Effects of Exercise Training on Nigrostriatal Glutamatergic Pathway and Receptors Interactions in Parkinson's Disease: A Systematic Review

Shahid Ishaq ¹ Iqbal Ali Shah ¹ Shin-Da Lee ^1* Bor-Tsang Wu ^2*

• ¹ PhD program in Healthcare Science, China Medical University, Taichung, Taiwan, Taichung, Taiwan
• ² National Taichung University of Science and Technology, Taichung, Taiwan

Background: Glutamatergic neuron's excitatory imbalance due to insufficient input from the dopaminergic neurons increases the pathogenesis of Parkinson's disease and exercise training is one of the non-pharmacological and non-invasive therapeutic approaches. Objective: This systematic review is the first to summarize the effects of exercise training on the regulation of protein and gene expressions within the nigrostriatal glutamatergic pathway and their receptor interactions in Parkinson's disease (PD) animal models. Methodology: PubMed, Web of Science, and EMBASE electronic databases were searched, 9/96 studies adhering to the PRISMA guidelines were included, and CAMARADES scored 4-6 out of 10. The included studies utilized pharmacologically induced PD models in mice or rats with MPTP or 6-OHDA. Most studies (89%) employed treadmill training, while 11% used voluntary wheel running, with protocols 5 days per week for 4 weeks. Results: Exercise training reduced extracellular Glu and increased the expression of GLT-1, GS, Gln, and mGluR2/3 and downregulated VGULT1 in the presynaptic terminal of glutamatergic neurons within the nigrostriatum of PD animal models. It also downregulated mGluR5 and modulated AMPA receptor subunits: GluA1 was downregulated, inhibiting longterm potentiation, while GluA2 and GluA3 were upregulated within the nigrostriatum of the PD animal model. Additionally, exercise training downregulated NMDA receptors, Arc, Cav1.3, CaMKII, and p-CaMKII in the nigrostriatum of the PD animal model. Conclusion: Exercise training exerted a neuroprotective effect on the glutamatergic pathway in Parkinson's disease (PD) animal models by limiting excess glutamate in the synaptic cleft. Exercise training modulated the ionotropic receptors and limited the glutamatergic excitatory imbalance within the nigrostriatum of PD. It also improved motor function, including balance, coordination, and gait parameters.