Shimazawa Masamitsu, Sugitani Sou, Inoue Yuki, Tsuruma Kazuhiro, Hara Hideaki
Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
Exp Eye Res. 2015 Mar;132:64-72. doi: 10.1016/j.exer.2015.01.017. Epub 2015 Jan 20.
Cutamesine dihydrochloride is an agonist of sigma-1 receptor, which is a ligand-operated receptor chaperone at the mitochondrion-associated endoplasmic reticulum (ER) membrane. ER stress plays a pivotal role in light irradiation-induced retinal damage. In the present study, we examined whether cutamesine is effective against experimental degenerative retinal damages in vitro and in vivo. The effects of cutamesine against white light-induced retinal photoreceptor damage were evaluated in vitro by measuring cell death. The expression of sigma-1 receptor after the light exposure was examined by immunoblot analysis. The disruption of the mitochondrial membrane potential and caspase-3/7 activation after excessive light exposure were also examined. In addition, retinal damage in mice induced by irradiation to white light was evaluated using histological staining and electroretinography. Cutamesine reduced the cell death rate induced by light exposure, and the protective effect was prevented by N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD-1047) dihydrobromide, a sigma-1 receptor antagonist. Sigma-1 receptor expression was decreased by light exposure, and cutamesine suppressed the decreased expression of sigma-1 receptor protein. Cutamesine also reduced the mitochondrial damage and reduced the elevated level of caspase 3/7 activity; this effect was attenuated by BD-1047. In in vivo studies, cutamesine suppressed the light-induced retinal dysfunction and thinning of the outer nuclear layer in the mouse retina. These findings indicate that cutamesine protects against retinal cell death in vitro and in vivo by the agonistic effect of sigma-1 receptor. Therefore, sigma-1 receptor may have a potential as a therapeutic target in retinal diseases mediated by photoreceptor degeneration.
盐酸库他美辛是σ-1受体的激动剂，σ-1受体是位于线粒体相关内质网（ER）膜上的配体门控受体伴侣。内质网应激在光照射诱导的视网膜损伤中起关键作用。在本研究中，我们检测了库他美辛在体外和体内对实验性退行性视网膜损伤是否有效。通过测量细胞死亡在体外评估库他美辛对白光诱导的视网膜光感受器损伤的作用。通过免疫印迹分析检测光暴露后σ-1受体的表达。还检测了过度光暴露后线粒体膜电位的破坏和半胱天冬酶-3/7的激活。此外，使用组织学染色和视网膜电图评估白光照射诱导的小鼠视网膜损伤。库他美辛降低了光暴露诱导的细胞死亡率，并且N-[2-(3,4-二氯苯基)乙基]-N-甲基-2-(二甲基氨基)乙胺（BD-1047）二氢溴酸盐（一种σ-1受体拮抗剂）可阻止这种保护作用。光暴露使σ-1受体表达降低，而库他美辛抑制了σ-1受体蛋白表达的降低。库他美辛还减少了线粒体损伤并降低了半胱天冬酶3/7活性的升高水平；BD-1047减弱了这种作用。在体内研究中，库他美辛抑制了光诱导的小鼠视网膜功能障碍和外核层变薄。这些发现表明，库他美辛通过σ-1受体的激动作用在体外和体内保护视网膜细胞免于死亡。因此，σ-1受体可能有潜力作为由光感受器变性介导的视网膜疾病的治疗靶点。
