Aromatase: a neuroprotective enzyme
Introduction
Decreased levels of estrogen after menopause are associated with loss of cognitive skills, the progression of neurodegenerative disorders, increased depressive symptoms, and other psychological disturbances in women (Fillit, 1994, Paganini-Hill, 1995, Paganini-Hill and Henderson, 1996, Yaffe et al., 1998, Saunders-Pullman et al., 1999, Sherwin, 1999, Wolf et al., 1999). Therefore, it has been proposed that estrogen replacement therapies may ameliorate the loss of brain function with aging (Costa et al., 1999, Hogervorst et al., 2000, Resnick and Maki, 2001, Tsang et al., 2000). This proposition is supported by substantial evidence from animal studies indicating that estradiol replacement is neuroprotective in both sexes (for recent reviews, see Chowen et al., 2000, Garcia-Segura et al., 2001, Green and Simpkins, 2000, Lee and McEwen, 2001, Wise et al., 2001). Neuroprotective properties have also been ascribed to estradiol precursors such as pregnenolone (3β-hydroxy-5-pregnen-20-one), dehydroepiandrosterone (DHEA, 3α-hydroxy-5-androstene-17-one) and testosterone. However, the results of several studies in humans have shown that hormonal replacement therapy (HRT) with estradiol and progesterone has no positive effect for neurodegenerative diseases or stroke and even may have a negative impact on cognition in postmenopausal women with Alzheimer’s disease (Shaywitz and Shaywitz, 2000, Fillit, 2002, Azcoitia et al., 2003a, Wise, 2003). Therefore, it is necessary to establish alternatives to HRT. One possibility is to increase local estrogen synthesis in the brain and not in other organs, to avoid health risks associated to peripheral actions of estradiol and to avoid the potential negative effects of progestagens in the brain. However, the potential neuroprotective role of endogenous estradiol formation has been largely neglected.
Testosterone and other C19 steroids are converted to estradiol by aromatase (Fig. 1), an enzyme that consists of two components: a cytochrome P450 (P450 aro), the product of the cyp19 gene, and the ubiquitous flavoprotein NADPH (reduced nicotinamide adenine dinucleotide phosphate)-cytochrome P450 reductase (Simpson and Davis, 2001, Kamat et al., 2002). Aromatase is expressed in the brain (Naftolin et al., 1971), where it is involved in the regulatory effects of androgens, via conversion to estrogens, on neural differentiation, neural plasticity, neuroendocrine function and sexual behavior (MacLusky and Naftolin, 1981, Hutchison, 1991, Lephart, 1996). In this study we review evidence indicating that local estradiol formation by aromatase participates in the endogenous mechanisms used by the brain to cope with neurodegeneration.
Section snippets
Aromatase expression is induced after brain injury
In teleost fishes aromatase is expressed in neurons (Gelinas and Callard, 1997) as well as in radial glia (Forlano et al., 2001, Menuet et al., 2003), under normal conditions. Furthermore, aromatase is expressed in both neuronal and glial cells in primary cultures of developing zebra finch telencephalon (Schlinger et al., 1994, Schlinger et al., 1995). In contrast, aromatase is expressed exclusively by neurons under normal conditions in the central nervous system of mammals (Negri-Cesi et al.,
Aromatase-deficient mice are more susceptible to neurodegeneration in the hippocampus
Systemic administration of domoic acid in mice results in neurodegenerative damage in the hippocampal formation (Strain and Tasker, 1991). The neurodegenerative effects of domoic acid are mediated by an increase in intracellular calcium, as well as by an increased release of glutamate that results in the activation of NMDA receptors (Berman and Murray, 1997, Nijjar and Nijjar, 2000). The administration of domoic acid has been used to assess the effect of aromatase deficiency in
Neuroprotection by testosterone is abolished by aromatase inhibition
Recent studies have shown that the hippocampal hilar neurons of castrated male mice are more sensitive to domoic acid-induced degeneration than the hilar neurons from intact males (Azcoitia et al., 2001). This was observed using a low dose of domoic acid that does not affect hilar neurons in intact animals. However, the same low dose of domoic acid is able to induce significant neuronal loss in mice with reduced androgen levels as a result of castration, indicating that physiological levels of
Is the brain or the periphery the source of substrates for brain aromatase?
A question that is still unsolved is whether the nervous tissue may be a source of substrates for brain aromatase. Pregnenolone is synthetized in the central nervous system from cholesterol (Baulieu et al., 2001, Kimoto et al., 2001). Furthermore, glial cells, at least in vitro, may convert pregnenolone to DHEA and may then metabolize DHEA to testosterone (Zwain and Yen, 1999a, Zwain and Yen, 1999b). There is also evidence that the brain is able to form testosterone in vivo (Stoffel-Wagner et
Therapeutic perspectives: neuroprotection and brain aging
The studies reviewed in this paper suggest that the endogenous response of neural tissue to cope with neurodegenerative insults may include the induction of aromatase and the consecutive increase in the local production of estradiol. Locally formed estradiol may act on estrogen receptors, which are known to mediate neuroprotection by estradiol in several experimental models in vivo (Azcoitia et al., 1999b, Sawada et al., 2000, Veliskova et al., 2000, Wilson et al., 2000, Wise et al., 2001). In
Acknowledgements
This study has been supported by grants from the Commission of the European Communities, specific RTD programme “Quality of Life and Management of Living Resources”, QLK6-CT-2000-00179 and from Ministerio de Ciencia y Tecnologı́a, Spain, SAF 2002-00652.
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