Table 1.

The effects of sex and estrogen on cerebral infarct in rodent models of stroke.

Ischemic Model	Species	Sexes Examined	Intervention/ Genetic Modification	Outcome	Mechanism/Important Findings	References
2 h MCAO + 22 h reperfusion	Rat	Female, male, OVX	WT & SHR-SP	Female rats (SHR-SP & WT) had ↓ infarct size & ↑ laser-doppler flow during ischemia compared to male & OVX.	Endogenous estrogen improves stroke outcome, likely via neuroprotection and CBF preservation.	Alkayed NJ, Harukuni I, Kimes AS, London ED, Traystman RJ, & Hurn PD (1998)
Permanent MCAO	Rat	Female	SHR-SP & Wistar-Kyoto females in different parts of estrous cycle: proestrus (high estradiol levels) & metestrus (low estradiol levels);	Females in proestrus had smaller infarct sizes in SHR-SP rats, but infarct volumes were similar at all estradiol levels in Wistar-Kyoto rats	Proestrus part of cycle is protective relative to metestrus in stroke prone animals	Carswell HV, Dominiczak AF, & Macrae IM (2000)
2 h MCAO + 22 h reperfusion	Mouse	Female, male, OVX	WT & bcl-2 overexpressing mice	WT female had ↓ infarct size compared with WT male, bcl-2 overexpression was protective in male, but provided no added benefit in female; OVX ↑ infarct size in WT female, but not in bcl-2 overexpressors.	Estrogen ↑ expression of bcl-2, which is involved in ↓ neuronal injury after ischemia	Alkayed NJ, Goto S, Sugo N, Joh HD, Klaus J, Crain BJ, Bernard O, et al. (2001)
90 min MCAO + 22 h reperfusion	Mouse	Female, OVX	WT & ArKO	ArKO mice had greatest amount of total ischemic damage; OVX WT had less injury than ArKO; WT treated with aromatase inhibitor had ↑ damage.	P450 aromatase is important to female neuroprotection.	McCullough LD, Blizzard K, Simpson ER, Oz OK, & Hurn PD (2003)
2 h MCAO + 22 h reperfusion	Rat	OVX	E2 vs placebo in ERKO and WT rats	E2 ↑ Ang-1 mRNA in WT, but not ERKO mice	Estrogen ↑ angiogenesis and enhances capillary density in the brain	Ardelt AA, McCullough LD, Korach KS, Wang MM, Munzenmaier DH, & Hurn PD (2005)
2 h MCAO + 22 h reperfusion	Mouse	Female, male, OVX	WT & nNOS KO mice; pharmacological inhibition of nNOS	↑ infarct size in nNOS KO intact females consistent with WT female; ↓ infarct size in nNOS KO males. Similar results seen with pharmacological inhibition in WT animals.	NO toxicity in the brain is specific to females and eradicate estrogen protection	McCullough LD, Zeng Z, Blizzard KK., Debchoudhury I, & Hurn PD (2005)
2 h MCAO + 6 or 24 h reperfusion	Rat	OVX	OVX rats with & without E2	E2 ↑ CART expression & secretion in neuron & CART decreases ischemic area	CART is highly induced in cerebral cortex by estradiol under ischemic conditions & is protective	Xu Y, Zhang W, Klaus J, Young J, Koerner I, Sheldahl LC, Hurn PD, et al. (2006)
Permanent MCAO	Rat	Female, OVX	E2 vs vehicle pretreatment	Decreased edema and infarct volume in E2 treated rats	E2 attenuates stimulation of BBB Na-K-Cl cotransporter activity, thereby decreasing edema & infarct volume	O'Donnell M, Lam T, Tran L, & Foroutan S (2006)
Permanent MCAO	Mouse	OVX	OVX implanted with vehicle vs. E2, MCAO 1 wk later	E2 treatment ↑ number of newborn neurons in dorsal SVZ after ischemia	Estradiol stimulates neurogenesis	Suzuki S, Gerhold LM, Böttner M, Rau SW, Cruz C, Yang E, Zhu H, et al. (2007)
2 h MCAO + 22 h reperfusion	Rat	OVX	Infarct size measured in E2-treated OVX female with & without STAT3 inhibitor cucurbitacin	E2 ↑ P-STAT3; inhibiting STAT3 ↑ infarct size after MCAO in E2 treated OVX rats	P-STAT3 is involved in estradiol-mediated neuroprotection	Dziennis S, Jia T, Rønnekleiv OK, Hurn PD, & Alkayed NJ (2007)
Permanent MCAO	Mouse	OVX	WT & iNOS-null OVX females +/- exogenous E2	E2 ↓ infarct size in WT OVX; iNOS KO OVX female had smaller infarct size than WT, but E2 did not further protect	Estradiol ↓, NOS, iNOS deletion is neuroprotective in OVX & estrogen-replaced females	Brown CM, Cruz CD, Yang E, & Wise PM (2008)
2 h MCAO + 24 h reperfusion	Mouse	Female, male, OVX	WT & sEHKO mice	Infarct size ↓, in WT female compared with WT male; protection abolished after OVX; no sex difference in sEHKO mice.	sEH is important mechanism underlying sex differences in ischemia; estradiol decreases sEH.	Zhang W, Iliff JJ, Campbell CJ, Wang RK, Hurn PD, & Alkayed NJ (2009)
90 min MCAO + 22 h reperfusion	Mouse	Female, male	Aged mice were given acute vs. chronic ERT prior to MCAO	Female mice on chronic ERT demonstrated improved outcomes after MCAO; females that had acute ERT did not; males benefitted from ERT regardless of the timing.	Chronic ERT after reproductive senescence may be protective, and this may be related to downregulation of NF-Kß via estrogen.	Liu F, Benashski SE, Xu Y, Siegel M, & McCullough LD (2011).

MCAO, middle cerebral artery occlusion; min, minute; ArKO, aromatase knockout; WT, wild-type; OVX, ovariectomized; KO, knockout; SHR-SP, stroke prone spontaneously hypertensive; CBF, cerebral blood flow; E2, 17ß-estradiol; NOS, nitric oxide synthase; iNOS, inducible nitric oxide synthase; SVZ, subventricular zone; Ang-1, angiopoietin-1; ERKO, estrogen receptor alpha knockout; STAT, signal transducer & activator of transcription; PSTAT3, phosphorylated STAT3; CART, cocaine- & amphetamine-regulated transcript; sEHKO, soluble epoxide hydrolase knockout; sEH, soluble epoxide hydrolase; ERT, estrogen replacement therapy; NF-Kß, nuclear factor-Kß