Ovariectomy Exacerbates and Estrogen Replacement Attenuates Photothrombotic Focal Ischemic Brain Injury in Rats

Abstract

Background and Purpose-We previously reported the infarct volumes in female spontaneously hypertensive rats (SHR) to be significantly smaller than those in male SHR. The purpose of the present study was to determine whether estrogen is responsible for the sex difference in ischemic vulnerability in SHR. Methods-In experiment 1, 1 week (short-term) or 4 weeks (long-term) after the ovariectomy (OVX), female SHR (5 months old) were randomly subjected to photothrombotic occlusion of the middle cerebral artery, and the infarct volumes were determined. In experiment 2, the rats were randomly assigned to 3 groups (ie, the sham-ovariectomized, ovariectomized, and estrogen replacement groups). In the replacement group, estradiol valerate (200 g/kg) was subcutaneously injected once a week after the OVX. Four weeks after the OVX or sham-OVX, all rats were subjected to middle cerebral artery occlusion. Changes in regional cerebral blood flow were determined by laser-Doppler flowmetry. Results-In experiment 1, the infarct volume produced 1 week after the OVX was not different from that of the sham-ovariectomized group. In contrast, the infarct volume produced 4 weeks after the OVX was significantly larger than that of the sham-ovariectomized group (82.4Ϯ11.6 versus 54.5Ϯ16.0 mm 3 , Pϭ0.0058). In experiment 2, estradiol replacement after the OVX was observed to attenuate the infarct volume compared with the ovariectomized group (55.6Ϯ18.8 versus 78.5Ϯ21.0 mm 3 , Pϭ0.0321). The degrees of regional cerebral blood flow reduction did not differ among the sham-ovariectomized, ovariectomized, and estrogen replacement groups. Conclusions-Chronic estrogen depletion was thus found to increase the infarct size, which was attenuated by estradiol replacement. These findings indicate that estrogen contributes to the sex difference in ischemic vulnerability and that endogenous estrogen also has a neuroprotective effect against ischemic brain damage. (Stroke. 2000;31:155-160.)

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

“…In particular, several investigators have examined the efficacy of 17␤-estradiol in models of stroke (Alkayed et al, 1998aCarswell et al, 2004;Dubal et al, 1998;Fukuda et al, 2000;Hurn et al, 1995;McCullough et al, 2001;Toung et al, 1998;Yang et al, 2000). Hurn and colleagues (1995) first described in a model of global cerebral ischemia the effects of chronic 17␤-estradiol treatment.…”

Dose-Related Neuroprotective versus Neurodamaging Effects of Estrogens in Rat Cerebral Ischemia: A Systematic Analysis

“…Estradiol benzoate (Sandstrom and Rowan, 2007), estradiol valerate (Fukuda et al, 2000), and conjugated equine estrogens (LittletonKearney et al, 2005;McCullough et al, 2001;Rusa et al, 1999) were administered in altogether five studies, all showing protective effects.…”

Role of Protein Phosphatases in Estrogen-Mediated Neuroprotection

“…In vitro studies indicate that estrogens increase the viability and differentiation of primary cultures from different neuronal populations from the hypothalamus, amygdala, neocortex, or hippocampus. Numerous in vivo studies have also demonstrated the neuroprotective effects of estrogens in a variety of animal stroke models, including transient and permanent middle cerebral artery occlusion Alkayed et al, 1998;Dubal et al, 1998), global forebrain ischemia (Sudo et al, 1997), photothrombotic focal ischemia (Fukuda et al, 2000), glutamate-induced focal cerebral ischemia (Mendelowitsch et al, 2001), and subarachnoid hemorrhage (Yang et al, 2001).…”