Effects of exercise training on nigrostriatal neuroprotection in Parkinson's disease: a systematic review

Abstract

Introduction: Parkinson's disease (PD) is characterized by progressive neurodegeneration within the nigrostriatum, leading to motor dysfunction. This systematic review aimed to summarize the effects of various exercise training regimens on protein or gene expression within the nigrostriatum and their role in neuroprotection and motor function improvement in animal models of Parkinson's disease (PD).

Methods: PubMed, EMBASE, and Web of Science were searched up to June 2024 and included sixteen studies that adhere to PRISMA guidelines and CAMARADES checklist scores ranging from 4 to 6 out of 10. Various exercise training regimens, administered 5 days per week for 6.5 weeks, were applied to MPTP, 6-OHDA, and PFF-α-synuclein-induced PD animal models.

Results: Exercise training was found to downregulate the inflammatory pathway by attenuating α-synuclein aggregation, inhibiting the TLR/MyD88/IκBα signaling cascade and NF-κB phosphorylation, and decreasing pro-inflammatory cytokines IL-1β and TNF-α while increasing anti-inflammatory cytokines IL-10 and TGF-β within the nigrostriatum. It also inhibited the ASC and NLRP3 inflammasome complex and reduced the BAX/ Bcl-2 ratio and caspase-1/3 proteins, thereby decreasing neuronal apoptosis in the nigrostriatum. Exercise training elevated the expression of Pro-BDNF, BDNF, GDNF, TrkB, and Erk1/2, providing neurotrophic support to dopaminergic neurons. Furthermore, it upregulated the dopaminergic signaling pathway by increasing the expression of TH, DAT, PSD-95, and synaptophysin in the nigrostriatum.

Discussion: The findings suggested that exercise training downregulated inflammatory and apoptotic pathways while upregulated BDNF/GDNF pathways and dopaminergic signaling within the nigrostriatum. These molecular changes contributed to neuroprotection, reduced dopaminergic neuron loss, and improved motor function in PD animal models.

Systematic review registration: CRD42024484537 https://www.crd.york.ac.uk/prospero/#recordDetails.

Keywords: Parkinson’s disease; exercise training; neuroprotection; nigrostriatum; treadmill training.

Figure 1

PRISMA flow diagram for selection methodology.

Figure 2

Hypothetical pathway regulated by exercise training for nigrostriatal (NS) neuronal protection. (A) Toll-like receptor (TLR) & binding protein Myeloid Differentiation Primary Response 88 (MYD88), Bone Marrow Tyrosine Kinase in Chromosome X (BMX) protein, Tumor Necrosis Factor Receptor Associated Factor 6 (TRAF6), TGF-beta Activated Kinase 1 (TAK-1), an Inhibitor of Kappa B alpha (IκBα), Protein 65 (P 65), a subunit of, Nuclear Factor kappa B (NF-kB), inducible Nitric Oxide Synthase (iNOS), Interleukin 1 Beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α), surface marker Cluster of Differentiation 11c/b (CD-11c/b), and Ionized Calcium-Binding Adapter Molecule 1 (Iba-1), Glial Fibrillary Acidic Protein (GFAP). Anti-inflammatory markers include Interleukin 10 (IL-10) and Transforming Growth Factor beta (TGF-β). (B) NOD-like receptor family, pyrin domain containing 3 (NLRP3) and Apoptosis-associated Speck-Like Protein (ASC), Nicotinamide Adenine Dinucleotide Phosphate (NADPH). Bcl-2 Associated X Protein (BAX), and B-cell Lymphoma 2 (Bcl-2). (C) Brain-Derived Neurotrophic Factor (BDNF), Tropomyosin Receptor Kinase B (TrkB), Glial Cell Line-Derived Neurotrophic Factor (GDNF), Extracellular Signal-Regulated Kinases 1 and 2 (Erk1/2), Mitogen-Activated Protein Kinase (MAPK), and cAMP Response Element-Binding Protein (CREB). Tyrosine Hydroxylase (TH), (D) Dopamine Transporter (DAT), Dopamine Level (DA), Dopamine Receptors (DARs), Synaptophysin (Syp), and Postsynaptic Density Protein 95 (PSD-95),