The neuroprotective mechanism of baicalein related to mitophagy mediated by MAPK1/RSK1 in a murine model of Parkinson's disease.

Abstract

This study aims to investigate the neuroprotective effects and underlying molecular mechanisms of baicalein (Bai) in a mouse model of Parkinson's disease (PD) induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Using an MPTP-induced PD mouse model, the effects of Bai intraperitoneal injection on motor function and dopaminergic neuronal injury were assessed. Adeno-associated virus serotype 9 (AAV9)-mediated mitogen-activated protein kinase 1 overexpression (oe-MAPK1) was employed for gain-of-function experiments. Western blot technique was adopted to measure the levels of MAPK1, ribosomal protein S6 kinase 1 (RSK1), phosphorylated RSK1, PTEN-induced putative kinase 1 (PINK1), Parkin, microtubule-associated protein 1 light chain 3 (LC3)-II/I, and p62. Additionally, mitochondrial membrane potential and mitochondrial ultrastructure were observed to assess mitochondrial function. The binding between Bai and MAPK1 was examined using molecular docking and cellular thermal shift assay. Bai intraperitoneal injection markedly alleviated motor deficits, mitigated dopaminergic neuronal loss, raised mitochondrial membrane potential, and reduced ultrastructural mitochondrial damage post MPTP-induced PD in mice. Meanwhile, Bai upregulated PINK1, Parkin, and the LC3-II/I ratio while downregulating p62, indicating enhanced mitophagy. With a binding energy of -7.8 kcal/mol, Bai could directly bind to MAPK1, which destabilized MAPK1 thermostability and suppressed MAPK1 expression as well as subsequent RSK1 phosphorylation. Notably, MAPK1 overexpression repressed mitophagy, aggravated motor dysfunction and neuronal damage, and partially abrogated the neuroprotective efficacy of Bai. Bai binds directly to MAPK1, suppresses the MAPK1/RSK1 signaling cascade, triggers mitophagy, and ultimately ameliorates motor impairment and neuronal degeneration, conferring neuroprotection against PD in mice.

Graphical abstract: Baicalein inhibits the MAPK1 and p-RSK1 signaling pathway in a Parkinson's disease mouse model treated with MPTP. This inhibition activates mitophagy, increases levels of PINK1, Parkin, and the LC3-II/I ratio, while decreasing p62.