Serotonin mitigates depression in a rotenone-induced mouse Parkinson’s disease model by inhibiting hippocampal neuronal pyroptosis and neuroinflammation

Abstract

Depression in Parkinson’s disease (dPD) is a prevalent comorbidity significantly impairing patients’ quality of life. Emerging evidence highlights the pivotal role of neuroinflammation in dPD pathogenesis, particularly the interaction between neuronal pyroptosis and microglial polarization. Serotonin (5-hydroxytryptamine, 5-HT) has been implicated in mood regulation and neuroinflammatory processes, yet its role in modulating pyroptosis and microglial polarization remains unclear. Therefore, this study aimed to investigate neuronal pyroptosis and microglial polarization in dPD pathogenesis and explore the regulation of 5-HT on these processes. A C57BL/6 mouse model of dPD was established using injected intraperitoneally of rotenone to observe changes in body weight, sucrose preference, and exercise time. ELISA and Western blotting were used to detect the expression of relevant proteins and cytokines in the hippocampus. Co-culture experiments with HT22 and BV2 cells were conducted to explore the effect of 5-HT on neuronal pyroptosis and microglial polarization. Rotenone-induced dPD in mice led to reduced body weight, sucrose preference, and activity, accompanied by upregulation of pyroptosis markers (NLRP1, N-GSDMD, Cleaved-caspase-1) and increased M1 microglial polarization. Treatment with 5-HT and the pyroptosis inhibitor Pep19–2.5 reversed these changes, mitigating neuronal pyroptosis and shifting microglial polarization towards a less inflammatory profile. In vitro, 5-HTP suppressed LPS-induced neuronal pyroptosis, reducing TNF-α, IL-1β, IL-18 levels and oxidative stress while preserving microglial viability. The 5-HT inhibitor Scopolamine abolished these effects. Neuronal pyroptosis and M1 microglial polarization contribute critically to dPD pathogenesis. By inhibiting these processes, 5-HT emerges as a promising therapeutic target for managing dPD, offering new insights into its treatment mechanisms.