Calpain Inhibitor Protects Cells against Light-Induced Retinal Degeneration
Calpain Inhibitor Protects Cells against Light-Induced Retinal Degeneration
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DOI：
10.1124/jpet.110.171298
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发表时间：
2010-12-01
影响因子：
3.5
通讯作者：
Hara, Hideaki
中科院分区：
文献类型：
--
作者：
Imai, Shunsuke;Shimazawa, Masamitsu;Hara, Hideaki
钙蛋白酶被过度曝光激活，与视网膜变性有关。我们研究了钙蛋白酶抑制剂（（1 S）-1-（1 S）-1-苄基-3-环丙基氨基-2，3-二氧丙基）氨基）羰基）-3-甲基丁基）氨基甲酸5-甲氧基-3-氧戊酯（SNJ-1945）对小鼠光诱导视网膜变性的保护作用。在光暴露前30分钟和光暴露后立即以100和200 mg/kg的剂量口服给予SNJ-1945。光诱导的钙蛋白酶激活通过使用α-血影蛋白和p35（细胞周期蛋白依赖性激酶5的神经元特异性激活剂）的蛋白水解进行评价。通过外核层（ONL）厚度检查SNJ-1945对抗光诱导的视网膜损伤的作用。通过计数ONL中末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）阳性细胞来评估感光细胞凋亡。视网膜功能的a-和b-波振幅通过使用视网膜电图来测量。作为SNJ-1945的作用机制，进行了caspase-3/7的测量。SNJ-1945抑制α-血影蛋白和p35的蛋白水解，并呈现TUNEL阳性细胞数量减少和ONL萎缩。此外，SNJ-1945呈现出由光暴露诱导的a-和b-波振幅和caspase-3/7活化的降低。这些发现表明，钙蛋白酶的激活在光暴露引起的感光细胞变性中起着关键作用，SNJ-1945可能是有效治疗感光细胞变性相关疾病的候选药物。
Calpains are activated by excessive light exposure and related to retinal degeneration. We investigated the protective effects of ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester (SNJ-1945), a calpain inhibitor, against light-induced retinal degeneration in mice. SNJ-1945 was orally administrated at doses of 100 and 200 mg/kg at 30 min before and just after light exposure. Light-induced calpain activation was evaluated by using proteolysis of alpha-spectrin and p35 (a neuron-specific activator for cyclin-dependent kinase 5). The effects of SNJ-1945 against light-induced retinal damage were examined by the thickness of the outer nuclear layer (ONL). Photoreceptor apoptosis was assessed by counting terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)positive cells in ONL. Retinal functions were measured in terms of a- and b-wave amplitudes by using an electroretinogram. As the mechanism of SNJ-1945, caspase-3/7 measurement was carried out. SNJ-1945 inhibited the proteolysis of alpha-spectrin and p35 by light exposure and presented a decrease in the numbers of TUNEL-positive cells and ONL atrophy. Furthermore, SNJ-1945 presented a decrease in a-and b-wave amplitude and caspase-3/7 activation induced by light exposure. These findings suggest that the activation of calpain plays a pivotal role in photoreceptor degeneration by light exposure, and SNJ-1945 may be a candidate for effectively treating diseases related to photoreceptor degeneration.