Abstract
Men have worse survival than premenopausal women after intracerebral hemorrhage (ICH). After ICH, overproduction of iron associated with induction of heme oxygenase-1 (HO-1) in brain was observed. Rodent ICH model using ferrous citrate (FC)-infusion into the striatum to simulate iron overload, showed a higher degree of injury severity in males than in females. However, the participation of HO-1 in sex-differences of iron-induced brain injury remains unknown. The present results showed a higher level of HO-1 expression associated with more severe injury in males compared with females after FC-infusion. Estradiol (E2) contributed to lower levels of FC-induced HO-1 expression in females compared with males. Heterozygote ho-1 KO decreased the levels of FC-induced injury severity, histological lesions, behavioral deficits, autophagy and autophagic cell death in the striatum of males but not in females. Moreover, ho-1 deficiency enhanced the neuroprotection by E2 only in males. These results suggested that over induction of HO-1 plays a harmful role in FC-induced brain injury in a male-specific manner. Suppression of HO-1 combined with E2 exhibits a synergistic effect on neuroprotection against FC-induced striatal injury in males. These findings open up the prospect for male-specific neuroprotection targeting HO-1 suppression for patients suffering from striatal iron overload.
Highlights
To know whether there is a correlation between the level of HO-1 induction and the sex-differences of striatal injury caused by iron overload, the levels of HO-1, injury severity, histological lesions and behavioral deficits were evaluated in both male and female mice after FC-infusion
To examine whether endogenous E2 contributes to the lower levels of FC-induced HO-1 expression and injury severity in females, the levels of HO-1 and cleavage of α-II spectrin were compared between FC-infused castrated mice with and without E2 implantation
The present study demonstrated that a higher level of HO-1 associated with higher levels of injury severity, histological lesions and behavioral deficits in males than in females was induced by striatal FC-infusion, which simulates iron overload in the striatum after Intracerebral hemorrhage (ICH)
Summary
To know whether there is a correlation between the level of HO-1 induction and the sex-differences of striatal injury caused by iron overload, the levels of HO-1, injury severity, histological lesions and behavioral deficits were evaluated in both male and female mice after FC-infusion. To elucidate the effect of heterozygote ho-1 KO on FC-induced striatal injury, cleavage of α-II spectrin, histological lesions, and behavioral deficits were compared between ho-1+/− and ho-1+/+ mice after FC infusion.
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