Envolvimento dos sistemas glutamatérgico e oxidonitrérgico no efeito antidepressivo e ansiolítico do 4-alil-2,6-dimetoxifenol: uma abordagem in silico e in vivo

Abstract

Depressive and anxiety disorders are among the most common mental health conditions worldwide. Several biological mechanisms have shown an important role in the pathophysiology, as well as in the etiology and progression of MDD and anxiety. Stress is the main environmental factor that can cause hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA), an important mechanism in the response to stress. 4-ally 2,6-dimethoxyphenol (ADMP) is a phenylpropanoid that has shown high antioxidant activity in previous studies, a relevant property for antidepressant drugs since the severity of depression and anxiety disorders are correlated with the increase in markers of oxidative stress. The present study investigated the antidepressant and anxiolytic activity of ADMP in mice submitted to the model of stress induced by dexamethasone and possible routes of action. In order to investigate the pharmacological activity, studies in silico and in vivo were carried out. The ADMP showed lower binding energy for the L-arginine / NO / cGMP pathway and the NMDAR receptor, showed no toxicity in the parameters of mutagenicity, carcinogenicity, toxicity of the reproductive system, irritability of the skin tissue in the in silico study., The animals were pre-administered with dexamethasone (64μg / kg sc) 4h before conducting the behavioral tests, with ADMP (25, 50 and 100 mg / kg ip) and imipramine (10 mg / kg ip) administered 45 and 30 minutes respectively before of the tests. In in vivo studies, the administration of ADMP produced an antidepressant effect at doses of 25 and 50 mg / kg and anxiolytic at doses of 25, 50 and 100 mg / kg, without altering locomotor and exploratory activity at the dose of 50 mg / kg. In the evaluation of the possible mechanisms of action of ADMP, the forced swimming test and the dose of 50 mg / kg were chosen, the results suggest that the antidepressant activity may be dependent on the inhibition of mediators of the NMDA-L-arginine / NO / pathway. CGMP. In the evaluation of oxidative parameters, an increase in GSH levels was observed in animals submitted to treatment with ADMP at doses of 25 and 100 mg / kg compared to the group treated with dexamethasone. Then treatment with ADMP produced antidepressant and anxiolytic effects, through the involvement of the NMDA receptor and mediators of the L arginine / NO / cGMP pathway, confirming the results in silica and antioxidant activity, in which it was shown to increase GSH levels.