Oleanolic acid acrylate elicits antidepressant-like effect mediated by 5-HT1A receptor.

The development of new drugs for the treatment of depression is strategic to achieving clinical needs of patients. This study evaluates antidepressant-like effect and neural mechanisms of four oleanolic acid derivatives i.e. acrylate (D1), methacrylate (D2), methyl fumarate (D3) and ethyl fumarate (D4). All derivatives were obtained by simple one-step esterification of oleanolic acid prior to pharmacological screening in the forced swimming (FS) and open field (OF) tests. Pharmacological tools like α-methyl-p-tyrosine (AMPT, catecholamine depletor), p-chlorophenylalanine (serotonin depletor), prazosin (PRAZ, selective α1-receptor antagonist), WAY-100635 (selective serotonin 5-HT1A receptor antagonist) as well as monoamine oxidase (MAO) and functional binding assays were conducted to investigate possible neural mechanisms. In the FS test, D1 showed the most promising antidepressant-like effect without eliciting locomotor incoordination. Unlike group of mice pretreated with AMPT 100 mg/kg, PCPA 100 mg/kg or PRAZ 1 mg/kg, the effect of D1 was attenuated by WAY-100635 0.3 mg/kg pretreatment. D1 demonstrated moderate inhibition of MAO-A (IC50 = 48.848 ± 1.935 µM), potency (pEC50 = 6.1 ± 0.1) and intrinsic activity (E max = 26 ± 2.0%) on 5-HT1A receptor. In conclusion, our findings showed antidepressant-like effect of D1 and possible involvement of 5-HT1A receptor.

Plurality of anxiety and depression alteration mechanism by oleanolic acid.

Our study sought to evaluate the anxiolytic and antidepressant activities of oleanolic acid as well as the neural mechanisms involved. Animal models such as barbiturate sleep-induction, light-dark box, elevated plus maze, forced swimming test, tail suspension test and open field test were conducted. Male Albino Swiss mice were treated orally with vehicle 10 mL/kg, fluoxetine 20 mg/kg, imipramine 15 mg/kg, diazepam 1 mg/kg or oleanolic acid 5-40 mg/kg. Pretreatment (intraperitoneal) of animals with pentylenetetrazole (PTZ) 20 mg/kg, 1-(2-methoxyphenyl)-4-[4- (2-phthalimido) butyl]piperazine hydrobromide (NAN-190) 0.5 mg/kg, p-chlorophenylalanine methyl ester (PCPA) 100 mg/kg or α-methyl-p-tyrosine (AMPT) 100 mg/kg, WAY100635 (WAY) 0.3 mg/kg, prazosin (PRAZ) 1 mg/kg, yohimbine 2 mg/kg as well as monoamine oxidase assay and hippocampal brain-derived neurotrophic factor (BDNF) quantification were carried out. Oleanolic acid potentiated the hypnotic effect of barbiturate and demonstrated an anxiolytic effect in both the light-dark box and elevated plus maze. This effect was not reversed by PTZ. Acute and/or chronic oral treatment of mice with oleanolic acid (5-20 mg/kg) elicited an antidepressant effect in the forced swimming test and the tail suspension test without interfering with the locomotor activity. The antidepressant effect of oleanolic acid was attenuated by NAN-190, AMPT, PCPA, WAY and PRAZ. Although monoamine oxidase activity remained unaltered by oleanolic acid, chronic administration of oleanolic acid augmented hippocampal BDNF level. These findings demonstrate multiple mechanisms of the anxiolytic and antidepressant effect of oleanolic acid.