D-4F治疗2型糖尿病小鼠脑卒中的作用机制探讨

Diabetes mellitus (DM) increases risk of experiencing ischemic stroke, develops more white matter damage and leads to a worse prognosis than non-DM patients. There is a compelling need to develop therapeutic approaches specifically designed to reduce neurological deficits after stroke in diabetic population. DM is associated with low high-density lipoprotein cholesterol (HDL-C), with reduced ATP-binding cassette transporter A1 (ABCA1) gene expression, which influences neuronal structure and function. D-4F, an ApoA-1 mimetic peptide, upregulates the ABCA1 gene expression,enhances the lipid efflux mediated by ABCA1 and increases HDL-C level which attenuates white matter damage after stroke. Our preliminary data show that D-4F treatment of stroke in non-diabetic mice improves white matter remodeling and recovery of neurological function；brain ABCA1 deficiency increases BBB leakage, white matter damage, and functional deficits after stroke in mice (Stroke. 2015). We propose that D-4F increases ABCA1 expression which mediates WM remodeling, improves functional outcome after extraluminal distal middle cerebral artery occlusion (dMCAo) stroke in Type-2 DM mice. Our studies will provide fundamental insights into neurorestorative therapy on stroke in DM populations and a fresh approach for studies on stroke with comorbidities.

糖尿病显著增加脑卒中的发病率，加重脑白质损伤并导致不良预后。合并糖尿病的脑卒中患者神经功能损伤治疗是一个亟待解决的问题。糖尿病降低体内高密度脂蛋白胆固醇(HDL-C)水平和ATP结合盒转运子A1(ABCA1)基因表达，影响神经结构和功能；ApoA1的模拟肽D-4F能上调ABCA1的表达，促进ABCA1介导的脂质外流，增加HDL-C水平,HDL-C可以减轻卒中后神经损伤。我们前期研究结果证实，D-4F可促进非糖尿病小鼠脑卒中后脑白质重塑，改善神经功能恢复。而敲除小鼠脑组织中ABCA1可加重卒中后小鼠血脑屏障、脑白质的损伤和神经功能缺损（Stroke.2015）。我们设想D-4F治疗2型糖尿病小鼠脑卒中能够上调ABCA1表达，促进ABCA1介导的脑白质重塑，改善卒中后神经功能恢复。本研究将为糖尿病脑卒中的神经功能恢复治疗研究奠定基础，并对合并其他疾病的脑卒中研究提供理论依据和借鉴。

糖尿病显著增加脑卒中的发病率，加重脑白质损伤并导致不良预后。合并糖尿病的脑卒中患者神经功能损伤治疗是一个亟待解决的问题。糖尿病降低体内高密度脂蛋白胆固醇(HDL-C)水平和ATP结合盒转运子A1(ABCA1)基因表达，影响神经结构和功能；ApoA1的模拟肽D-4F能上调ABCA1的表达，促进ABCA1介导的脂质外流，增加HDL-C水平,HDL-C可以减轻卒中后神经损伤。我们前期研究结果证实，D-4F可促进非糖尿病小鼠脑卒中后脑白质重塑，改善神经功能恢复。而敲除小鼠脑组织中ABCA1可加重卒中后小鼠血脑屏障、脑白质的损伤和神经功能缺损（Stroke.2015）。我们设想D-4F治疗2型糖尿病小鼠脑卒中能够上调ABCA1表达，促进ABCA1介导的脑白质重塑，改善卒中后神经功能恢复。本研究将为糖尿病脑卒中的神经功能恢复治疗研究奠定基础，并对合并其他疾病的脑卒中研究提供理论依据和借鉴。