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Evaluation of the aldose reductase inhibitor fidarestat on ischemia-reperfusion injury in rat retina

Obrosova, Irina G.; Maksimchyk, Yury; Pacher, Pal; Agardh, Elisabet LU ; Smith, Maj-Lis LU ; El-Remessy, Azza B. and Agardh, Carl-David LU (2010) In International Journal of Molecular Medicine 26(1). p.135-142
Abstract
This study evaluated the effects of retinal ischemia-reperfusion (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-elucamine) or fidarestat, 32 mg kg(-1)d(-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... (More)
This study evaluated the effects of retinal ischemia-reperfusion (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-elucamine) or fidarestat, 32 mg kg(-1)d(-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 ER 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 non-ischemic 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
sorbitol dehydrogenase, ischemia-reperfusion, retinal, nitrated proteins, fidarestat, aldose reductase, apoptosis
in
International Journal of Molecular Medicine
volume
26
issue
1
pages
135 - 142
publisher
D.A. Spandidos
external identifiers
  • wos:000279132000019
  • scopus:77954735649
ISSN
1791-244X
DOI
10.3892/ijmm_00000445
language
English
LU publication?
yes
id
30587201-3fc4-4c0c-99d8-3b2b53b73e8c (old id 1630141)
date added to LUP
2010-07-23 12:40:52
date last changed
2018-05-29 12:12:57
@article{30587201-3fc4-4c0c-99d8-3b2b53b73e8c,
  abstract     = {This study evaluated the effects of retinal ischemia-reperfusion (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-elucamine) or fidarestat, 32 mg kg(-1)d(-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&lt;0.01), and this increase was partially prevented by fidarestat. AR expression (Western blot analysis) increased by 19% in the IR group (p&lt;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 ER 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 non-ischemic controls (p&lt;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.},
  author       = {Obrosova, Irina G. and Maksimchyk, Yury and Pacher, Pal and Agardh, Elisabet and Smith, Maj-Lis and El-Remessy, Azza B. and Agardh, Carl-David},
  issn         = {1791-244X},
  keyword      = {sorbitol dehydrogenase,ischemia-reperfusion,retinal,nitrated proteins,fidarestat,aldose reductase,apoptosis},
  language     = {eng},
  number       = {1},
  pages        = {135--142},
  publisher    = {D.A. Spandidos},
  series       = {International Journal of Molecular Medicine},
  title        = {Evaluation of the aldose reductase inhibitor fidarestat on ischemia-reperfusion injury in rat retina},
  url          = {http://dx.doi.org/10.3892/ijmm_00000445},
  volume       = {26},
  year         = {2010},
}