Evaluation of the aldose reductase inhibitor fidarestat on ischemia-reperfusion injury in rat retina.
Evaluation of the aldose reductase inhibitor fidarestat on ischemia-reperfusion injury in rat retina.
复制标题
DOI：
10.3892/ijmm_00000445
复制
发表时间：
2010-07
影响因子：
5.4
通讯作者：
Agardh CD
中科院分区：
文献类型：
--
作者：
Obrosova IG;Maksimchyk Y;Pacher P;Agardh E;Smith ML;El-Remessy AB;Agardh CD
本研究评价了视网膜缺血再灌注（IR）损伤和有效的特异性醛糖还原酶抑制剂非达司他预处理对细胞凋亡、醛糖还原酶和山梨醇脱氢酶表达、山梨醇途径中间浓度和氧化-亚硝化应激的影响。雌性Wistar大鼠经右颈静脉给予溶剂（N-甲基-D-葡糖胺）或非达司他（32 mg kg − 1 d −1）预处理，连续3天。一组溶剂和非达司他处理的大鼠进行45分钟的视网膜缺血，然后进行24小时的再灌注。在最后一次溶媒或非达司他给药后30分钟诱导缺血。视网膜IR导致视网膜细胞死亡显著增加。与非缺血对照组相比，IR组中TUNEL阳性细胞核的数量增加了48倍（p<0.01），非达司他部分阻止了这种增加。IR组中AR表达（Western印迹分析）增加19%（p<0.05），并且这种增加被非达司他阻止。山梨醇脱氢酶和硝化蛋白的表达在所有实验组中相似。视网膜山梨醇浓度在IR组中倾向于增加，但与非缺血对照组的差异未达到统计学显著性（p=0.08）。IR组视网膜果糖浓度是非缺血对照组的2.2倍（p<0.05）。非达司他预处理IR大鼠可将视网膜山梨醇浓度降低至非缺血对照组水平。非达司他预处理IR组与未处理缺血对照组相比，视网膜果糖浓度降低了41%（p=0.0517），但仍比非缺血对照组高30%。总之，大鼠视网膜的IR损伤与细胞死亡、AR表达升高和山梨醇途径中间产物积累的急剧增加相关。AR抑制剂非达司他可预防或缓解这些变化。结果确定AR作为涉及IR损伤的疾病的重要治疗靶点，并为开发非达司他和其他AR抑制剂提供了理论基础。
This study evaluated the effects of retinal ischemiareperfusion (IR) injury and pre-treatment with the potent and specific aldose reductase inhibitor fidarestat on apoptosis, aldose reductase and sorbitol dehydrogenase expression, sorbitol pathway intermediate concentrations, and oxidative-nitrosative stress. Female Wistar rats were pre-treated with either vehicle (N-methyl-D-glucamine) or fidarestat, 32 mgkg−1d−1 for both, in the right jugular vein, for 3 consecutive days. A group of vehicle- and fidarestat-treated rats were subjected to 45-min retinal ischemia followed by 24-h reperfusion. Ischemia was induced 30 min after the last vehicle or fidarestat administration. Retinal IR resulted in a remarkable increase in retinal cell death. The number of TUNEL-positive nuclei increased 48-fold in the IR group compared with non-ischemic controls (p<0.01), and this increase was partially prevented by fidarestat. AR expression (Western blot analysis) increased by 19% in the IR group (p<0.05), and this increase was prevented by fidarestat. Sorbitol dehydrogenase and nitrated protein expressions were similar among all experimental groups. Retinal sorbitol concentrations tended to increase in the IR group but the difference with non-ischemic controls did not achieve statistical significance (p=0.08). Retinal fructose concentrations were 2.2-fold greater in the IR group than in the nonischemic controls (p<0.05). Fidarestat pre-treatment of rats subjected to IR reduced retinal sorbitol concentration to the levels in non-ischemic controls. Retinal fructose concentrations were reduced by 41% in fidarestat-pre-treated IR group vs. untreated ischemic controls (p=0.0517), but remained 30% higher than in the non-ischemic control group. In conclusion, IR injury to rat retina is associated with a dramatic increase in cell death, elevated AR expression and sorbitol pathway intermediate accumulation. These changes were prevented or alleviated by the AR inhibitor fidarestat. The results identify AR as an important therapeutic target for diseases involving IR injury, and provide the rationale for development of fidarestat and other AR inhibitors.
登录
查看更多内容
DOI：
10.1152/ajpheart.01012.2008
发表时间：
2009-02-01
影响因子：
4.8
作者：
Ananthakrishnan, Radha;Kaneko, Michiyo;Ramasamy, Ravichandran
通讯作者：
Ramasamy, Ravichandran
影响因子：
16.2
作者：
Hamada, Y;Nakamura, J;Hotta, N
通讯作者：
Hotta, N
DOI：
10.1016/0006-3002(60)90086-x
发表时间：
1960-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
HERS, HG
通讯作者：
HERS, HG
影响因子：
4.2
作者：
Ji, Dan;Li, Guang-Yu;Osborne, Neville N.
通讯作者：
Osborne, Neville N.
影响因子：
15.9
作者：
Barber, AJ;Lieth, E;Gardner, TW
通讯作者：
Gardner, TW