Alpha lipoic acid ameliorates motor deficits by inhibiting ferroptosis in Parkinson’s disease

•Alpha lipoic acid (ALA) ameliorates MPTP-induced motor deficits in mice.•ALA decreases iron levels by upregulating FTH1 and downregulating DMT1.•ALA prevents ferroptosis effectively by inhibiting the downregulation of glutathione peroxidase 4 (GPX4) and cysteine/glutamate transporter (xCT) in PD.•M...

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Published in:Neuroscience letters 2023-07, Vol.810, p.137346-137346, Article 137346
Main Authors: Zheng, Qian, Ma, Pengfei, Yang, Pan, Zhai, Suzhen, He, Meina, Zhang, Xiangming, Tu, Qiuxia, Jiao, Ling, Ye, Lan, Feng, Zhanhui, Zhang, Chunlin
Format: Article
Language:English
Subjects:
Alpha lipoic acid
Animals
Ferroptosis
Iron
Iron Chelating Agents
Neurodegenerative Diseases
NF-E2-Related Factor 2
NRF2
Parkinson Disease - drug therapy
Parkinson's disease
SIRT1
Sirtuin 1
Thioctic Acid - pharmacology
Thioctic Acid - therapeutic use
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Summary:•Alpha lipoic acid (ALA) ameliorates MPTP-induced motor deficits in mice.•ALA decreases iron levels by upregulating FTH1 and downregulating DMT1.•ALA prevents ferroptosis effectively by inhibiting the downregulation of glutathione peroxidase 4 (GPX4) and cysteine/glutamate transporter (xCT) in PD.•Mechanistic study indicates that the activation of SIRT1/NRF2 pathway is involved the upregulation effect of GPX4 and FTH1. Parkinson’s disease (PD) is a neurodegenerative disease. Ferroptosis shares several features with PD pathophysiology, and anti-ferroptosis molecules are neuroprotective in PD animal models. As an antioxidant and iron chelating agent, alpha lipoic acid (ALA) has a neuroprotective effect on PD; however, the influence of ALA on ferroptosis in PD remains unclear. This study aimed to determine the mechanism of ALA in regulating ferroptosis in PD models. Results showed that ALA could ameliorate motor deficits in PD models and regulate iron metabolism by upregulating ferroportin (FPN) and ferritin heavy chain 1 (FTH1) and downregulating iron importer divalent metal transporter 1 (DMT1). Moreover, ALA decreased the accumulation of reactive oxygen species (ROS) and lipid peroxidation, rescued mitochondrial damage, and prevented ferroptosis effectively by inhibiting the downregulation of glutathione peroxidase 4 (GPX4) and cysteine/glutamate transporter (xCT) in PD. Mechanistic study indicated that the activation of SIRT1/NRF2 pathway was involved in the upregulation effect of GPX4 and FTH1. Thus, ALA ameliorates motor deficits in PD models by regulating iron metabolism and mitigating ferroptosis through the SIRT1/NRF2 signaling pathway.
ISSN:0304-3940
1872-7972
DOI:10.1016/j.neulet.2023.137346