Brain aromatase is neuroprotective

The expression of aromatase, the enzyme that catalyzes the biosynthesis of estrogens from precursor androgens, is increased in the brain after injury, suggesting that aromatase may be involved in neuroprotection, In the prese nt study, the effect of inactivating aromatase has been assessed in a model of neurodegeneration induced by the systemic administration of neurotoxins , Domoic acid, at a dose that is not neurotoxic in intact male mice, induce d significant neuronal loss in the hilus of the hippocampal formation of mi ce with reduced levels of aromatase substrates as a result of gonadectomy, Furthermore, the aromatase substrate testosterone, as well as its metabolit e estradiol, the product of aromatase, were able to protect hilar neurons f rom domoic acid. In contrast, dihydrotestosterone, the 5 alpha -reduced met abolite of testosterone and a nonaromatizable androgen, was not. These find ings suggest that aromatization of testosterone to estradiol may be involve d in the neuroprotective action of testosterone in this experimental model. In addition, aromatase knockout mice showed significant neuronal loss afte r injection of a low dose of domoic acid, while control littermates did not , indicating that aromatase deficiency increases the vulnerability of hilar neurons to neurotoxic degeneration, The effect of aromatase on neuroprotec tion was also tested in male rats treated systemically with the specific ar omatase inhibitor fadrozole and injected with kainic acid, a well character ized neurotoxin for hilar neurons in the rat. Fadrozole enhanced the neurod egenerative effect of kainic acid in intact male rats and this effect was c ounterbalanced by the administration of estradiol, Furthermore, the neuropr otective effect of testosterone against kainic acid in castrated male rats was blocked by fadrozole, These findings suggest that neuroprotection by ar omatase is due to the formation of estradiol from its precursor testosteron e. Finally, a role for local cerebral aromatase in neuroprotection is indic ated by the fact that intracerebral administration of fadrozole enhanced ka inic acid induced neurodegeneration in the hippocampus of intact male rats, These findings indicate that aromatase deficiency decreases the threshold for neurodegeneration and that local cerebral aromatase is neuroprotective. Brain aromatase mat therefore represent a new target for therapeutic appro aches to neurodegenerative diseases. (C) 2001 John Wiley & Sons, Inc.