Gender-Specific Response to Isoflurane Preconditioning in Focal Cerebral Ischemia

Abstract

Inhalation anesthetics are effective chemical preconditioning agents in experimental cerebral ischemia. However, previous work has been performed exclusively in male animals. We determined if there is a gender difference in ischemic outcome after isoflurane preconditioning (IsoPC), and if this sex-specific response is linked to differences in Akt phosphorylation or expression of neuronal inducible cell-death putative kinase (NIPK), a negative modulator of Akt activation. Young and middle-aged male and female mice were preconditioned for 4 h with air (sham PC) or 1.0% IsoPC and recovered for 24 h. Cortices were subdissected from preconditioned young male and female mice for measurement of Akt phosphorylation (Western blot) and NIPK mRNA (quantitative polymerase chain reaction). Additional cohorts underwent 2 h of reversible middle cerebral artery occlusion. Lastly, male and female Akt1+/+ and Akt1−/– mice were studied to determine if gender differences in ischemic outcome after IsoPC is Akt1-dependent. Infarction volume was determined at 22 h reperfusion (2,3,5-triphenyltetrazolium chloride). As expected, IsoPC decreased ischemic damage as compared with sham PC in young and middle-aged male mice. In contrast, IsoPC markedly increased infarction in young female mice and had no effect in middle-aged female mice. Cortical phospho-Akt was increased by IsoPC versus sham PC only in male mice. No increase was observed in IsoPC female mice. NIPK mRNA was higher in female mice than in male mice regardless of preconditioning status. Male IsoPC neuroprotection was lost in Akt1-deficient male mice. We conclude that IsoPC is beneficial only in ischemic male brain and that sex differences in IsoPC are mediated through Akt activation and basal NIPK expression.

Sex differences in the mechanism of Met5-enkephalin-induced cardioprotection: role of PI3K/Akt

“…The current study extends earlier findings to now demonstrate sex-dependent differences in opioid-induced cytoprotective signaling. Sexspecific differences in the mechanisms of ischemic injury and tolerance have also been reported for the brain (16,26,29) and the kidney (23).…”

Akt1 gene deletion and stroke

“…Triciribine is highly selective for Akt and has no known effects on upstream activators of Akt such as PI3-kinase and PDK1 [20] making it more selective than PI3K inhibitors such as Wortmannin and LY294002 which compete at the ATP binding site of the lipid kinase catalytic domain of all PI3Ks leading to broad specificity [32]. Earlier studies utilizing LY294002 demonstrated a reduction in p-Akt (Ser-473) levels and an increase in DNA damage after focal stroke [6,15]. The specificity of these upstream inhibitors for the Akt pathways is poor and conflicting data in in vitro models has been documented as LY294002 had a protective effect in PC12 cells exposed to oxygenglucose deprivation [33].…”

“…However, limited data are available on mice lacking Akt, which would be expected to lead to an exacerbation of injury due to the loss of p-Akt mediated neuroprotection. A recent study utilizing Akt1 deficient mice found that deletion protected male mice from stroke damage, and had no effect in female mice [15]. Hormonal effects on Akt have been documented [16] and the contribution of estrogen to this observed gender dichotomy has not yet been investigated.…”

Gender and the injured brain

“…Surprisingly, however, Kitano et al also found that while isoflurane preconditioning induced Akt activation in brains of male mice, this was not the case in females. 68 In the context of anesthetic preconditioning, E2 therefore may prevent rather than induce the activation of neuroprotective pathways. More definitive studies on this phenomenon are urgently needed to ensure optimal safety when developing an anesthesia plan and choosing the anesthetic drug, particularly, for female patients at risk for perioperative stroke.…”