Mitofusin-2 mediates cannabidiol-induced neuroprotection against cerebral ischemia in rats

Bing-tian Xu1,2, Meng-fan Li1, Ke-chun Chen1, Xing Li1, Ning-bo Cai1, Jiang-ping Xu1,3,4, Hai-tao Wang1,3,4
1 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
2 Department of Neurology, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou 510180, China
3 Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou 510515, China
4 Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou 510515, China
Correspondence to: Jiang-ping Xu:, Hai-tao Wang:,
DOI: 10.1038/s41401-022-01004-3
Received: 1 June 2022
Accepted: 21 September 2022
Advance online: 13 October 2022


Cannabidiol (CBD) reportedly exerts protective effects against many psychiatric disorders and neurodegenerative diseases, but the mechanisms are poorly understood. In this study, we explored the molecular mechanism of CBD against cerebral ischemia. HT-22 cells or primary cortical neurons were subjected to oxygen-glucose deprivation insult followed by reoxygenation (OGD/R). In both HT-22 cells and primary cortical neurons, CBD pretreatment (0.1, 0.3, 1 μM) dose-dependently attenuated OGD/R-induced cell death and mitochondrial dysfunction, ameliorated OGD/R-induced endoplasmic reticulum (ER) stress, and increased the mitofusin-2 (MFN2) protein level in HT-22 cells and primary cortical neurons. Knockdown of MFN2 abolished the protective effects of CBD. CBD pretreatment also suppressed OGD/R-induced binding of Parkin to MFN2 and subsequent ubiquitination of MFN2. Overexpression of Parkin blocked the effects of CBD in reducing MFN2 ubiquitination and reduced cell viability, whereas overexpressing MFN2 abolished Parkin’s detrimental effects. In vivo experiments were conducted on male rats subjected to middle cerebral artery occlusion (MCAO) insult, and administration of CBD (2.5, 5 mg · kg−1, i.p.) dose-dependently reduced the infarct volume and ER stress in the brains. Moreover, the level of MFN2 within the ischemic penumbra of rats was increased by CBD treatment, while the binding of Parkin to MFN2 and the ubiquitination of MFN2 was decreased. Finally, short hairpin RNA against MFN2 reversed CBD’s protective effects. Together, these results demonstrate that CBD protects brain neurons against cerebral ischemia by reducing MFN2 degradation via disrupting Parkin’s binding to MFN2, indicating that MFN2 is a potential target for the treatment of cerebral ischemia.
Keywords: cannabidiol; MFN2; Parkin; cerebral ischemia; oxidative stress

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