title: Aldose reductase inhibition ameliorates the detrimental effect of estrogen replacement therapy on neuropathology in diabetic rats subjected to transient forebrain ischemia.
abstract: Estrogen replacement therapy (ERT) elicits a deleterious, instead of protective, effect on neuropathology in diabetic ovariectomized (OVX) rats subjected to cerebral ischemia. This transformation may be linked to an estrogen-associated increase in function of the receptor for advanced glycation end-products (RAGE). Moreover, under diabetic conditions, advanced glycation end-products (AGEs) are excessively generated through the aldose reductase (AR)-polyol pathway. As such, in diabetic rats given ERT, a RAGE-related exacerbation of post-ischemic brain injury can occur. Thus, in the present study, we evaluated the contribution of AR in estrogen's detrimental effect on diabetic animals subjected to transient forebrain ischemia (TFI). Streptozotocin- and 17-beta estradiol-treated OVX female rats were divided into two groups, where AR activity was blocked using epalrestat; or AGEs production was restricted, via administrating the protein glycation crosslink breaker, ALT-711. In all animals, ERT was initiated approximately 10days before TFI. Pial venular leukocyte adhesion was evaluated over 10h post-TFI using a cranial window/intravital microscopy technique. In vehicle-treated control groups, a significant increase in leukocyte adhesion was observed post-TFI. Leukocyte extravasation, starting at approximately 6h post-TFI, was detected in most of the control animals. Chronic administration of either epalrestat or ALT-711 was associated with a marked decrease in post-TFI leukocyte adhesion, and the complete prevention of leukocyte extravasation. Animals receiving either epalrestat or ALT-711 exhibited a significant improvement in neurologic function, at 72h post-ischemia, compared to vehicle-treated controls. Post-ischemic (72h) histopathology was significantly reduced by epalrestat. Compared to the non-diabetic (ND) controls, diabetic OVX rats in the absence or presence of ERT showed a significant 2-fold or 3-fold increase in cortical AR mRNA levels, respectively. In contrast, only a modest increase in AR protein expression, relative to ND control, was detected in the two diabetic groups. The present findings suggest that AR participates in estrogen's deleterious action on post-ischemic neuropathology in diabetics by promoting inflammation. Targeting the AR-controlled polyol pathway may be a clinically promising strategy to restore the neuroprotection of ERT in diabetic females.
authors.affiliation: Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Shen
authors.forename: Francesco
authors.initials: F
authors.lastname: Vetri
authors.forename: Lizhen
authors.initials: L
authors.lastname: Mao
authors.forename: Hao-Liang
authors.initials: HL
authors.lastname: Xu
authors.forename: Chanannait
authors.initials: C
authors.lastname: Paisansathan
authors.forename: Dale A
authors.initials: DA
authors.lastname: Pelligrino
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology; D048909:Diabetes Complications / Q000201:enzymology* / Q000378:metabolism / Q000628:therapy*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000201:enzymology; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D000449:Aldehyde Reductase