Aldo-Keto Reductase 1C15 Characterization and Protection in Ischemic Brain Injury.
Aldo-Keto Reductase 1C15 Characterization and Protection in Ischemic Brain Injury.
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DOI：
10.3390/antiox12040909
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发表时间：
2023-04-11
期刊：
影响因子：
7
通讯作者：
Zhang, Feng
中科院分区：
文献类型：
--
作者：
Yang, Tuo;Li, Qianqian;Fadoul, George;Alraqmany, Nour;Ikonomovic, Milos;Zhang, Feng
醛酮还原酶(AKR)1C15是新近发现和克隆的AKR超家族成员，具有减轻啮齿动物肺内皮细胞氧化应激的作用。然而，它在脑和缺血性脑病中的表达和作用尚未被研究。实时定量聚合酶链式反应检测AKR1C15的表达。分别用大脑中动脉阻塞(MCAO)1h和12min建立小鼠缺血性卒中和缺血预适应(IPC)模型。重组AKR1C15经腹腔注射，通过神经行为测试和脑梗塞体积评估卒中结果。对原代培养的大鼠脑细胞进行缺氧-葡萄糖剥夺(OGD)，模拟脑缺血损伤。测定细胞存活率和体外血脑屏障(BBB)通透性，并检测一氧化氮(NO)释放。免疫染色和Western blotting检测氧化应激相关蛋白的表达。AKR1C15可减少卒中后2d的脑梗塞体积和神经功能缺失，IPC后早期(1h)应用AKR1C15可取消IPC对卒中的保护作用。在原代培养的大鼠脑细胞中，AKR1C15在脑微血管内皮细胞(BMVECs)和小胶质细胞中大量表达。OGD后，除BMVEC和小胶质细胞外，其在大多数细胞类型中的表达均下降。在原代培养的神经元中，AKR1C15治疗阻止了OGD诱导的细胞死亡，同时降低了4-羟基-2‘-脱氧鸟苷和血红素加氧酶-1的水平。在培养的BMVEC中，AKR1C15处理对OGD诱导的细胞死亡和体外BBB泄漏具有保护作用。在原代培养的小胶质细胞中，AKR1C15减少了促炎刺激下NO的释放。我们的结果提供了新型抗氧化剂AKR1C15的特征，并证明了其在体内和体外对缺血损伤的保护作用。AKR1C15可能是治疗缺血性中风的一种有前途的药物。
Aldo-keto reductase (AKR) 1C15, a member of the AKR superfamily, was recently identified and cloned, and reported to alleviate oxidative stress in endothelial cells in rodent lungs. However, its expression and role in the brain and ischemic brain diseases have not been investigated. AKR1C15 expression was detected with real-time PCR. Mouse ischemic stroke and ischemic preconditioning (IPC) were established with middle cerebral artery occlusion (MCAO) for 1 h or 12 min, respectively. Recombinant AKR1C15 was administered intraperitoneally, and stroke outcome was evaluated with neurobehavioral tests and infarct volumes. Rat primary brain cell cultures were subjected to oxygen–glucose deprivation (OGD) to mimic ischemic injury. Cell survival or in vitro blood–brain barrier (BBB) permeability was measured, and nitric oxide (NO) release was detected. Immunostaining and Western blotting were used to evaluate oxidative-stress-related protein expression. AKR1C15 administration decreased the infarct volume and neurological deficits 2d post-stroke, and its early (1-h) administration after IPC abolished the protection of IPC against stroke. In rat primary brain cell cultures, AKR1C15 was most abundantly expressed in brain microvascular endothelial cells (BMVECs) and microglia. Its expression decreased upon OGD in most cell types except for BMVECs and microglia. In primary neuronal cultures, AKR1C15 treatment prevented OGD-induced cell death accompanied by decreased levels of 4-hydroxynonenal, 8-hydroxy-2′-deoxyguanosine, and heme oxygenase-1. In BMVEC cultures, AKR1C15 treatment protected against OGD-induced cell death and in vitro BBB leakage. In primary microglial cultures, AKR1C15 reduced the release of NO upon proinflammatory stimulation. Our results provide a characterization of the novel antioxidant AKR1C15 and demonstrate its protective role against ischemic injury, both in vivo and in vitro. AKR1C15 may be a promising agent for ischemic stroke treatment.
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影响因子：
10.6
作者：
Schaur, R. J.
通讯作者：
Schaur, R. J.
影响因子：
5.1
作者：
Hyndman, D;Bauman, DR;Penning, TM
通讯作者：
Penning, TM
影响因子：
37.3
作者：
Velica, Pedro;Davies, Nicholas J.;Bunce, Chris M.
通讯作者：
Bunce, Chris M.
影响因子：
8.3
作者：
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STAIR Group
影响因子：
4.1
作者：
Penning, TM;Burczynski, ME;Ratnam, K
通讯作者：
Ratnam, K