Effects of 17beta-oestradiol on cerebral ischaemic damage and lipid peroxidation.
BACKGROUND
Numerous studies demonstrate oestrogen's neuroprotective effect in stroke models, although the mechanisms are unclear. Since oestrogen is an antioxidant, we tested the hypothesis that oestrogen reduces stroke-induced damage by reducing free radical damage, particularly lipid peroxidation.


METHODS
Sprague-Dawley rats were ovariectomised and a 17beta-oestradiol (0.25 mg, 21 day release) or placebo pellet implanted subcutaneously. Two weeks later, permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal filament. At 2 and 24 h post-MCAO, neurological deficits were assessed. At the 24 h end point, plasma oestradiol was measured and brain sections stained with haematoxylin and eosin or lipid peroxidation marker, 4-hydroxynonenol (4-HNE) immunohistochemistry carried out to measure infarct volume and volume of tissue displaying oxidative damage, respectively.


RESULTS
Plasma 17beta-oestradiol in oestradiol and placebo groups was 72.6+/-38.0 and 9.3+/-7.4 pg/ml (mean+/-SD), respectively. Infarct volume was significantly increased (118%) with oestradiol treatment (oestradiol=124+/-84.5, placebo=57+/-46.4 mm3, mean+/-SD, P<0.05). The relationship between 4-HNE and infarct volume was significantly influenced by 17beta-oestradiol. Neurological deficits were similar between groups (oestradiol median=13, placebo=14, max score=33).


CONCLUSIONS
Two week pre-treatment with a high physiological dose of 17beta-oestradiol increased infarct volume after permanent MCAO. Although contrary to our original hypothesis, this result demonstrates that oestrogen does have the capacity to promote detrimental actions in the stroke-injured brain. Given the wide use of oestrogen (contraception, osteoporosis and menopause), more research to clarify the influence of oestrogen on brain injury is urgently required.
Gordon
Kirsty B
KB
Division of Clinical Neuroscience, Wellcome Surgical Institute, University of Glasgow, Garscube Estate, Bearsden Road, Glasgow G61 1QH, UK.
Macrae
I Mhairi
IM
Carswell
Hilary V O
HV
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000009:adverse effects; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002544:Cerebral Infarction / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004343:Drug Implants; D004958:Estradiol / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D009460:Neurologic Examination; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000447:Aldehydes; D000975:Antioxidants; D004343:Drug Implants; D004958:Estradiol; C027576:4-hydroxy-2-nonenal