Memantine blocks mitochondrial OPA1 and cytochrome c release and subsequent apoptotic cell death in glaucomatous retina.
Memantine blocks mitochondrial OPA1 and cytochrome c release and subsequent apoptotic cell death in glaucomatous retina.
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DOI：
10.1167/iovs.08-2499
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发表时间：
2009-02
影响因子：
4.4
通讯作者：
Weinreb RN
中科院分区：
文献类型：
--
作者：
Ju WK;Kim KY;Angert M;Duong-Polk KX;Lindsey JD;Ellisman MH;Weinreb RN
确定眼内压（IOP）升高是否改变OPA 1表达并触发OPA 1释放，以及非竞争性N-甲基-D-天冬氨酸（NMDA）谷氨酸受体拮抗剂美金刚是否阻断OPA 1释放和随后的凋亡性细胞死亡。青光眼前期DBA/2 J小鼠接受美金刚胺（5 mg/kg，腹膜内注射，每天两次，持续3个月），并且每月测量眼睛中的IOP。在Fluoro-Gold标记后计数RGC损失。Taqman定量PCR检测OPA 1、Dnm 1、Bcl-2和Bax mRNA的表达。免疫组化和Western blot检测OPA 1蛋白表达。通过TUNEL染色评估凋亡细胞死亡。美金刚胺治疗显著增加了胶质瘤DBA/2 J小鼠的RGC存活率。美金刚治疗增加了75 kDa的OPA 1亚型，但没有改变80和90 kDa的亚型。OPA 1亚型在溶剂处理的青光眼视网膜的胞质溶胶中显著增加，但在美曼汀处理的青光眼视网膜中显著降低。OPA 1免疫反应性降低的光感受器的车辆和美曼汀治疗的视网膜，但增加的外丛状层的只有美曼汀治疗的视网膜。美金刚可阻断GCL中的凋亡性细胞死亡，增加Bcl-2基因表达，降低Bax基因表达。阻断谷氨酸受体激活可抑制脑水肿小鼠视网膜线粒体OPA 1的释放由于这种OPA 1效应伴随着Bcl-2表达增加、Bax表达减少和细胞凋亡阻断，因此在青光眼视网膜中谷氨酸受体激活可能涉及独特的谷氨酸介导的细胞死亡途径。
To determine whether intraocular pressure (IOP) elevation alters OPA1 expression and triggers OPA1 release, as well as whether the uncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist memantine blocks OPA1 release and subsequent apoptotic cell death in glaucomatous DBA/2J mouse retina. Preglaucomatous DBA/2J mice received memantine (5 mg/kg, i.p. injection, twice a day for 3 months) and IOP in the eyes was measured monthly. RGC loss was counted following Fluoro-Gold labeling. OPA1, Dnm1, Bcl-2 and Bax mRNA were measured by Taqman qPCR. OPA1 protein was assessed by immunohistochemistry and Western blot. Apoptotic cell death was assessed by TUNEL staining. Memantine treatment significantly increased RGC survival in glaucomatous DBA/2J mice. Memantine treatment increased the 75 kDa OPA1 isoform but did not alter the 80 and 90 kDa isoforms. The isoforms of OPA1 were significantly increased in the cytosol of the vehicle-treated glaucomatous retinas but were significantly decreased in memantine-treated glaucomatous retinas. OPA1 immunoreactivity was decreased in the photoreceptors of both vehicle- and memantine-treated glaucomatous retinas but was increased in the outer plexiform layer of only the memantine-treated glaucomatous retinas. Memantine blocked apoptotic cell death in the GCL, increased Bcl-2 gene expression, and decreased Bax gene expression. OPA1 release from mitochondria in glaucomatous mouse retina is inhibited by blockade of glutamate receptor activation. Because this OPA1 effect was accompanied by increased Bcl-2 expression, decreased Bax expression and apoptosis blockade, glutamate receptor activation in the glaucomatous retina may involve a distinct mitochondria-mediated cell death pathway.
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影响因子：
2.9
作者：
Araki, CM;Hamassaki-Britto, DE
通讯作者：
Hamassaki-Britto, DE
影响因子：
12.4
作者：
Estaquier, J.;Arnoult, D.
通讯作者：
Arnoult, D.
影响因子：
4.4
作者：
Aijaz, S;Erskine, L;Votruba, M
通讯作者：
Votruba, M
影响因子：
56.9
作者：
Antonsson, B;Conti, F;Martinou, JC
通讯作者：
Martinou, JC
影响因子：
2
作者：
Chow, S. K.;Hakozaki, H.;Ellisman, M. H.
通讯作者：
Ellisman, M. H.