Post-Stroke Administration of L-4F Promotes Neurovascular and White Matter Remodeling in Type-2 Diabetic Stroke Mice.
Post-Stroke Administration of L-4F Promotes Neurovascular and White Matter Remodeling in Type-2 Diabetic Stroke Mice.
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DOI：
10.3389/fneur.2022.863934
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发表时间：
2022
影响因子：
3.4
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中科院分区：
文献类型：
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与非糖尿病人群相比，2型糖尿病（T2 DM）患者表现出明显的缺血性卒中高风险，卒中后神经血管和白色物质（WM）预后更差。在中枢神经系统中，ATP结合盒转运体成员A1（ABCA 1），一种流出细胞胆固醇的胆固醇反向转运体，在高密度脂蛋白（HDL）生物合成和维持神经血管稳定性和WM完整性中起重要作用。我们前期的研究表明，L-4F是一种经济的载脂蛋白A成员I（ApoA-I）模拟肽，通过减轻db/db-T2 DM卒中小鼠脑内的神经血管和WM损伤而具有神经保护作用。为了进一步研究L-4 F是否对2型糖尿病卒中后缺血性脑具有神经恢复益处并阐明潜在的分子机制，我们对中年、脑ABCA 1缺陷（ABCA 1-B/-B）和ABCA 1-floxed（ABCA 1 fl/fl）2型糖尿病对照小鼠进行了远端大脑中动脉闭塞。L-4F（16 mg/kg，皮下注射）治疗在卒中后24小时开始，每天给药一次，持续21天。用L-4F治疗T2 DM-中风改善了神经功能结果，并降低了出血、死亡率和BBB渗漏，这通过减少白蛋白浸润和增加紧密连接和星形胶质细胞终足密度、增加脑小动脉直径和平滑肌细胞数量来确定，与溶媒组相比，ABCA 1-B/-B和ABCA 1 fl/fl T2 DM-卒中小鼠缺血性脑中WM密度和少突细胞生成增加。对照小鼠（p < 0.05，n = 9或21/组）。L-4 F处理减少了巨噬细胞浸润和神经炎症，通过缺血性脑中艾德-1、单核细胞趋化蛋白-1（MCP-1）和toll样受体4（TLR 4）表达的减少以及抗炎因子胰岛素样生长因子1（IGF-1）及其受体IGF-1受体β（IGF-1 R β）的增加来鉴定（p < 0.05，n = 6/组）。这些结果表明，中风后给予L-4F可能会通过促进神经血管和WM重塑为T2 DM中风提供一种恢复策略。减少受损大脑中的神经炎症可能至少部分地有助于L-4F独立于ABCA 1信号通路的恢复作用。
Patients with type 2 diabetes mellitus (T2DM) exhibit a distinct and high risk of ischemic stroke with worse post-stroke neurovascular and white matter (WM) prognosis than the non-diabetic population. In the central nervous system, the ATP-binding cassette transporter member A 1 (ABCA1), a reverse cholesterol transporter that efflux cellular cholesterol, plays an important role in high-density lipoprotein (HDL) biogenesis and in maintaining neurovascular stability and WM integrity. Our previous study shows that L-4F, an economical apolipoprotein A member I (ApoA-I) mimetic peptide, has neuroprotective effects via alleviating neurovascular and WM impairments in the brain of db/db-T2DM stroke mice. To further investigate whether L-4F has neurorestorative benefits in the ischemic brain after stroke in T2DM and elucidate the underlying molecular mechanisms, we subjected middle-aged, brain-ABCA1 deficient (ABCA1−B/−B), and ABCA1-floxed (ABCA1fl/fl) T2DM control mice to distal middle cerebral artery occlusion. L-4F (16 mg/kg, subcutaneous) treatment was initiated 24 h after stroke and administered once daily for 21 days. Treatment of T2DM-stroke with L-4F improved neurological functional outcome, and decreased hemorrhage, mortality, and BBB leakage identified by decreased albumin infiltration and increased tight-junction and astrocyte end-feet densities, increased cerebral arteriole diameter and smooth muscle cell number, and increased WM density and oligodendrogenesis in the ischemic brain in both ABCA1−B/−B and ABCA1fl/fl T2DM-stroke mice compared with vehicle-control mice, respectively (p < 0.05, n = 9 or 21/group). The L-4F treatment reduced macrophage infiltration and neuroinflammation identified by decreases in ED-1, monocyte chemoattractant protein-1 (MCP-1), and toll-like receptor 4 (TLR4) expression, and increases in anti-inflammatory factor Insulin-like growth factor 1 (IGF-1) and its receptor IGF-1 receptor β (IGF-1Rβ) in the ischemic brain (p < 0.05, n = 6/group). These results suggest that post-stroke administration of L-4F may provide a restorative strategy for T2DM-stroke by promoting neurovascular and WM remodeling. Reducing neuroinflammation in the injured brain may contribute at least partially to the restorative effects of L-4F independent of the ABCA1 signaling pathway.
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影响因子：
6.5
作者：
Duong, PT;Collins, HL;Phillips, MC
通讯作者：
Phillips, MC
影响因子：
8.3
作者：
Cui X;Chopp M;Zacharek A;Karasinska JM;Cui Y;Ning R;Zhang Y;Wang Y;Chen J
通讯作者：
Chen J
影响因子：
1.9
作者：
Freret, Thomas;Bouet, Valentine;Boulouard, Michel
通讯作者：
Boulouard, Michel
影响因子：
6.3
作者：
Ennis, Stenten R.;Keep, Richard F.
通讯作者：
Keep, Richard F.
影响因子：
8.3
作者：
Cui X;Chopp M;Zacharek A;Cui Y;Roberts C;Chen J
通讯作者：
Chen J