缺血性脑中风中NAMPT通过小胶质细胞介导髓磷脂吞噬作用保护白质损伤的新颖机制研究

White matter injury (WMI) is a major cause of functional disability in stroke. Disappointingly, no effective treatment is available in clinic and no clinical trial has been performed targeting WM in stroke. Oligodendrocytic death plays an essential role in WMI following cerebral ischemia. Ours and others' studies found that a few days after ischemia, increased numbers of oligodendrocytes/OPCs were present in the lateral ventricles and penumbra, which indicats that ischemic damage to oligodendrocytes can be compensated for, at least in part, by the regeneration of oligodendrocytes. Thus, interventions targeted at oligodendrocyte protection as well as oligodendrogenesis may improve post-stroke WM repair and long-term functional recovery. Present studies indicated that Microglia protect WM by removing myelin/cell debris (phagocytosis) during the late phase of ischemic recovery. NAMPT is the rate-limiting step in the salvage pathway of NAD biosynthesis. The exact neuroprotective mechanism of NAMPT against cerebral ischemia remains unknown, but previous study indicated that NAMPT may mediate neuroprotection by providing extra energy and activating NAD-dependent survival signaling pathways. We found that NAMPT protein can cross the BBB and protect both white and gray matter against ischemic brain injury. Therefore, the central hypothesis to be tested is that NAMPT overexpression, using we have established a neuron-specific transgenic mouse line or administration of recombinant NAMPT protein, protects against WMI after cerebral ischemia by enhancing oligodendrogenesis and microglial myelin phagocytosis. NAMPT may play a role in long-term improvement of neurological function after cerebal ischemia.

白质损伤（WMI）是引起中风后神经功能丧失的主要原因之一，至今临床和临床试验中无针对WMI治疗。少突胶质细胞死亡对WMI起着至关重要的作用，缺血后出现了少突胶质细胞/OPCs的增加，因此，针对于少突胶质细胞保护和少突再生的靶向治疗，可能改善中风后的白质修复。当前的研究发现缺血后期小胶质细胞可通过吞噬作用清除髓磷脂/细胞碎片来保护白质。NAMPT是NAD合成限速酶，许多研究认为NAMPT可能通过提供额外能量以及激活NAD-依赖的存活通路来介导神经保护作用，然而NAMPT更详细的脑保护机制仍不清楚。我们前期研究显示NAMPT重组蛋白可透过BBB并同时保护中风后白质和灰质损伤。因此本课题将采用我们构建的神经元条件性NAMPT转基因鼠和NAMPT重组蛋白治疗，验证过表达NAMPT通过促进少突再生并提高小胶质细胞髓磷脂吞噬作用，从而削弱了脑缺血后白质损伤,起到长期改善神经功能缺失的作用。

白质损伤（WMI）是引起脑卒中后神经功能丧失的主要原因，至今临床和临床试验中无针对WMI治疗。许多研究认为NAMPT具有脑保护作用，但其作用机制还未完全清楚。本研究采用我们构建的神经元条件性NAMPT转基因鼠和NAMPT重组蛋白治疗，结果发现，缺血后过表达NAMPT神经元可释放胞间NAMPT(eNAMPT)对遭受缺血损伤的少突胶质细胞具有保护作用，并且eNAMPT可促进小胶质细胞向有助于损伤后修复的M2型激活，从而促进吞噬髓鞘碎片、促进少突再生、削弱脑缺血后白质损伤，最终起到长期改善神经功能的作用。此外，神经元特异性过表达NAMPT小鼠在缺血损伤后具有显著的神经再生和血管再生能力，有助于缺血损伤后的长期的神经功能恢复。我们的研究结果提示，NAMPT对缺血性损伤具有潜在的临床治疗价值。此外，我们在本基金的资助下，参与了其他课题的研究：1）阐明了APE1对缺血后神经元氧化性DNA损伤修复的关键作用，提高APE1的活性不仅对缺血脑的灰质而且对白质都具有保护作用，提高APE1的活性可改善缺血后长期的神经功能缺失；2）针对不同年龄脑卒中模型，发现n-3PUFAs都具有预防或治疗性保护作用，其机制与白质损伤修复相关。我们的结果提示，缺血性脑中风后白质的保护作用直接影响到长期的神经功能转归。

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