Mechanism analysis of rotenone toxic exposure inducing neurotoxicity through the MAPK/MMPs signaling pathway

Rotenone can enter the animal body directly through the skin and stomach, leading to neurotoxic effects. In this study, a mouse model of rotenone exposure was established to investigate the pathological changes and underlying mechanisms of rotenone-induced neurotoxicity. Behavioral tests, molecular biology techniques, gut microbiota analysis, and short-chain fatty acid (SCFA) content measurements were employed. The results demonstrated that rotenone exposure significantly reduced body weight, impaired motor coordination, and resulted in the loss of dopaminergic neurons (TH + ) in the substantia nigra. It also activated microglia (Iba-1 + ) and astrocytes (GFAP + ), and promoted the expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) as well as oxidative stress markers (iNOS, COX2). Furthermore, rotenone disrupted blood-brain barrier (BBB) integrity, evidenced by degradation of tight junction (TJ) proteins and Evans blue leakage, via activation of the MAPK-MMPs pathway (upregulation of p-P38 and p-JNK). Additionally, rotenone disturbed the intestinal microenvironment, manifesting as inflammatory cell infiltration, reduced SCFA levels, and gut microbiota dysbiosis. Intervention with Wuzi Yanzong Pill (WYP) reversed the aforementioned pathological alterations. This study reveals for the first time that rotenone induces Parkinson’s disease (PD)-like pathology by disrupting the gut-brain axis through the MAPK-MMPs pathway. Meanwhile, WYP exerts multi-target therapeutic effects by modulating the central-peripheral interaction network, offering novel insights into the pathogenesis and intervention strategies of PD. • Rotenone induces PD-like pathology via MAPK/MMPs activation, disrupting BBB and gut microbiota. • Gut–brain axis disruption by rotenone reduces SCFAs and promotes neuroinflammation. • WYP ameliorates motor deficits, neuron loss, and neuroinflammation via MAPK/MMP inhibition. • WYP restores BBB integrity and tight junction expression. • WYP modulates gut microbiota and SCFAs, attenuating systemic inflammation.