多巴胺转运体是缺血性脑卒中的新靶点。

The Dopamine Transporter Is a New Target for Ischemic Stroke.

机构信息

Department of Pharmacy Research, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

MOE Frontier Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.

出版信息

CNS Neurosci Ther. 2024 Oct;30(10):e70092. doi: 10.1111/cns.70092.

DOI:10.1111/cns.70092

PMID:39467829

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11518691/

Abstract

AIMS

Dopamine transporter (DAT) can regulate DA homeostasis and has been implicated in many nervous system diseases. Whether DAT is involved in the protection against ischemic stroke is unclear.

METHODS

In vivo microdialysis measurements of DA were recorded in the ischemic penumbral area of mice with middle cerebral artery occlusion (MCAO). DAT coding gene, Slc6a3 mutation, and DAT overexpression animals were performed MCAO. Madopar (compound formulation of levodopa) and nomifensine (DA reuptake inhibitor) were administered in MCAO animals. Brain slices were prepared in Slc6a3 mutation or wild-type (WT) animals with MCAO to record miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs). The effects of DA and its dopamine-1 receptor (DR) antagonists (SCH-23390) on mEPSCs, mIPSCs, and neurons protection were recorded.

RESULTS

MCAO caused a prominent increase in DA. Slc6a3 mutation significantly attenuated the ischemic injury, whereas DAT overexpression aggravated this injury. Both nomifensine and madopar protected against brain injury. Slc6a3 mutation and DA restored the disturbance of mEPSCs and mIPSC, and protected against neuron death, which was abolished by SCH-23390.

CONCLUSION

DAT inhibition might be explored as a strategy for ischemic stroke prevention. DA and DR involve in the restoration of synaptic dysfunction and neuron protection.

摘要

目的

多巴胺转运体（DAT）可以调节多巴胺的稳态，并且与许多神经系统疾病有关。然而，DAT 是否参与对缺血性中风的保护作用尚不清楚。

方法

通过在大脑中动脉闭塞（MCAO）的小鼠缺血半影区记录多巴胺的体内微透析测量值，来研究该问题。对多巴胺转运体编码基因 Slc6a3 突变体和 DAT 过表达动物进行 MCAO 实验。在 MCAO 动物中给予 Madopar（左旋多巴的复方制剂）和诺米芬辛（多巴胺再摄取抑制剂）。在 Slc6a3 突变体或野生型（WT）动物的 MCAO 模型中制备脑切片，以记录微小兴奋性突触后电流（mEPSC）和微小抑制性突触后电流（mIPSC）。记录多巴胺及其多巴胺-1 受体（DR）拮抗剂（SCH-23390）对 mEPSC、mIPSC 和神经元保护的影响。