Abstract
[Purpose]We investigated whether treadmill exercise (TE)-induced neuroprotection was associated with enhanced autophagy and reduced apoptosis in a mouse model of pharmacologically induced Parkinson's disease (PD).[Methods]PD was induced via the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). C57BL/6 male mice were randomly assigned to the following three groups: control (C57BL, n=10), MPTP with probenecid (MPTP/C, n=10), and MPTP/ C plus exercise (MPTP-TE, n=10). The MPTP-TE mice performed TE training (10 m/min, 60 min/day, 5 days/week) for 8 weeks. The rotarod test was used to assess motor function.[Results]TE restored MPTP/P-induced motor dysfunctionand increased tyrosine hydroxylase levels. Furthermore, TE diminished the levels of α-synuclein (α-syn), a neurotoxin; modulated the levels of autophagy-associated proteins, including microtubule-associated protein 1 light chain 3-II, p62, BECLIN1, BNIP3, and lysosomal-associated membrane protein-2, which enhanced autophagy; inhibited the activation of proapoptotic proteins (caspase-3 and BAX);and upregulated BCL-2, an antiapoptosis protein.[Conclusion]Taken together, these results suggested that the TE-induced neuroprotection against MPTP-induced cell death was associated with enhanced autophagy and neuronal regeneration based on the findings of inhibited proapoptotic events in the brains of the TE-trained animals.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor dysfunction, including bradykinesia, tremor, rigidity, and postural instability[2] The main cause of PD is the progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta (SNpc) and the accumulation of Lewy bodies, which are primarily composed of alpha-synuclein (α-syn) proteins
We examined the expression of lysosomal-associated membrane protein-2 (LAMP2), which is a lysosomal biosynthesis marker
The present results demonstrated that treadmill exercise (TE) restored motor function and preventedthe dopaminergic neuronal loss in the SNpc caused by pharmacologicallyinduced PD
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor dysfunction, including bradykinesia, tremor, rigidity, and postural instability[2] The main cause of PD is the progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta (SNpc) and the accumulation of Lewy bodies, which are primarily composed of alpha-synuclein (α-syn) proteins. Normal α-syn functions are necessary for neurotransmission, dopamine metabolism, and synaptic vesicle release[3] the aberrant aggregation of α-syn contribute to mitochondrial dysfunction and cellular oxidative stress, which triggers neuronal death in PD4-5. The exact mechanisms of PD remain unclear, recent studies have suggested that autophagy plays a crucial role in the pathogenesis and progression of the neurodegenerative disease[6]. Because autophagy plays a key role in the elimination of abnormal α-syn proteins[8], autophagy interference contributes to the neuronal cell death resulting from α-syn-induced toxicity in dopaminergic neurons in PD7. Given that basal levels of autophagy must be maintained for proper brain function and that impaired autophagy contributes to the progression of PD, positive modulations of autophagy mightserve as potential therapeutic strategiesfor PD
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