana was tested in the MES test (mice, intraperitoneal administration), confirming dose-dependent anticonvulsant effect. Afterward, isolated stevioside and rebaudioside A were tested in the MES test, with positive results. Though drug repositioning most often focuses on known therapeutics, this article illustrates the possibilities of this strategy to find new functionalities and therapeutic indications for food constituents and natural products.

Is there a relationship between sweet taste and seizures? Anticonvulsant and proconvulsant effects of non-nutritive sweeteners.

From a virtual screening campaign, a number of artificial and natural sweeteners were predicted as potential anticonvulsant agents with protective effects in the seizure animal model Maximal Electroshock Seizure (MES) test. In all cases, the predictions were experimentally confirmed in the aforementioned preclinical seizure model. The article reviews and expands previous reports from our group on anticonvulsant activity of those non-nutritive sweeteners, illustrating the potential of virtual screening approaches to propose new medical uses of food additives. This constitutes a particular case of knowledge-based drug repositioning, which may greatly shorten the development time and investment required to introduce novel medications to the pharmaceutical market. We also briefly overview evidence on possible molecular explanations on the anticonvulsant and proconvulsant effects of different non-nutritive sweeteners. Our analysis -based on Swanson's ABC model- suggests that group I metabotropic glutamate receptors and carbonic anhydrase isoform VII (both proposed or validated molecular targets of antiepileptic drugs) might be involved in the anticonvulsant effect of artificial sweeteners. The first hypothesis is in line with recent advances on development of selective modulators of group I metabotropic glutamate receptors as potential antiepileptic agents.

Antispasmodic effects of Aloysia polystachya and A. gratissima tinctures and extracts are due to non-competitive inhibition of intestinal contractility induced by acethylcholine and calcium

The antispasmodic effects of acqueous extracts (AE) and tinctures (T) of Aloysia polystachya (Griseb.) Moldenke and Aloysia gratissima (Gillies & Hook.) Tronc., Verbenaceae, were studied on rat isolated ileum and duodenum. These plants are used for gastrointestinal disorders and as eupeptic in South America. Both AE non-competitively inhibited the dose-response curves (DRC) of ACh and the DRC of Ca2+ in high-[K+]o, as well as the T. The T of A. polystachya and A. gratissima respectively inhibited the ACh-DRC at the IC50 of 3.15±0.57 and 6.46±2.28 mg leaves/mL. The Ca2+- antagonist activity of both T occurred with IC50 respectively similar to those of the ACh-DRC, and was potentiated by the depolarization produced by 10 mM TEA, a blocker of K+- channels. The spasmolytic effect of T does not involve DA release and binding to D2, since it was not reduced by 10 µ M metoclopramide. Also, T induced dose-dependent relaxation on the tonic contracture produced by high -[K+]o and ACh. By TLC there were detected in the leaves the presence of carvone, and flavonoids such as quercetin and hesperidin. By HPLC there were not found vitexin nor isovitexin, identified in A. citriodora. The monoterpene (-)- carvone non-competitively inhibited the ACh-DRC (pD'2 of 4.0±0.1) and the DRC of Ca2+ (pD'2 of 3.86±0.19), suggesting that the Ca2+- influx blockade is the mechanism of its antispasmodic effect. Results suggest that the antispasmodic effect of A. polystachya and A. gratissima are mostly explained by the non-competitive blockade of Ca+2 influx. It could be associated to the presence of flavonoids, and in the tinctures to some spasmolytic components of the essential oil such as carvone.

Anti-inflammatory activity of Heterotheca subaxillaris var. latifolia (Buckley) Gandhi & R.D. Thomas, Asteraceae

The anti-inflammatory activity of the petroleum ether, dichloromethane and methanol extracts from Heterotheca subaxillaris var. latifolia were assayed using 12-O-tetradecanoyl phorbol acetate (TPA) induced ear edema test in mice and carrageenan-induced paw edema test in rats. The dichloromethane extract showed a significant anti-inflammatory activity (91 percent of inhibition) in TPA-induced ear edema test (topical administration at 1 mg/ear). No effects were seen on carragenan-induced edema. Bio-guided fractionation deal to the isolation of the major flavonoids santin, pectolinaringenin, 3,6-dimethoxy-5,7,4'-trihydroxyflavone and hispidulin present in the active fractions.

A atividade antiinflamatória de extratos éter petróleo, diclorometânico e metanólico de Heterotheca subaxillaris var. latifolia, foi testada pelo método de edema induzido pelo 12-O-tetradecanoil phorbol acetato (TPA) na orelha do camundongos e pelo método do edema de pata induzido por carragenina em ratos. O extrato diclorometânico mostrou atividade antiinflamatória significativa (91 por cento inibição) no edema de orelha induzido por TPA (administração tópica de 1 mg/orelha). Não houve efeitos significativos no teste do edema induzido pela carragenina. O fracionamento bioguiado das frações ativas levou ao isolamento dos flavonoides majoritários santina, pectolinaringenina, 3,6-dimetoxi-5, 7,4 '-trihidroxiflavona e hispidulina.