Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection

Abstract

Female animals are protected from many forms of neurological injury and degeneration relative to their male counterparts, in part attributable to their native estrogens. We hypothesized that estradiol aromatized from precursor androgens via the cytochrome P450 aromatase contributes to ischemic neuroprotection in the female. Female homozygous aromatase knock-out (ArKO) mice and randomly cycling, wild-type (WT) female littermates were treated with reversible middle cerebral artery occlusion (90 min; 22 hr reperfusion). Total and regional ischemic damage was greater in female ArKOs (total, 33.5 +/- 4.8%; cortical, 47.4 +/- 5.7%; striatal, 44.8 +/- 7.8%) compared with WT (total, 14.2 +/- 5%; cortical, 14.2 +/- 4.5%; striatal, 17.5 +/- 8%). Baseline blood pressure and intra-ischemic cortical perfusion were comparable in knock-outs and WT, suggesting that vascular factors do not explain ArKO ischemic sensitivity. Injury was smaller in ovariectomized WT than in ArKO, emphasizing that extragonadal local estradiol plays a critical role in females. Similar increases in cortical and striatal damage were observed in female WT mice chronically treated with the aromatase inhibitor fadrozole compared with vehicle-treated control mice. Restoration of plasma 17beta-estradiol to physiological levels completely reversed the ArKO female's susceptibility to injury. These findings indicate that the biosynthetic enzyme P450 aromatase is key to endogenous neuroprotection in females and suggest that enhancing local, nongonadal estrogen formation could have therapeutic implications is ischemic neuropathology.

Figure 1.

Relative reduction in cortical cerebral blood flow in female mice as measured by LDF in experiment 1. Baseline LDF is expressed as 100%. Equivalent reductions are seen at the time of occlusion (time 0) and during the 90 min stroke. Cerebral blood flow recovery during reperfusion (RP) was also equivalent between the four groups (ArKO, WT, E2, and OVX).

Figure 2.

Total and regional infarction [percentage of contralateral (CL) structure] in female mice. ArKO mice had significantly greater ischemic damage in both the cortex (CTX) and caudate-putamen (CP) compared with ovary-intact WT mice. ArKO females also had significantly more total and cortical damage than ovariectomized WT mice. Supplementation of ArKO females with E2 ameliorated ischemic damage to levels seen in intact WT mice. ^*p < 0.05; ^**p < 0.01).

Figure 3.

WT female mice treated with the aromatase inhibitor fadrozole had significantly larger infarcts (as measured as a percentage of the contralateral structure) compared with oil-treated mice in both the cortex and caudate-putamen (CP). ^*p < 0.01.