髓鞘再生对非动脉炎性前部缺血性视神经病变的神经保护作用研究

Non-arteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in patients over 50 years of age, and can cause permanent visual impairment. The pathogenesis of NAION is still controversial. Up to now these is no consistently effective therapy available. Pathologic studies revealed that demyelination process precedes, rather than follows, axon degeneration and retinal ganglion cells (RGC) apoptosis. In addition to ischemic damage, demyelination itself can contribute to axon degeneration and cause oxidative stress to RGC, which may trigger oxidative phosphorylation dysfunction of mitochondria and eventually result in apoptosis of RGC. We presume that upon the onset of this disease, axons in optic nerve receive double-hit from ischemia and demyelination, which accelerates apoptosis of RGC. Although the efficacy of revascularization treatment is still unclear, a recent study reported myelin regeneration effect of benztropine in a multiple sclerosis model. These is no published study about the role of remyelination in NAION. This study is aimed at confirming remyelination effect of benztropine in a rat NAION model, which is supposed to decrease degeneration of optic nerve axons. And preservation of axons is assumed to improve the function of mitochondria, down-regulate apoptosis pathway, and enhance the surviving of RGC. The results of this study will provide a new therapy target of NAION.

非动脉炎性前部缺血性视神经病变（NAION）是50岁以上人群最常见的急性视神经病变，常导致永久性视力损害。其发病机制尚存在争议，急需有效的治疗手段。研究发现视神经脱髓鞘改变的出现早于轴突破坏及节细胞(RGC)凋亡。除缺血性损伤外，脱髓鞘病变本身亦可造成轴突变性，引起氧化应激，干扰线粒体氧化磷酸化功能，并导致RGC凋亡。我们推测在NAION的发病机制中，视神经轴突可能受到缺血和脱髓鞘改变的双重打击，进而加剧RGC凋亡。然而，目前缺乏有效改善视神经血流灌注的药物。最近一项研究发现苯扎托品具有促进中枢神经系统髓鞘再生的功能。脱髓鞘改变在NAION发病机制中的作用尚无研究。本研究拟在大鼠NAION模型中验证苯扎托品的髓鞘再生作用，并希望通过髓鞘再生减少视神经轴突变性，改善RGC线粒体氧化磷酸化功能，下调凋亡通路，从而起到RGC保护作用。上述研究结果可为NAION的防治提供全新的思路及治疗靶点。

本研究采用光动力法诱导NAION模型，模型组以孟加拉玫瑰红作为光敏剂，结合532nm YAG激光照射SD大鼠视盘；透射电镜观察视神经的超微结构改变；经上丘荧光金逆行标记了解视网膜神经节细胞（retinal ganglion cells， RGCs）的数量变化。将大鼠随机分为5组，分别于造模后的1周、2周、4周、8周处死，电镜下观察视神经超微结构的变化趋势。将大鼠随机分为2组：苯扎托品组和PBS组造模后分别以苯扎托品（10mg/kg）或PBS连续腹腔注射3周。4周后观察视神经超微结构的改变及RGCs存活情况。结果发现造模4周后，电镜下可见视神经RGCs轴突密度减少，胶质瘢痕增生明显，RGCs轴突凋亡明显。荧光显微镜下见造模4周后，大鼠RGCs密度明显减少，荧光点分布稀疏，盘周、中周部及周边部的RGCs密度均减少。造模1w后，RGCs轴突大致仍呈束状分布，RGCs数量减少并不明显，部分RGCs轴突开始变性凋亡。造模2w后， RGCs轴突的形态变化明显，RGCs数量明显减少，并可见RGCs轴突间胶质增生。造模4w后，正常形态的RGCs轴突明显变少。出现各种形态的洋葱样小体，轴突间胶质增生更加明显。造模8w后，视神经内的RGCs轴突稀疏，残存的RGCs轴突组织之间有大量胶质瘢痕增生，多数轴突髓鞘已崩解，残留少量未完全凋亡的洋葱小体。注药后，苯扎托品组的电镜超微结构改变较PBS组明显为轻，荧光显微镜下可见苯扎托品组的RGCs密度较PBS组高，苯扎托品组的RGCs的凋亡较少，脱髓鞘反应较轻。可初步得出结论：研究建立的大鼠NAION模型与临床患者的病理机制具有相似性，可用于NAION的相关研究。NAION模型的RGCs轴突损伤是逐渐加重的，前3周是治疗干预的窗口期。苯扎托品腹腔注射显示出一定的视神经保护作用。

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