PDF(Pubmed)
Abstract：
Vascular cognitive impairment and dementia (VCID) is a series of cognitive dysfunction associated with cerebrovascular diseases and currently lacks effective treatments. The white matter, which is essential for neuronal information processing and integration, is nourished by a network of capillaries and is vulnerable to chronic hypoperfusion. Here, we show that metformin, a widely used drug for the treatment of type 2 diabetes, alleviates the white matter damage and improves cognitive impairment in a mouse model of VCID established by bilateral carotid artery stenosis (BCAS)-induced chronic hypoperfusion. Mechanistically, metformin restores the dysfunctions of oligodendrocyte precursor cells (OPCs) under hypoxia. Metformin up-regulates prolyl hydroxylases 2 via activating the AMP-activated protein kinase pathway, leading to hypoxia-inducible factor-1α (HIF-1α) degradation in OPCs. These findings suggest that metformin may have a promising therapeutic role in alleviating cognitive abnormalities by ameliorating white matter damage of VCID.
摘要：
血管性认知障碍和痴呆(VCID)是与脑血管疾病相关的一系列认知功能障碍,目前缺乏有效的治疗方法。白质，这对于神经元信息处理和整合至关重要，由毛细血管网络滋养，容易受到慢性灌注不足的影响。这里,我们显示二甲双胍，一种广泛用于治疗2型糖尿病的药物，在双侧颈动脉狭窄（BCAS）诱导的慢性低灌注建立的VCID小鼠模型中，减轻白质损伤并改善认知障碍。机械上,二甲双胍可恢复缺氧条件下少突胶质前体细胞（OPCs）的功能障碍。二甲双胍通过激活AMP激活的蛋白激酶途径上调脯氨酸羟化酶2，导致OPCs缺氧诱导因子-1α（HIF-1α）降解。这些发现表明，二甲双胍可能通过改善VCID的白质损伤在减轻认知异常方面具有有希望的治疗作用。
