Neuroprotective effects of VCP modulators in mouse models of glaucoma.
Neuroprotective effects of VCP modulators in mouse models of glaucoma.
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DOI：
10.1016/j.heliyon.2016.e00096
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发表时间：
2016-04
期刊：
影响因子：
4
通讯作者：
Yoshimura N
中科院分区：
文献类型：
--
作者：
Nakano N;Ikeda HO;Hasegawa T;Muraoka Y;Iwai S;Tsuruyama T;Nakano M;Fuchigami T;Shudo T;Kakizuka A;Yoshimura N
青光眼是由于视网膜神经节细胞的逐渐死亡而导致成人失明的主要原因。目前，没有治疗剂可用于保护这些细胞免于细胞死亡。我们最近成功地合成了新型化合物KUS（京都大学物质），它可以通过特异性抑制VCP（细胞中主要的ATP酶）的ATP酶活性来减少细胞ATP消耗，我们已经证明KUS可以减轻视网膜色素变性小鼠模型rd 10的疾病进展，而没有任何明显的副作用。在这里，我们表明，KUSs（如KUS 121和KUS 187）可以防止抗霉素和寡霉素诱导的ATP耗竭，内质网（ER）的压力，并在神经元分化的PC 12细胞的细胞死亡。此外，KUSs对几种青光眼小鼠模型表现出显著的功效。在用N-甲基-D-天冬氨酸诱导的视网膜神经节细胞丧失的急性损伤小鼠模型中，KUS给药预防或减轻了视网膜神经节细胞的ER应激和随后的凋亡性细胞死亡。在具有高眼内压的青光眼小鼠模型中，KUSs预防了典型的青光眼病理，即视盘杯状扩大和视网膜神经纤维层变薄。KUS还保留了GLAST敲除小鼠的视觉功能，这是一种慢性视网膜神经节细胞丢失的小鼠模型。我们提出通过抑制VCP的ATP酶活性来“ATP维持”作为目前无法治愈的眼病（如青光眼）的一种有前途的新的神经保护策略。
Glaucoma is a major cause of adult blindness due to gradual death of retinal ganglion cells. Currently, no therapeutics are available for the protection of these cells from the cell death. We have recently succeeded in synthesizing novel compounds, KUSs (Kyoto University Substances), which can reduce cellular ATP consumption by specifically inhibiting the ATPase activities of VCP, a major ATPase in the cell, and we have shown that KUSs could mitigate the disease progression of rd10, a mouse model of retinitis pigmentosa, without any apparent side effects. Here we show that KUSs (e.g. KUS121 and KUS187) can prevent antimycin- and oligomycin-induced ATP depletion, endoplasmic reticulum (ER) stress, and cell death in neuronally differentiated PC12 cells. Furthermore, KUSs manifest significant efficacies on several mouse models of glaucoma. KUS administration prevented or mitigated ER stress and subsequent apoptotic cell death of retinal ganglion cells in an acute injury mouse model of retinal ganglion cell loss, which was induced with N-methyl-D-aspartate. In a mouse model of glaucoma with high intraocular pressure, KUSs prevented the typical glaucoma pathologies, i.e. enlargement of optic disc cupping and thinning of the retinal nerve fiber layer. KUSs also preserved visual functions in GLAST knockout mice, a mouse model for chronic retinal ganglion cell loss. We propose “ATP maintenance” via inhibition of ATPase activities of VCP as a promising new neuroprotective strategy for currently incurable eye diseases, such as glaucoma.