Increased expression of aromatase after focal cerebral ischemia: Relevance to neuroprotection and functional recovery

Aim: Aromatase is the key enzyme in the biosynthesis of 17β-estradiol, the most potent estrogen, which has pleiotropic neuroprotective properties. Aromatase levels increase in the brain after stroke, and its gene variants increase susceptibility to stroke. This study aims to determine whether aromatase overexpression improves stroke outcome and whether aromatase inhibition exacerbates outcome after permanent focal cerebral ischemia. Methods/Design: All animals (3-4 months old) underwent permanent middle cerebral artery occlusion (MCAO) by diathermy. Time course of aromatase expression following MCAO in female ovariectomized spontaneously hypertensive stroke prone (SHRSP) rats was assessed by semi-quantitative immunohistochemistry and quantitative polymerase chain reaction (qPCR). The effect of aromatase expression on stroke outcome was assessed using a male mouse model over-expressing aromatase (Dax-1 KO mice) and by letrozole treatment. Volume of ischemic damage was assessed by magnetic resonance imaging (MRI) and functional recovery was assessed by the corner test and foot-fault test. All analyses were performed using GraphPad Prism version 9.0. Results: The key findings are that aromatase expression was significantly increased in SHRSP in both the dorsal and ventral peri-infarct zones and hippocampus at 24 h post-MCAO as measured by areas of immunostaining but not qPCR. There was no improvement in stroke outcome by Dax-1 KO, despite significantly higher plasma 17β-estradiol levels and increased brain aromatase immunoreactivity after stroke. There was no exacerbation on stroke outcome by letrozole, despite decreased plasma 17β-estradiol levels. Conclusion: The time course and location of increased aromatase indicate a potential role in neuroprotection and repair; however, manipulation of aromatase expression does not influence outcome after permanent MCAO in male mice.