Esketamine relieves depressive-like behaviors in MPTP-induced Parkinson disease mice via GPR109A-dependent reduction of neuroinflammation

Background: Depression is a common complication of Parkinson disease (PD). This study investigated whether a single dose of esketamine could alleviate depressive symptoms in an MPTP mouse model by activating G protein-coupled receptor 109 A (GPR109A) and reducing neuroinflammation.

Methods: Adult male C57BL/6 J mice (8 weeks, 25–30 g) were allocated into three groups: saline, Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and MPTP plus esketamine. To elucidate the specific functional contribution of GPR109A signaling to esketamine’s effects, the selective GPR109A antagonist mepenzolate bromide (MPN) was administered. Depressive-like behaviors were evaluated using the tail suspension test (TST) and forced swim test (FST) for assessing behavioral despair, and the sucrose preference test (SPT) for measuring anhedonia. Western blot analysis was employed to quantify protein expression levels of GPR109A, Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 beta (IL-1β), and Interleukin-6 (IL-6). The presence of GPR109A in microglia was also evaluated using immunofluorescence and flow cytometry.

Results: A single injection of esketamine elicited a rapid improvement in the behavior of MPTP-treated mice, accompanied by increased GPR109A expression in the medial prefrontal cortex (mPFC) and reduced pro-inflammatory markers. However, co-administration of MPN negated these benefits, suggesting that intact GPR109A signalling is involved in the antidepressant-like and anti-inflammatory effects of esketamine.

Conclusions: Esketamine alleviates PD-related depressive-like behavior by suppressing microglial inflammation in the mPFC via GPR109A. These findings emphasise the importance of GPR109A in linking immune modulation to the rapid behavioral effects of esketamine, and indicate the need for further research into GPR109A-targeted treatments for PD-related depression.