Autophagy-mediated neuroprotection induced by octreotide in an ex vivo model of early diabetic retinopathy
Autophagy-mediated neuroprotection induced by octreotide in an ex vivo model of early diabetic retinopathy
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DOI：
10.1016/j.phrs.2017.09.022
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发表时间：
2018-02-01
影响因子：
9.3
通讯作者：
Casini, Giovanni
中科院分区：
文献类型：
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作者：
Amato, Rosario;Catalani, Elisabetta;Casini, Giovanni
神经元损伤在糖尿病视网膜病变（DR）中起主要作用。我们的假设是，神经元死亡和存活之间的平衡可能取决于凋亡和自噬之间的类似平衡，神经保护剂可能通过影响这种平衡而起作用。用高葡萄糖（HG）处理离体小鼠视网膜外植体10天，并使用生长抑素类似物奥曲肽（OCT）作为神经保护剂。氯喹（CQ）被用作自噬抑制剂。采用蛋白质印迹和免疫组织化学方法评价细胞凋亡和自噬标志物。HG处理的外植体显示出凋亡的显著增加，这可能是由于自噬调节剂mTOR（雷帕霉素的哺乳动物靶）的活性增加而导致的自噬通量的显著降低。OCT治疗可使HG处理的视网膜外植体免于凋亡，并确定自噬活性增加伴mTOR抑制。阻断CQ的自噬通量完全取消OCT的抗凋亡作用。免疫组织化学观察表明，OCT诱导的自噬是本地化的双极和无长突细胞和神经节细胞的人口。这些观察结果揭示了细胞凋亡和自噬的对立作用，突出了它们的平衡，神经元的存活可能依赖于此。这些数据表明，自噬所涵盖的关键作用，这可以被认为是DR神经保护治疗策略的分子靶点。(C)2017爱思唯尔有限公司版权所有
Neuronal injury plays a major role in diabetic retinopathy (DR). Our hypothesis was that the balance between neuronal death and survival may depend on a similar equilibrium between apoptosis and autophagy and that a neuroprotectant may act by influencing this equilibrium. Ex vivo mouse retinal explants were treated with high glucose (HG) for 10 days and the somatostatin analog octreotide (OCT) was used as a neuroprotectant. Chloroquine (CQ) was used as an autophagy inhibitor. Apoptotic and autophagic markers were evaluated using western blot and immunohistochemistry. HG-treated explants displayed a significant increase of apoptosis paralleled by a significant decrease of the autophagic flux, which was likely to be due to increased activity of the autophagy regulator mTOR (mammalian target of rapamycin). Treatment with OCT rescued HG-treated retinal explants from apoptosis and determined an increase of autophagic activity with concomitant mTOR inhibition. Blocking the autophagic flux with CQ completely abolished the anti-apoptotic effect of OCT. Immunohistochemical observations showed that OCT-induced autophagy is localized to populations of bipolar and amacrine cells and to ganglion cells. These observations revealed the antithetic role of apoptosis and autophagy, highlighting their equilibrium from which neuronal survival is likely to depend. These data suggest the crucial role covered by autophagy, which could be considered as a molecular target for DR neuroprotective treatment strategies. (C) 2017 Elsevier Ltd. All rights reserved.