Pyrroloquinoline quinone promotes mitochondrial biogenesis in rotenone-induced Parkinson's disease model via AMPK activation

• 作者: Qiong Cheng Juan Chen Hui Guo Jin-li Lu Jing Zhou Xin-yu Guo Yue Shi Yu Zhang Shu Yu Qi Zhang Fei Ding
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（5）
• 所属期刊栏目: Article Neuropharmacology
• 页码范围: 665-678
• 页数: 14页
• 语种: 英文

摘要

Mitochondrial dysfunction is considered to be one of the important pathogenesis in Parkinson's disease (PD).We previously showed that pyrroloquinoline q uinone (PQQ) could protect SH-SY5Y cells and dopaminergic neurons from cytotoxicity and prevent mitochondrial dysfunction in rotenone-induced PD models.In the present study we investigated the mechanisms underlying the protective effects of PQQ in a mouse PD model,which was established by intraperitoneal injection of rotenone (3 mg·kg-1·d-1,ip) for 3 weeks.Meanwhile the mice were treated with PQQ (0.8,4,20 mg·kg-1·d-1,ip) right after rotenone injection for 3 weeks.We showed that PQQ treatment dose-dependently alleviated the locomotor deficits and nigral dopaminergic neuron loss in PD mice.Furthermore,PQQ treatment significantly diminished the reduction of mitochondria number and their pathological change in the midbrain.PQQ dose-dependently blocked rotenone-caused reduction in the expression of PGC-1α and TFAM,two key activators of mRochondrial gene transcription,in the midbrain.In rotenone-injured human neuroblastoma SH-SY5Y cells,PTMScan Direct analysis revealed that treatment with PQQ (100 μM) differentially regulated protein phosphorylation;the differentially expressed phosphorylated proteins included the signaling pathways related with adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway.We conducted Western blot analysis and confirmed that AMPK was activated by PQQ both in PD mice and in rotenone-injured SH-SY5Y cells.Pretreatment with AMPK inhibitor dorsomorphin (4 μM) significantly attenuated the protective effect and mitochondrial biogenesis by PQQ treatment in rotenone-injured SH-SY5Y cells.Taken together,PQQ promotes mitochondrial biogenesis in rotenone-injured mice and SH-SY5Y cells via activation of AMPK signaling pathway.