Background

Glaucoma is a leading cause of irreversible blindness manifesting as an age-related, progressive optic neuropathy with associated retinal ganglion cell (RGC) loss. Mitogen-activated protein kinases (MAPKs: p42/44 MAPK, SAPK/JNK, p38 MAPK) are activated in various retinal disease models and likely contribute to the mechanisms of RGC death. Although MAPKs play roles in the development of retinal pathology, their action in the optic nerve head (ONH), where the initial insult to RGC axons likely resides in glaucoma, remains unexplored.

Methods

An experimental paradigm representing glaucoma was established by induction of chronic ocular hypertension (OHT) via laser-induced coagulation of the trabecular meshwork in Sprague-Dawley rats. MAPKs were subsequently investigated over the following days for expression and activity alterations, using RT-PCR, immunohistochemistry and Western immunoblot.

Results

p42/44 MAPK expression was unaltered after intraocular pressure (IOP) elevation, but there was a significant activation of this enzyme in ONH astrocytes after 6–24 h. Activated SAPK/JNK isoforms were present throughout healthy RGC axons but after IOP elevation or optic nerve crush, they both accumulated at the ONH, likely due to RGC axon transport disruption, and were subject to additional activation. p38 MAPK was expressed by a population of microglia which were significantly more populous following IOP elevation. However it was only significantly activated in microglia after 3 days, and then only in the ONH and optic nerve; in the retina it was solely activated in RGC perikarya.

Conclusions

In conclusion, each of the MAPKs showed a specific spatio-temporal expression and activation pattern in the retina, ONH and optic nerve as a result of IOP elevation. These findings likely reflect the roles of the individual enzymes, and the cells in which they reside, in the developing pathology following IOP elevation. These data have implications for understanding the mechanisms of ocular pathology in diseases such as glaucoma.

中文翻译：

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高眼压大鼠视神经乳头中促分裂原活化蛋白激酶的表达和激活

背景

青光眼是不可逆性失明的主要原因，表现为与年龄相关的进行性视神经病变并伴有视网膜神经节细胞（RGC）丢失。丝裂原激活的蛋白激酶（MAPK：p42 / 44 MAPK，SAPK / JNK，p38 MAPK）在各种视网膜疾病模型中均被激活，可能有助于RGC死亡的机制。尽管MAPKs在视网膜病理学发展中起作用，但它们在视神经乳头（ONH）中的作用仍未得到研究，在该视神经头中，RGC轴突最初受到的损害可能是在青光眼中。

方法

通过在Sprague-Dawley大鼠中通过激光诱导的小梁网的凝结诱导慢性高眼压（OHT），建立了代表青光眼的实验范式。随后，使用RT-PCR，免疫组化和Western免疫印迹，在随后的几天中对MAPK的表达和活性变化进行了研究。

结果

眼内压（IOP）升高后，p42 / 44 MAPK表达未改变，但在6-24 h后，ONH星形胶质细胞中该酶显着激活。活化的SAPK / JNK亚型遍布整个健康的RGC轴突，但在IOP升高或视神经压迫后，它们都可能聚集在ONH处，这可能是由于RGC轴突运输中断所致，并受到了额外的活化。p38 MAPK由一群小胶质细胞表达，这些小胶质细胞在IOP升高后明显更多。然而，仅在3天后在小胶质细胞中才被显着激活，然后仅在ONH和视神经中被激活。在视网膜中，它仅在RGC核周膜中被激活。

结论

总之，由于IOP升高，每个MAPK在视网膜，ONH和视神经中均表现出特定的时空表达和激活模式。这些发现可能反映了IOP升高后病理发展过程中单个酶及其所在细胞的作用。这些数据对于理解诸如青光眼的疾病中的眼部病理机制具有启示意义。