我们还发现,牛眼小梁细胞在AEA作用后,前列腺素PGE2的A值呈剂量依赖性升高,细胞上清中的PGE2含量明显升高,与对照组有显著性差异(P<0.05)。这说明AEA可促进牛眼小梁细胞表达PGE2。前列腺素衍生物在青光眼治疗中具有良好的降眼压效果[14]。前列腺素衍生物是通过增加巩膜—葡萄膜通道的房水外流而降低眼压的。其作用机制是前列腺素衍生物通过作用于睫状肌和巩膜—葡萄膜通道的基质金属蛋白酶(MMP),造成睫状肌松弛,肌间隙增宽;同时MMP活性增加,也减少了房水外流的阻力,导致房水经巩膜—葡萄膜通道的外流增加和眼压的降低[15,16]。实验证实,吲哚美辛可以抑制AEA的降眼压作用,而吲哚美辛是一种环氧化酶抑制剂,可以抑制花生4—烯酸合成前列腺素[17]。另有研究发现,AEA可以诱导人眼非色素睫状体上皮细胞环氧化酶2(Cox2)和MMP的表达,提示AEA可能是通过这两种酶调节眼压的[18]。PGE2有4种受体,分别为EP1,EP2,EP3,EP4。现有研究发现,有些PGE2(如比马前列腺素及乌诺前列酮)也可能是通过作用于传统房水流出通道(小梁网通道)来降低眼压的[1924],并且这种促进作用也可以被非甾体抗炎药所抑制[23,24]。 近代研究表明,视网膜神经节细胞(RGC)的慢性进行性丢失是青光眼最主要的病理学特征。现已明了,高眼压、缺血等原发性损伤因素首先引起一部分对高眼压敏感的RGC崩解死亡,这些崩解死亡的RGC可以释放出NO、谷氨酸等毒性物质,后者可刺激邻近已逃避原发病因的健康RGC表面的N甲基D天门冬氨酸(NMDA)受体,使之产生毒性反应,通过一系列信号传导使大量Ca2+流入RGC,使其进入凋亡程序而最终丢失。已有研究证实AEA以及其它内源性大麻素[2,25]可以阻滞NMDA诱导神经细胞内Ca2的聚集,起到神经保护作用,也可以阻滞NMDA诱导的视网膜神经毒性[26],可以减少轴突变性和促进轴突的再生[27]。这些发现都有力地证明AEA对视神经有保护作用。也有文献报道PGE2也具有细胞保护作用[28]。 青光眼治疗的策略包括降低眼压,控制眼压波动,保护视神经。AEA可以降低眼压,保护视神经,因而有可能成为抗青光眼治疗的新药,但目前还有很多问题有待进一步研究。我们有理由相信随着对AEA的深入研究,有可能为寻找治疗青光眼的新药物提供一条新的途径。
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