| 摘要: | 青光眼是一種神經系統的退化症,會造成視網膜神經細胞(RGC)逐漸走向細胞凋零死亡(apoptosis)的過程.目前認為麩氨酸(glutamate)引起的過激細胞毒性反應 (excitotoxicity)可能造成青光眼的視神經細胞死亡.一些體外培養的視網膜神經細胞的研究也發現的確與麩氨酸(glutamate)引起的過激細胞毒性反應有關.此外許多動物的青光眼模型研究及人類的青光眼病人體內的確發現也發現麩氨酸有過量的情形.但是對於麩氨酸引發的過激細胞毒性是如何造成青光眼的機轉仍然不是完全明瞭的.第一介白素(IL-1)是一種在發炎前的細胞激素(cytokine),在神經系統內經常造成神經細胞及膠質細胞的各種變化,也會調節發炎反應及產生一些神經退化的反應.此外細胞激素也經常在受損的神經組織及受傷的視網膜也發現有過度的表現.在一些眼內疾病的玻璃體內經常發現有高劑量的第一介白素(IL-1b),也有些研究指出第一介白素(IL-1b)會減緩缺血及神經細胞的毒性反應.此外第一介白素(IL-1b)也會引發眼內細胞的許多不同細胞激素的產生.也有不同的證據指出被誘導出來的細胞激素與其所產生的發炎細胞也會改善神經系統的神經細胞的活性.此外,有一種內生型的第一介白素(IL-1b)的拮抗劑IL-Ira也被發現對是第一介白素(IL-1)的受體有特別的親和性.IL-1ra會抑制IL的生物活性,在視網膜及許多眼內的組織都有發現.IL-1ra也被認為有抑制缺血及神經細胞的毒性反應的.此外目前也認為細胞激素彼此之間產生的反應是相當複雜的.因此 IL-1b有可能引起我們大家所不知的生物活性,可能對神經細胞產生直接或間接的影響。近來有一些研究也指出IL-1b的雙重的效果,內生型的IL-1b 可能會產生神經細胞死亡,而IL-1ra反而會結抗它產生神經保護的作用,但是外來的IL-1b又會產生對NMDA所引發的視網膜破壞產生神經保護的作用,因此IL-1b的確對神經細胞死亡有它特殊的雙重的機制.因此進一步去了解IL-1b及其拮抗劑IL-1ra其在神經細胞的作用及角色是非常重要的. 此外,p38是一群與分化有關的激麩,它與細胞內的訊號傳導有關.最近的研究指出,P38與一些細胞凋零死亡的過程有關,包刮神經元細胞.此外P38的抑制劑也被指出對於視神經受損及青光眼有潛在的治療作用.因此在我目前這個研究中我們將評估P38是否與IL-1ra或IL-1b在對麩氨酸所引發的視網膜神經細胞死亡的體外模型內的神經保護作用之訊號傳導機轉有關.藉由這樣的研究,我們期待能更進一步了解麩氨酸在青光眼的神經細胞死亡的致病機轉及P38抑制劑在治療青光眼的可能性.
Glaucoma is a neurodegenerative disease typified by progressive loss of retinal ganglion cells (RGCs). It was suggested that glutamatergic excitotoxicity could contribute to the death of ganglion cells in glaucoma. However, the role of glutamate excitotoxicity in glaucoma remains unclear. Interleukin-1 (IL-1), a pro-inflammatory cytokine, elicits various changes in cellular behavior of neuronal and glial cells in the nervous system, resulting in the modulation of inflammatory and neurodegenerative reactions. It has been shown that IL-1beta attenuates ischemic and╱or excitotoxic neuronal damage. On the other hand, an endogenous IL-1 receptor antagonist (IL-1ra) has been identified that binds preferentially to type I IL-1 receptor. IL-1ra can inhibit the biologic activities of IL-1, and is expressed in retina and other ocular tissues. IL-1ra has been shown to inhibit ischemia and excitotoxic neuronal damage. It is well known that numerous cytokines, including IL-1beta, cause alteration in the expression and function of other cytokines, resulting in a complicated interactive system (cytokine network). Recently, some studies report that endogenous IL-1beta induces neuronal cell death directly, as shown by the neuroprotective effect of IL-1ra. Therefore, further studies are recommended to identify the exact mechanisms related to the neuroprotective effect of IL-1beta against the excitotoxicity on retinal neurons and its association with its antagonist receptor, IL-1ra. p38 is a member of the mitogen-activated protein (MAP) kinase superfamily and mediates intracellular signal transduction. Recent studies suggest that p38 is involved in apoptotic signaling in several cell types, including neurons. And p38 inhibitors was also reported to be potentially useful for the treatment of optic nerve trauma and neurodegenerative diseases that affect RGCs, such as glaucoma. Here we aim to evaluate if P38 signaling pathway is involved in the neuroprotective effect of interleukin-1b or interleukin-1ra on the glutamate induced RGC cell death-in vitro model in this current study. We hope to understand the possible mechanism involving in the glutamate induced neuotoxicity in glaucoma optic neuropathy and the potential effect of p38 inhibitors in treatment of glaucoma. |
