Neuroprotective and neurotoxic effects of estrogens
Introduction
Experimental data in animal models have provided exhaustive evidence of the neuroprotective properties of 17β-estradiol (E2). This hormone increases neuronal survival after different forms of brain injury in vivo and protects neuronal cultures from serum or growth factor deprivation, anoxia, excitotoxicity or oxidative damage [25], [28], [38], [67], [68]. E2 is thought to protect neurons against numerous traumatic or chronic neurological and mental diseases in humans as well. However, the clinical evidence is controversial [2].
To develop new therapeutic approaches using E2, it is important to determine the basis for the neuroprotective actions of the hormone. One of the possible mechanisms is related with the antioxidant properties of E2 that depend on the presence of the hydroxyl group in the C3 position on the A ring of the steroid molecule and are independent of the activation of estrogen receptors [7], [9]. In several tissues, including the brain, E2 is metabolized to 2-hydroxyestradiol (2OHE2) by a NADPH-dependent cytochrome P-450-linked monooxygenase system [6], [34], [41]. This metabolite is rapidly O-methylated by the ubiquitously present catechol-O-methyl transferase to 2-methoxyestradiol (2MEOHE2) [21], [71]. 2OHE2 and 2MEOHE2 are the most biologically active metabolites of E2 [18], [72]. Both steroids share antioxidant properties against the lipid peroxidation induced by metal-derived chemicals [36], [40], inhibit angiogenesis [23], [69] and decrease cell proliferation [37], [58], [69], [70]. Furthermore, these metabolites, in addition to their estrogenic action on reproductive tissues, induce important biological effects in the brain [18].
The transformation of E2 in 2OHE2 and 2MEOHE2 may have important consequences in the neuroprotective effects of E2. However, the potential neuroprotective effects of these estradiol metabolites have been poorly investigated in vivo. Therefore, the present study was designed to assess and compare the capacity of E2, 2OHE2 and 2MEOHE2 to protect hippocampal neurons from kainic acid toxicity in vivo. The insult produced by kainic acid on hilar hippocampal neurons has been validated as an useful experimental model of excitotoxic cell death [11], [22] and previous studies have shown that E2 is neuroprotective in this model [3], [4], [51], [62], [63].
Section snippets
Materials
All hormones and kainic acid were purchased from Sigma (St. Louis, MO), while 2,2,2,tribromoethanol and (2-hydroxypropyl)-β-cyclodextrin (cyclodextrin) were obtained from Fluka Chemika (Buchs, Switzerland). Hormones were dissolved in 20% cyclodextrin and kainic acid in phosphate-buffered saline solution, pH 7.4.
Animals
Wistar albino female rats were raised and maintained on a 12:12-h light–dark cycle, with free access to chow and water. Manipulation of the rats followed the European Union Normative
Results
The first experiment was designed to determine the optimal dose of E2 that protects hilar neurons against kainic acid. Treatment with kainic acid resulted in a significant loss of hilar neurons Fig. 1, Fig. 2. E2, at the highest dose tested (100 μg/rat), prevented hilar neuronal loss in rats treated with kainic acid Fig. 1, Fig. 2. However, lower doses of E2 were unable to protect hilar neurons (Fig. 2).
In contrast to E2, 2OHE2 was unable to protect hilar neurons from kainic acid, even at the
Discussion
As shown previously [3], [4], [51], [62], [63], our study confirms that E2 is able to protect hilar neurons of ovariectomized rats against kainic acid in vivo. Furthermore, our findings indicate that the neuroprotective effect of E2 in this model is obtained only with a high dose of the hormone that results in high physiological proestrus concentration of E2 in plasma by 24 h, followed by a decrease to low levels by 48 h [57].
It has been proposed that E2 exerts neuroprotection by the
Acknowledgements
This study has been carried out with financial support from Ministerio de Ciencia y Tecnologı́a (SAF 2002-00652), Instituto de Salud Carlos III (01/1214) and the Commission of the European Communities, specific RTD programme “Quality of Life and Management of Living Resources” (QLK6-CT-2000-00179). OP thanks the support for this study of CSIC, CONACyT, CEGEPI-IPN and COFAA.
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