松果菊苷对大鼠青光眼性视神经损伤的保护作用及其机制研究

Glaucoma is the leading cause of irreversible blindness. Lowering intraocular pressure can merely delay the progression of vision loss, but not stop, as multiple factors are involved in the pathogenesis of glaucoma, including neurotrophic factors deprivation. In response to this situation, neuroprotection which aims to protect the damaged retinal ganglion cells may shed light on curing glaucoma. However, neurotrophic factors have low oral bioavailability and poor blood-brain barrier permeability, thus could not enter the central nervous system following systemic administration, which makes it impossible to treat glaucomatous optic nerve injury with neurotrophic factors directly. Echinacoside (ECH) is the major active component of Cistanches Herba, a widely used Chinese herb, and it has significant neuroprotective effects against several kinds of neuronal injury. Our earlier studies suggest that ECH initiates neuroprotection by mimicking neurotrophic functions and activating Trk-ERK pathway. We then found that ECH remarkably suppressed glutamate-induced injury of primary rat retinal ganglion cell cultures. These indicate that ECH may be a potential treatment for glaucoma. Hence, in this study, we will further investigate the neuroprotection of ECH in a rat model of chronic intraocular hypertension and possible mechanisms underlying. It will provide a theoretical basis for the future clinical application of ECH.

青光眼是一种常见致盲性眼病，有效降低眼压并不能完全阻止患者的视神经损伤和视功能损害。该病发病机制复杂，除了高眼压引起的机械压力损伤，神经营养因子剥夺也是视神经原发性损伤的主要诱因。因此，采用调节眼压联合补充神经营养因子的方法来治疗青光眼可能具有广阔前景；但神经营养因子存在易降解和血脑屏障通透性低等问题，不能直接用来治疗视神经损伤。松果菊苷（echinacoside, ECH）是传统补益中药肉苁蓉提取物的主要活性分子。申请人的前期研究发现，ECH有类神经营养因子样作用，能通过激活Trk-ERK通路起到神经保护效应。同时申请人又在青光眼体外实验模型上发现，ECH能有效减少谷氨酸诱导的原代培养大鼠视网膜神经节细胞凋亡，提示ECH有阻止青光眼性视神经损伤的潜在价值。故本项目拟在慢性高眼压模型大鼠上进一步明确ECH的视神经保护作用，并揭示ECH神经保护作用的可能机制，为其今后的临床应用提供理论基础。

青光眼是一种常见致盲性眼病，有效降低眼压并不能完全阻止患者的视神经损伤和视功能损害。该病发病机制复杂，除了高眼压引起的机械压力损伤，神经营养因子剥夺也是视神经原发性损伤的主要诱因。因此，采用调节眼压联合补充神经营养因子的方法来治疗青光眼可能具有广阔前景；但神经营养因子存在易降解和血脑屏障通透性低等问题，不能直接用来治疗视神经损伤。松果菊苷（echinacoside, ECH）是传统补益中药肉苁蓉提取物的主要活性分子。申请人的前期研究发现，ECH具有神经营养因子样作用。本项目基于前期研究基础，在慢性高眼压模型大鼠上进一步研究ECH对青光眼性视神经损伤的保护作用，并深入探讨该神经保护作用的可能机制。研究发现，ECH能够有效减少慢性高眼压模型大鼠视网膜神经节细胞（RGC）的死亡、线粒体钙超载、氧化应激、线粒体膜电势去极化、细胞色素c释放、caspase激活，ECH还可以激活RGC中Trk-ERK通路，增加视网膜中神经营养因子的蛋白水平。同时给予Trk-ERK通路抑制剂能够逆转以上所有ECH的神经保护作用，说明该通路在ECH的神经保护效应中起着重要的作用。以上研究结果提示ECH有阻止青光眼性视神经损伤的潜在价值，可为其今后的临床应用提供理论基础。