Differential Effects of 17β-Estradiol upon Stroke Damage in Stroke Prone and Normotensive Rats

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Abstract
We previously reported that during pro-estrus (high endogenous estrogen levels), brain damage after middle cerebral artery occlusion (MCAO) was reduced in stroke-prone spontaneously hypertensive rats (SHRSP) but not in normotensive Wistar Kyoto rat (WKY). In the present study, we examined the effect of exogenous estrogen on brain damage after MCAO in SHRSP and WKY. A 17β-estradiol (0.025mg or 0.25mg, 21 day release) or matching placebo pellet was implanted into ovariectomized WKY and SHRSP (3 to 4 months old) who then underwent distal diathermy-induced MCAO 2 weeks later. Plasma 17β-estradiol levels for placebo and 17β-estradiol groups were as follows: WKY 0.025 mg 16.4 ± 8.5 (pg/mL, mean ± SD) and 25.85 ± 12.6; WKY 0.25 mg 18.2 ± 9.0 and 69.8 ± 27.4; SHRSP 0.25 mg 20.7 ± 8.8 and 81.0 ± 16.9. In SHRSP, infarct volumes at 24 hours after MCAO were similar in placebo and 17β-estradiol groups: SHRSP 0.025 mg 126.7 ± 15.3 mm3 (n = 6) and 114.0 ± 14.1 mm3 (n = 8) (not significant); SHRSP 0.25 mg 113.5 ± 22.3 mm3 (n = 8) and 129.7 ± 26.2 mm3 (n = 7) (not significant), respectively. In WKY, 17β-estradiol significantly increased infarct volume by 65% with 0.025mg dose [36.1 ± 20.7 mm3 (n = 8) and 59.7 ± 19.3 mm3 (n = 8) ( P = 0.033, unpaired t-test)] and by 96% with 0.25 mg dose [55.9 ± 36.4 mm3 (n = 8) and 109.7 ± 6.7 mm3 (n = 4) ( P = 0.017)]. Thus, 17β-estradiol increased stroke damage in normotensive rats with no significant effect in stroke-prone rats. Despite being contrary to our hypothesis, our findings add substance to the recently reported negative effects of 17β-estradiol in clinical studies.