Estradiol Attenuates Neuroprotective Benefits of Isoflurane Preconditioning in Ischemic Mouse Brain

Abstract

Isoflurane preconditioning (IsoPC) neuroprotection in experimental stroke is male-specific. We determined whether estradiol alters ischemic outcomes in IsoPC brain and examined the role of estrogen receptors (ERs). Seven to 10 days before preconditioning, ovariectomized (OVX) mice were implanted with estradiol, vehicle, or ER subtype agonists. OVX ± estradiol, OVX ± vehicle, OVX ± ER agonists, and ER subtype wild-type (WT) and knockout (KO) mice were preconditioned for 4 h with sham anesthetic preconditioning (sham PC) or 1% IsoPC and recovered for 24 h. Mice then underwent 2 h of middle cerebral artery occlusion followed by 22 h of reperfusion. Infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride staining, with comparisons between IsoPC and corresponding sham PC for each treatment group. Decreased infarct injury was seen in IsoPC OVX ± vehicle, whereas estradiol in IsoPC OVX mice enhanced ischemic damage. In ER studies, increased infarct volumes were seen in IsoPC ERWT mice regardless of ER subtype. IsoPC in ERαKO mice had no effect on infarction volume but reduced only cortical ischemic damage in ERβKO mice. In OVX + ERα agonist, IsoPC had no effect on infarction volume. In OVX + ERβ agonist, IsoPC increased cortical infarct volume. Estradiol depresses the brain’s protective response to IsoPC and may exacerbate cortical ischemic injury mainly through an ERβ-dependent mechanism.

Complexities of oestrogen in stroke

“…Oestrogen also increased infarct size after transient MCAO [32] and increased neuronal cell loss after forebrain ischaemia [33,34] in diabetic animals. Furthermore, oestrogen has been shown to attenuate the neuroprotective effects of isoflurane pre-conditioning in mice exposed to transient MCAO [35]. These studies highlight the potential for oestrogen to have detrimental effects where there is pre-existing disease, prior exposure to anaesthetics or other pre-conditioning stimuli.…”

Inhalation versus endovenous sedation in subarachnoid hemorrhage patients

“…Other factors that could be involved are the suppression of energy requirements, inhibition of excitatory neurotransmission and potentiation of inhibitory receptors, regulation of intracellular calcium responses during ischemia, and the attenuation of ubiquitin-conjugated protein aggregation (36)(37)(38)(39). Surprisingly, recent animal studies have shown that isoflurane preconditioning response is attenuated by estradiol (40) and that is androgen-dependent in male mice and gender-specific (41,42).…”

Purinergic receptor P2Y, G-protein coupled, 2 (P2RY2) gene is associated with cerebral infarction in Japanese subjects

“…Although being male is recognized as a risk factor for CI, some basic and clinical studies have shown the opposite results. 30,31 ATP, the ligand for P2RY2, has been shown to increase the production of progesterone and estradiol in human granulosa-luteal cells. 32 Several clinical and experimental studies have suggested that estrogen is not universally neuroprotective in experimental cerebral ischemia 31 and may not be beneficial for ischemic preconditioning in experimental ischemia models.…”