Estrogen may contribute to ischemic tolerance through modulation of cellular stress-related proteins

• Published in: Neuroscience research 2009-04, Vol.63 (4), p.273-279
• Main Authors: Saleh, Monique C., Connell, Barry J., Saleh, Tarek M.
• Format: Article
• Language: English
• Subjects: Animals; Calpain - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Endoplasmic reticulum stress; Estradiol - pharmacology; Estrogens - pharmacology; Gene Expression Regulation - drug effects; Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - metabolism; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - prevention & control; Ischemic tolerance; Male; MCAO; Membrane Proteins - metabolism; Molecular Chaperones - metabolism; Rats; Rats, Sprague-Dawley; Time Factors; Tunicamycin; Tunicamycin - pharmacology
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/j.neures.2009.01.004

Ischemic tolerance describes a phenomenon whereby subcritical stimuli evoke cellular protective mechanisms resulting in increased tolerance to subsequent ischemia. In the present study we propose that the cytoprotective effects attributed to 17β-estradiol and tunicamycin in an in vivo rodent model of ischemia are reflected by changes in neuronal tissue levels of m-calpain, HSP70, GRP94 and GRP78. Rats pretreated with 17β-estradiol, tunicamycin or both demonstrated dose-dependent reductions in infarct area following 4 h of permanent middle cerebral artery occlusion (MCAO). Western blot analysis revealed that 4 h of MCAO was associated with decreased cortical expression of HSP70 and m-calpain and increased expression of GRP78. Pretreatment with 12.5 μg/kg 17β-estradiol did not change this pattern of protein expression following MCAO. While GRP94 expression was elevated in sham-operated rats pretreated with 17β-estradiol, the ensuing ischemic tolerance did not appear to be mediated by changes in cellular stress proteins. Pretreatment with 50 μg/kg tunicamycin significantly reduced HSP70 in cortical tissue samples taken from sham-operated rats and appeared to attenuate the threshold for activation of m-calpain in rats undergoing 4 h of MCAO. Lastly, a combined treatment in which rats undergoing MCAO were pretreated with both tunicamycin (24 h prior) and 17β-estradiol (30 min prior) was associated with an attenuated stress response as indicated by reduced expression of GRP78 and GRP94 when compared to saline-treated controls. The results of this study suggest that the ischemic tolerance observed following MCAO in rats pretreated with either 17β-estradiol or tunicamycin is likely mediated in part through differential effects on cellular stress proteins.