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. 2024 Nov;76(8):e70002.
doi: 10.1111/jpi.70002.

Melatonin Protects Against Cocaine-Induced Blood-Brain Barrier Dysfunction and Cognitive Impairment by Regulating miR-320a-Dependent GLUT1 Expression

Jia-Yi Wei  1 , Hui Liu  1 , Yuan Li  1 , Dan Zhao  1 , Bo Wang  2 , Hui-Jie Wang  1 , Li Wang  1 , Kang-Ji Wang  1 , Jin-Li Yue  1 , Hong-Yan Zhang  1 , Tian-Yue Li  1 , Yi-Jue Miao  1 , Kai-Li Wang  1 , Pai-Ge Tong  1 , Zhuo Zhang  1 , Ze-Ye Li  1 , Zheng Shi  1 , Jia-Yuan Yao  1 , Dong-Xin Liu  1 , Wen-Gang Fang  1 , Bo Li  1 , De-Shu Shang  1 , Yuan Lyu  3 , Hong-Zan Sun  2 , Wei-Dong Zhao  1 , Yu-Hua Chen  1
Affiliations

Melatonin Protects Against Cocaine-Induced Blood-Brain Barrier Dysfunction and Cognitive Impairment by Regulating miR-320a-Dependent GLUT1 Expression

Jia-Yi Wei et al. J Pineal Res. 2024 Nov.

Abstract

Cocaine abuse has been strongly linked to blood-brain barrier (BBB) dysfunction, though the exact mechanism by which cocaine disrupts the BBB remains unclear. In this study, we found that cocaine treatment reduces the expression of glucose transporter 1 (GLUT1) in brain microvascular endothelial cells, a key factor in cocaine-induced brain glucose uptake, BBB leakage, and cognitive impairment. Mechanistically, our results show that cocaine upregulates miR-320a, which in turn suppresses GLUT1 expression via the beta 2-adrenergic receptor (ADRB2). Notably, the administration of adeno-associated viruses encoding full-length GLUT1 or miR-320a inhibitors to the brain microvascular endothelium significantly mitigated cocaine-induced BBB leakage and cognitive deficits. Additionally, we discovered that melatonin, a well-known neuroprotective hormone, alleviates cocaine-induced BBB disruption and cognitive impairment. This protective effect of melatonin was mediated through the upregulation of miR-320a-dependent GLUT1 expression in brain endothelial cells via MT1 receptor-mediated inhibition of the cAMP/PKA/CREB signaling pathway. In conclusion, our findings demonstrate that cocaine downregulates brain microvascular GLUT1, leading to BBB dysfunction, and highlight melatonin as a potential therapeutic agent for treating cocaine-related complications.

Keywords: GLUT1; blood−brain barrier; cocaine; glucose; melatonin; microRNA‐320a.

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