Asiaticoside produces an antidepressant-like effect in a chronic unpredictable mild stress model of depression in mice, involving reversion of inflammation and the PKA/pCREB/BDNF signaling pathway

Abstract

Asiaticoside is one of the triterpenoid components found in Centella asiatica that has promising neuroprotective properties. The present study aimed to evaluate the antidepressant-like properties of asiaticoside and to investigate the possible mechanisms underlying its mode of action using a mouse model of chronic unpredictable mild stress (CMS). Behavioral tests, including sucrose preference test, forced swimming test and tail suspension test, were performed to evaluate symptoms of depression. The expression levels of neurotransmitters, 5-hydroxytryptamine (5-HT) and norepinephrine (NE), in the hippocampus were measured by high-performance liquid chromatography. ELISA and western blotting were used to detect protein expression. It was demonstrated that asiaticoside treatment (20 and 40 mg/kg; intragastric) significantly reversed the decrease in sucrose consumption, and reduced the immobility time in tail suspension tests and forced swimming tests in CMS mice. Furthermore, asiaticoside treatment upregulated the expression of 5-HT and NE in the CMS mouse model. Asiaticoside administration also downregulated the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-a in the hippocampus, and reduced the phosphorylation of nuclear factor (NF)-κBp65 and the expression of nod-like receptor protein 3 (NLRP3), thus decreasing the expression of mature caspase-1. Furthermore, asiaticoside significantly increased the levels of cAMP and protein kinase A (PKA), and enhanced phosphorylation of the cAMP-related specific marker vasodilator-stimulated phosphoprotein at serine 157. Therefore, asiaticoside may activate the cAMP/PKA signaling pathway to inhibit NF-κB- and NLRP3-related inflammation. Moreover, phosphorylation of the cAMP-responsive element-binding protein at serine 133 and the expression of brain-derived neurotrophic factor were increased after asiaticoside administration. Collectively, the present results suggested that asiaticoside may play a vital role as an antidepressant and anti-inflammatory agent in the CMS mouse model by regulating the cAMP/PKA signaling pathway.