Mechanism analysis of MPTP-induced Parkinson's disease-like pathology via the HPA axis–microglial glucocorticoid receptor pathway

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxicant widely used to model Parkinson's disease (PD). However, the mechanisms by which MPTP induces neuroinflammation and dopaminergic (DA) degeneration via the hypothalamic-pituitary-adrenal (HPA) axis remain incompletely understood. In this study, we established a mouse model of MPTP-induced neurotoxicity to investigate the associated pathological changes and underlying mechanisms. Behavioral assessments, Nissl staining, immunofluorescence, immunohistochemistry, ELISA, and Western blotting were employed. MPTP exposure significantly impaired motor coordination, reduced neuronal viability, and led to the loss of tyrosine hydroxylase (TH)-positive DA neurons in the substantia nigra (SN). MPTP also activated the HPA axis, as evidenced by elevated levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), their respective receptors (CRHR, ACTHR), and glucocorticoids (GCs), along with reduced glucocorticoid receptor (GR) expression. Furthermore, MPTP promoted microglial activation and microglia-mediated neuroinflammation, characterized by upregulated expression of iNOS, TNF-α, IL-1β, and IL-6, and downregulated expression of Arg-1 and IL-10. Electroacupuncture (EA) intervention reversed these pathological changes. Notably, pharmacological activation of the HPA axis with Urocortin III counteracted the protective effects of EA, resulting in renewed DA neuron loss, reduced microglial GR expression, and exacerbated neuroinflammation. In summary, MPTP-induced PD is accompanied by HPA axis overactivation and downregulation of microglial GR signaling, suggesting that this pathway contributes to MPTP neurotoxicity. EA reversed these pathological changes. These findings provide new insights into the pathogenesis of environmental neurotoxin-induced PD.