The Enantiomer of Allopregnanolone Prevents Pressure-Mediated Retinal Degeneration Via Autophagy.
The Enantiomer of Allopregnanolone Prevents Pressure-Mediated Retinal Degeneration Via Autophagy.
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DOI：
10.3389/fphar.2022.855779
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发表时间：
2022
影响因子：
5.6
通讯作者：
Izumi Y
中科院分区：
文献类型：
--
作者：
Ishikawa M;Nakazawa T;Kunikata H;Sato K;Yoshitomi T;Krishnan K;Covey DF;Zorumski CF;Izumi Y
在体外大鼠高眼压模型中，神经类固醇别孕激素通过增强GABAA受体和自噬发挥神经保护作用。我们现在检查它的对映体(ent-allP)是否在体外和体内的大鼠OHT模型中提供了类似的神经保护作用。将体外大鼠视网膜标本置于高压(10和75 mm Hg)中孵育24 h，采用房内注射聚苯乙烯微珠的方法建立体内高眼压(OHT)模型。我们从组织学和生物化学的角度研究了allP、ent-allP、印防己毒素(GABAA受体拮抗剂)和3-MA(自噬抑制剂)的药理作用。我们发现，异丙酚和异丙酚在视网膜中都有明显的神经保护作用，但非天然对映体的作用不依赖于GABAA受体。电子显微镜分析表明，压力升高可显着增加神经纤维层的自噬小体(APs)，加入AllP还可增加APs和退行性自噬空泡(AVDS)。Et-AlloP组较AlloP组AP和AVDS显著增加。免疫印迹法检测LC3B-II和SQSTM1蛋白水平显示，AlloP使LC3B-II升高，而Ent-allP进一步增强了LC3B-II，抑制了SQSTM1，提示自噬是Ent-AlloP保护神经的主要机制。在大鼠体内OHT模型中，单次玻璃体腔内注射AllP可防止视网膜神经节细胞的凋亡性细胞死亡，其作用类似于AlloP。然而，即使在这个模型中，ent-allP在激活自噬方面也比allP更有效。我们的结论是，作为一种不影响GABA受体的自噬增强剂，ent-allP可能是治疗青光眼的一个潜在的治疗原型。
In an ex vivo rat ocular hypertension (OHT) model, the neurosteroid allopregnanolone (AlloP) exerts neuroprotective effects via enhancement of both GABAA receptors and autophagy. We now examine whether its enantiomer (ent-AlloP), which is largely inactive at GABA receptors, offers similar neuroprotection in ex vivo and in vivo rat OHT models. Ex vivo rat retinal preparations were incubated in a hyperbaric condition (10 and 75 mmHg) for 24 h. An in vivo ocular hypertension (OHT) model was induced by intracameral injection of polystyrene microbeads. We examined pharmacological effects of AlloP, ent-AlloP, picrotoxin (a GABAA receptor antagonist), and 3-MA (an autophagy inhibitor) histologically and biochemically. We found that both AlloP and ent-AlloP have marked neuroprotective effects in the retina, but effects of the unnatural enantiomer are independent of GABAA receptors. Electron microscopic analyses show that pressure elevation significantly increased autophagosomes (APs) in the nerve fiber layer and addition of AlloP also increased APs and degenerative autophagic vacuoles (AVds). ent-AlloP markedly increased APs and AVds compared to AlloP. Examination of LC3B-II and SQSTM1 protein levels using immunoblotting revealed that AlloP increased LC3B-II, and ent-AlloP further enhanced LC3B-II and suppressed SQSTM1, indicating that autophagy is a major mechanism underlying neuroprotection by ent-AlloP. In an rat in vivo OHT model, single intravitreal ent-AlloP injection prevented apoptotic cell death of retinal ganglion cells similar to AlloP. However, even in this model, ent-AlloP was more effective in activating autophagy than AlloP. We conclude that ent-AlloP may be a prototype of potential therapeutic for treatment of glaucoma as an autophagy enhancer without affecting GABA receptors.
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影响因子：
9
作者：
通讯作者：
--
DOI：
10.1016/0309-1651(86)90027-5
发表时间：
1986-07-01
期刊：
CELL BIOLOGY INTERNATIONAL REPORTS
影响因子：
--
作者：
DEWAAL, EJ;VREELINGSINDELAROVA, H;JAMES, J
通讯作者：
JAMES, J
DOI：
10.1039/a703212i
发表时间：
1997-12-21
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1
影响因子：
--
作者：
Hu, YF;Wittmer, LL;Covey, DF
通讯作者：
Covey, DF
青光眼中的视网膜神经节细胞凋亡与眼内压和IOP诱导的细胞外基质有关。
影响因子：
4.4
作者：
Guo L;Moss SE;Alexander RA;Ali RR;Fitzke FW;Cordeiro MF
通讯作者：
Cordeiro MF
影响因子：
2.7
作者：
Covey, Douglas F.
通讯作者：
Covey, Douglas F.