LY353381.HCl, a selective estrogen receptor modulator, and experimental stroke.
OBJECTIVE
The impact of postmenopausal estrogen replacement therapy on stroke prevention and stroke severity remains controversial. Previously we have shown that cerebral tissue infarction volume sustained after middle cerebral artery (MCA) occlusion is smaller in female than in male animals. This protection is lost after ovariectomy but is restored by 17ss-estradiol replacement. However, the therapeutic range for estradiol is suboptimal, since only doses resulting in a narrow range of plasma levels are protective in brain. The present study tested the hypothesis that a benzothiophene analogue and selective estrogen receptor modulator, LY353381.HCl (LY), reduces tissue infarction after MCA occlusion in estrogen-deficient, ovariectomized female rats.


METHODS
Ovariectomized female Wistar rats received LY 10 mg/kg (n=16) or an equivalent volume of vehicle (n=14) by gavage for 5 to 8 days. Subsequently, each animal was anesthetized with halothane (1.2%) and treated with 2 hours of MCA occlusion by the intraluminal filament technique and 22 hours of recovery. Infarction volumes in the cerebral cortex and caudoputamen were determined by 2, 3,5-triphenyltetrazolium chloride staining and digital image analysis. End-ischemic regional cerebral blood flow (CBF) was measured in separate animal cohorts by quantitative [(14)C]iodoantipyrine autoradiography.


RESULTS
Caudoputamen infarction was reduced by LY treatment (49+/-6% versus 64+/-4% of ipsilateral caudoputamen in LY and vehicle groups, respectively; P:<0.05). Cerebral cortical infarction was not different in the LY compared with vehicle group (7+/-3% versus 13+/-4% of ipsilateral cerebral cortex, respectively). Intra-ischemic blood pressure, arterial blood gases, and temporalis muscle temperature were controlled and equivalent between treatment groups. Averaged laser-Doppler flow during MCA occlusion was 36+/-3% of baseline in the LY group versus 29%+/-2% in the vehicle group. However, end-ischemic CBF or blood flow distribution within the MCA territory was not altered by LY treatment. Cortical or caudoputamen tissue volumes with end-ischemic CBF <20 mL/100 g per minute were similar in both groups.


CONCLUSIONS
We conclude that LY confers neuroprotection from focal cerebral ischemia in caudoputamen in ovariectomized female rats. The mechanism of protection is not linked to preservation of ischemic cerebral blood flow, as determined by end-occlusion quantitative autoradiography.
Rossberg
M I
MI
Departments of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Murphy
S J
SJ
Traystman
R J
RJ
Hurn
P D
PD
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives*; D001345:Autoradiography; D002545:Brain Ischemia / Q000517:prevention & control; D002250:Carbon Radioisotopes; D002544:Cerebral Infarction / Q000175:diagnosis / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004965:Estrogen Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D010052:Ovariectomy; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*
D002250:Carbon Radioisotopes; D004965:Estrogen Antagonists; D010880:Piperidines; D011960:Receptors, Estrogen; D013876:Thiophenes; C115121:LY 353381; D000983:Antipyrine; C008135:iodoantipyrine