Estudo dos mecanismos associados ao efeito tipo antidepressivo dos polifenóis hesperidina e mangiferina em camundongos

Abstract

Depressive disorder is one of the most prevalent of serious mental disorders that contribute to a significant portion of illness-related disability across the world. Considering the promising pharmacological properties of polyphenols, this study aims the investigation the antidepressant-like effect of polyphenols hesperidin and mangiferin, as well as the mechanisms involved in this effect in mice. The following results were obtained: (i) hesperidin and hesperetin produced similar antidepressant-like effect in tail suspension test (TST) in chronic treatment. Besides, the pretreatement with L-arginine, sildenafil or with SNAP were able to reverse the antidepressant-like effect of hesperidin in the TST. A subeffective dose of L-NNA, 7-NI, MB, or ODQ in combination with subeffective dose of hesperidin produced an antidepressant-like effect. Further, nitrate/nitrite levels decreased in the hippocampus in acute and chronic treatments with hesperidin. Chronic treatment with hesperidin increased in the levels hippocampal brain-derived neurotrophic factor. The hesperidin inhibited L-arginine-NO-cGMP pathway; (ii) the administration of TEA, glibenclamide, charybdotoxin, or apamin combined with a subeffective dose of hesperidin were able to produce a synergistic antidepressant-like effect in TST. Moreover, the antidepressant-like effect elicited by an effective dose of hesperidin in TST was abolished by the treatment with cromakalim or minoxidil. These results suggest that the antidepressant-like effect of hesperidin in TST may involve, at least in part, the modulation of neuronal excitability through inhibition of K+ channels and may act through a mechanism dependent on the inhibition of L-arginine-NO pathway; (iii) mangiferin produced an antidepressant-like effect in the forced swimming test (FST) and TST. Pretreatment with PCPA completely abolished the antidepressant-like effect induced by mangiferin. Pretreatment with WAY100635, but not with SB 224289, ritanserin, MDL 72222, GR 125487 or SB 269970 prevented the antidepressant-like effect of mangiferin in the TST. Combined treatment of mangiferin with paroxetine or sertraline demonstrated antidepressant-like effect. Also increased the hippocampal 5-HT levels, whereas 5-HIAA levels decreased in the cerebral cortex. The ratio of 5-HIAA/5-HT reduced significantly in the hippocampus and in cerebral cortex. Furthermore, mangiferin inhibited significantly synaptosomal [3H] 5-HT uptake. Taken together, mangiferin demonstrated that the antidepressant-like effect was mediated by 5-HT1A receptors, probably due to alterations in the modulation of serotonergic system, decreasing the 5-HT turnover and blocking 5-HT reuptake; (iv) pretreatment with sulpiride, but not with SCH23390 or haloperidol prevented the antidepressant-like effect of mangiferin in the TST. A combinatory antidepressant-like effect in co-administration of subeffective doses of mangiferin vii

with apomorphine, but not with SKF 38393. Synergistic antidepressant-like effect of the combined administration of a subeffective doses of bupropion with mangiferin. In addition, tendency to increase the dopamine levels, associated with a decrease in DOPAC and HVA levels in the cerebral cortex, hippocampus and striatum, while significant reductions, were only observed in levels of DOPAC metabolite in the hippocampus. We also found a significant decrease in the dopamine turnover in the hippocampus and striatum. These results indicate that antidepressant-like the effect of mangiferin depends of the dopaminergic system modulation, mediated by dopamine D2 receptors. Therefore, altogether the results suggest that these polyphenols may be a novel therapeutic strategy for the treatment of depression, as well as its association with conventional antidepressants, which could be used to reduce the dose of these drugs.