Creatine supplementation with exercise reduces α-synuclein oligomerization and necroptosis in Parkinson's disease mouse model

MPTP公司 神经保护 内科学 内分泌学 黑质 多巴胺能 肌酸 酪氨酸羟化酶 坏死性下垂 肌酸激酶 医学 化学 生物 程序性细胞死亡 多巴胺 生物化学 细胞凋亡
作者
Yea-Hyun Leem,Jin-Sun Park,Jung Eun Park,Do‐Yeon Kim,Hee-Sun Kim
出处
期刊:Journal of Nutritional Biochemistry [Elsevier]
卷期号:: 109586-109586
标识
DOI:10.1016/j.jnutbio.2024.109586
摘要

Parkinson's disease (PD) is an incurable neurological disorder that causes typical motor deficits. In this study, we investigated the effects of creatine supplementation and exercise in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We found that 2% creatine supplementation and/or exercise intervention for 4 weeks elicited neurobehavioral recovery and neuroprotective effects regarding dopaminergic cell loss in MPTP-treated mice; this effect implies functional preservation of dopaminergic cells in the substantia nigra, as reflected by tyrosine hydroxylase expression recovery. Creatine and exercise reduced necroptotic activity in dopaminergic cells by lowering mixed lineage kinase domain-like protein (MLKL) modification to active phenotypes (phosphorylation at Ser345 and oligomerization) and phosphorylated receptor-interacting protein kinase 1 (RIPK1) (Ser166-p) and RIPK3 (Ser232-p) levels. In addition, creatine and exercise reduced the MPTP-induced increase in pathogenic α-synuclein forms, such as Ser129 phosphorylation and oligomerization. Furthermore, creatine and exercise had anti-inflammatory and antioxidative effects in MPTP mice, as evidenced by a decrease in microglia activation, NF-κB-dependent pro-inflammatory molecule expression, and increase in antioxidant enzyme expression. These phenotypic changes were associated with the exercise/creatine-induced AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) and sirtuin 3 (SIRT3)/forkhead box O3 (FoxO3a) signaling pathways. In all experiments, combining creatine with exercise resulted in considerable improvement over either treatment alone. Consequently, these findings suggest that creatine supplementation with exercise has anti-inflammatory, antioxidative, and anti-α-synucleinopathy effects, thereby reducing necroptotic cell death in a PD mouse model.
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