Aerobic Exercise Exerts Neuroprotective Effects on MPTP-Induced Parkinsons Disease Mice by Regulating the STAT3/NLRP3 Signaling Pathway

Abstract

Background: Parkinsons disease (PD) is a degenerative neurological disorder that could affect body and cognitive functions. Previous research has reported the beneficial role of exercise in the treatment of PD-linked motor defects. This study aimed to explore the role of aerobic exercise in neuroinflammation in PD and further investigated the underlying molecular mechanisms. Methods: C57BL/6 mice (n = 36) were randomly divided into the Control group (n = 12), PD group (n = 12), and PD+Aerobic exercise (P+E) group (n = 12). Using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the PD mice model was established. In the P+E group, aerobic exercise was delivered after the PD model establishment. The motor function was evaluated using rotarod and pole tests. Immunofluorescence was utilized for evaluating α-synuclein-mediated neurotoxicity and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation in MPTP-induced PD mice. Immunohistochemistry (IHC) was performed to examine glial cell activation and the loss of dopaminergic neurons in MPTP-induced PD mice. Western blot was conducted to assess the expression of the signal transducer and activator of transcription 3 (STAT3)/NLRP3 pathway and pro-inflammatory cytokines, including interleukin-18 (IL-18) and interleukin-1β (IL-1β). Fura-2/AM was used to detect the intracellular concentration of Ca²⁺ in the striatum. Results: Aerobic exercise alleviated motor deficits and decreased α-synuclein expression, a neurotoxicity protein in PD (p < 0.05). Moreover, aerobic exercise suppressed MPTP-caused glial cell activation and rescued MPTP-induced loss of dopaminergic neurons in PD mice (p < 0.05). Aerobic exercise negatively regulated the STAT3-mediated activation of NLRP3 inflammasome in MPTP-induced PD mice (p < 0.05), leading to the decreased expression of pro-inflammatory cytokines (p < 0.05). Besides, aerobic exercise in PD mice reversed the upregulated intracellular concentration of Ca²⁺ in the striatum induced by MPTP (p < 0.05). Conclusion: These findings indicate that the inhibition effects of aerobic exercise on neuroinflammation through the STAT3/NLRP3 pathway contribute to the improvement of MPTP-caused motor deficits in PD mice.