期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 37, 期 3, 页码 914-926出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X16647738
关键词
Cerebral ischemia; neuroregeneration; lithium; miRNA; stroke; RE1-silencing transcription factor
资金
- German Research Council ( DFG) [HE3173/2-2, HE3173/3-1]
- TUBITAK [2221]
Lithium promotes acute poststroke neuronal survival, which includes mechanisms that are not limited to GSK3 inhibition. However, whether lithium induces long-term neuroprotection and enhanced brain remodeling is unclear. Therefore, mice were exposed to transient middle cerebral artery occlusion and lithium (1mg/kg bolus followed by 2mg/kg/day over up to 7 days) was intraperitoneally administered starting 0-9h after reperfusion onset. Delivery of lithium no later than 6h reduced infarct volume on day 2 and decreased brain edema, leukocyte infiltration, and microglial activation, as shown by histochemistry and flow cytometry. Lithium-induced neuroprotection persisted throughout the observation period of 56 days and was associated with enhanced neurological recovery. Poststroke angioneurogenesis and axonal plasticity were also enhanced by lithium. On the molecular level, lithium increased miR-124 expression, reduced RE1-silencing transcription factor abundance, and decreased protein deubiquitination in cultivated cortical neurons exposed to oxygen-glucose deprivation and in brains of mice exposed to cerebral ischemia. Notably, this effect was not mimicked by pharmacological GSK3 inhibition. This study for the first time provides efficacy data for lithium in the postacute ischemic phase, reporting a novel mechanism of action, i.e. increased miR-124 expression facilitating REST degradation by which lithium promotes postischemic neuroplasticity and angiogenesis.
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