Zhou Min, Li Rongwen, Venkat Poornima, Qian Yu, Chopp Michael, Zacharek Alex, Landschoot-Ward Julie, Powell Brianna, Jiang Quan, Cui Xu
Department of Neurology, Henry Ford Hospital, Detroit, MI, United States.
Department of Physics, Oakland University, Rochester, MI, United States.
Front Neurol. 2022 Apr 28;13:863934. doi: 10.3389/fneur.2022.863934. eCollection 2022.
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 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), and ABCA1-floxed (ABCA1) 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 and ABCA1 T2DM-stroke mice compared with vehicle-control mice, respectively ( < 0.05, = 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 ( < 0.05, = 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.
2型糖尿病（T2DM）患者发生缺血性中风的风险独特且高，与非糖尿病人群相比，中风后神经血管和白质（WM）预后更差。在中枢神经系统中，ATP结合盒转运蛋白成员A1（ABCA1）是一种将细胞内胆固醇外流的逆向胆固醇转运蛋白，在高密度脂蛋白（HDL）生物合成以及维持神经血管稳定性和WM完整性方面发挥重要作用。我们之前的研究表明，L-4F是一种经济的载脂蛋白A成员I（ApoA-I）模拟肽，具有神经保护作用，可减轻db/db-T2DM中风小鼠大脑中的神经血管和WM损伤。为了进一步研究L-4F在T2DM中风后的缺血性脑中是否具有神经修复益处并阐明潜在的分子机制，我们对中年、脑ABCA1缺陷（ABCA1）和ABCA1基因敲除（ABCA1）的T2DM对照小鼠进行大脑中动脉远端闭塞。中风后24小时开始L-4F（16毫克/千克，皮下注射）治疗，每天给药一次，共21天。与载体对照小鼠相比，L-4F治疗T2DM中风分别改善了ABCA1和ABCA1 T2DM中风小鼠缺血性脑的神经功能结局，减少了出血、死亡率和血脑屏障渗漏，表现为白蛋白浸润减少、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增加、WM密度和少突胶质细胞生成增加（P<0.05，每组n = 9或21）。L-4F治疗减少了缺血性脑中巨噬细胞浸润和神经炎症，表现为ED-1、单核细胞趋化蛋白-1（MCP-1）和Toll样受体4（TLR4）表达降低，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-1Rβ）增加（P<0.05，每组n = 6）。这些结果表明，中风后给予L-4F可能通过促进神经血管和WM重塑为T2DM中风提供一种修复策略。减少受损脑中的神经炎症可能至少部分有助于L-4F的修复作用，且不依赖于ABCA1信号通路。
