<scp>CYP1B1</scp> affects the integrity of the blood–brain barrier and oxidative stress in the striatum: An investigation of manganese‐induced neurotoxicity
Juan Wu, Yueran Li, Shuwei Tian, Shufang Na, Hongyan Wei, Yafei Wu, Yafei Yang, Zixia Shen, Jiayue Ding, Shenglan Bao, Siqi Liu, Lingyun Li, Rongling Feng, Yong Zhu, Chunyan He, Jiang Yue
Abstract
Abstract Aims Excessive influx of manganese (Mn) into the brain across the blood–brain barrier induces neurodegeneration. CYP1B1 is involved in the metabolism of arachidonic acid (AA) that affects vascular homeostasis. We aimed to investigate the effect of brain CYP1B1 on Mn‐induced neurotoxicity. Method Brain Mn concentrations and α‐synuclein accumulation were measured in wild‐type and CYP1B1 knockout mice treated with MnCl 2 (30 mg/kg) and biotin (0.2 g/kg) for 21 continuous days. Tight junctions and oxidative stress were analyzed in hCMEC/D3 and SH‐SY5Y cells after the treatment with MnCl 2 (200 μM) and CYP1B1‐derived AA metabolites (HETEs and EETs). Results Mn exposure inhibited brain CYP1B1, and CYP1B1 deficiency increased brain Mn concentrations and accelerated α‐synuclein deposition in the striatum. CYP1B1 deficiency disrupted the integrity of the blood–brain barrier (BBB) and increased the ratio of 3, 4‐dihydroxyphenylacetic acid (DOPAC) to dopamine in the striatum. HETEs attenuated Mn‐induced inhibition of tight junctions by activating PPARγ in endothelial cells. Additionally, EETs attenuated Mn‐induced up‐regulation of the KLF/MAO‐B axis and down‐regulation of NRF2 in neuronal cells. Biotin up‐regulated brain CYP1B1 and reduced Mn‐induced neurotoxicity in mice. Conclusions Brain CYP1B1 plays a critical role in both cerebrovascular and dopamine homeostasis, which might serve as a novel therapeutic target for the prevention of Mn‐induced neurotoxicity.