Soluble Epoxide Hydrolase Blockade after Stroke Onset Protects Normal but Not Diabetic Mice.
Soluble Epoxide Hydrolase Blockade after Stroke Onset Protects Normal but Not Diabetic Mice.
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DOI：
10.3390/ijms22115419
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发表时间：
2021-05-21
影响因子：
5.6
通讯作者：
Alkayed NJ
中科院分区：
文献类型：
--
作者：
Davis CM;Zhang WH;Allen EM;Bah TM;Shangraw RE;Alkayed NJ
可溶性环氧化物水解酶（sEH）在脑中含量丰富，在2型糖尿病（DM 2）中上调，并且可能通过神经保护性环氧二十碳三烯酸（Epoxyeicosatrienoic Acids，EEP）的分解而成为缺血性损伤的介质。用4-[[反式-4-[[（三环[3.3.1.13，7]癸-1-基氨基）羰基]氨基]环己基]氧基]-苯甲酸（tAUCB）预防性缺血前sEH阻断减少了正常和糖尿病小鼠中中风诱导的梗死，在DM 2中具有更大的神经保护作用。本研究测试了如果在中风发作后施用tAUCB，在正常和DM 2小鼠中是否发生益处。我们将年轻成年雄性C57 BL小鼠分为四组：正常组或DM 2组，在再灌注前30分钟给予t-AUCB 2 mg/kg或溶媒，进行60分钟的大脑中动脉闭塞。终点为（1）激光多普勒脑血流（CBF）和（2）24 h脑梗死。在非糖尿病小鼠中，与溶剂处理的小鼠相比，t-AUCB使皮质中的梗死面积减少了30%（分别为31.4 ± 4 vs. 43.8 ± 3（SEM）%），使整个半球中的梗死面积减少了26%（26.3 ± 3 vs. 35.2 ± 2%，均p < 0.05）。相反，在DM 2小鼠中，tAUCB未能改善皮质或半球损伤。CBF无差异。我们得出结论，缺血性卒中发作后给予tAUCB对非糖尿病小鼠而非DM 2小鼠发挥脑保护作用，神经保护作用似乎独立于总CBF的变化，DM 2诱导的高血糖症在卒中发作后消除了t-AUCB介导的神经保护作用。
Soluble epoxide hydrolase (sEH) is abundant in the brain, is upregulated in type 2 diabetes mellitus (DM2), and is possible mediator of ischemic injury via the breakdown of neuroprotective epoxyeicosatrienoic acids (EETs). Prophylactic, pre-ischemic sEH blockade with 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (tAUCB) reduces stroke-induced infarct in normal and diabetic mice, with larger neuroprotection in DM2. The present study tested whether benefit occurs in normal and DM2 mice if tAUCB is administered after stroke onset. We performed 60 min middle cerebral artery occlusion in young adult male C57BL mice divided into four groups: normal or DM2, with t-AUCB 2 mg/kg or vehicle 30 min before reperfusion. Endpoints were (1) cerebral blood flow (CBF) by laser Doppler, and (2) brain infarct at 24 h. In nondiabetic mice, t-AUCB reduced infarct size by 30% compared to vehicle-treated mice in the cortex (31.4 ± 4 vs. 43.8 ± 3 (SEM)%, respectively) and 26% in the whole hemisphere (26.3 ± 3 vs. 35.2 ± 2%, both p < 0.05). In contrast, in DM2 mice, tAUCB failed to ameliorate either cortical or hemispheric injury. No differences were seen in CBF. We conclude that tAUCB administered after ischemic stroke onset exerts brain protection in nondiabetic but not DM2 mice, that the neuroprotection appears independent of changes in gross CBF, and that DM2-induced hyperglycemia abolishes t-AUCB-mediated neuroprotection after stroke onset.
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DOI：
10.1016/s0140-6736(15)60401-9
发表时间：
2015-02-01
期刊：
The lancet. Diabetes & endocrinology
影响因子：
--
作者：
Shah, Anoop Dinesh;Langenberg, Claudia;Hemingway, Harry
通讯作者：
Hemingway, Harry
影响因子：
6.3
作者：
Ferris, Jennifer K.;Peters, Sue;Boyd, Lara A.
通讯作者：
Boyd, Lara A.
影响因子：
48
作者：
Gray, Christopher S.;Hildreth, Anthony J.;Alberti, K. George M. M.
通讯作者：
Alberti, K. George M. M.
影响因子：
9.9
作者：
Larsson, Susanna C.;Scott, Robert A.;Markus, Hugh S.
通讯作者：
Markus, Hugh S.
DOI：
10.1056/nejmoa1506930
发表时间：
2016-04-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Kernan WN;Viscoli CM;Furie KL;Young LH;Inzucchi SE;Gorman M;Guarino PD;Lovejoy AM;Peduzzi PN;Conwit R;Brass LM;Schwartz GG;Adams HP Jr;Berger L;Carolei A;Clark W;Coull B;Ford GA;Kleindorfer D;O'Leary JR;Parsons MW;Ringleb P;Sen S;Spence JD;Tanne D;Wang D;Winder TR;IRIS Trial Investigators
通讯作者：
IRIS Trial Investigators