Sex steroids differently prevent glutamate excitotoxicity via NOS activity induction in neural cells.

P. MANNELLA; A.M. SANCHEZ; M.S. GIRETTI; A. CARUSO; S. GARIBALDI; M. FLAMINI; X.D. FU; C. BALDACCI; A.R. GENAZZANI; T. SIMONCINI

8-11 March, Rome, Italy

Congreso; The 2nd World Congress on Gender-Specific Medicine and Ageing. The Endocrine Impact.; 2007

Sex steroids present several effects on the brain as  protecting neural cells against toxic stimuli action. On the basis of these data, hormone replacement therapy (HRT) has been largely used in the past to restore a hormonal environment which protects brain from damages. However, last clinical trials have completely challenged these issues and nowadays HRT has been reconsidered. To go over these mismatches on HRT between basic science and evidence-based medicine, we used in vitro models which recreate a steroid deprived or a HRT system in neuroblastoma cells and we sought to assess the neuroprotective efficacy of 17â-estradiol (E2), Progesterone (P) and Medroxyprogesterone acetate  (MPA) against L-glutamate-induced neurodegeneration. Results of these analyses indicate that E2, P and MPA either alone or in co-administration promotes neural cell survival but these effects depend on the timing of exposure and on the steroid preparation of neural cells. In fact, in steroid deprived cells neuroprotective effects induced by E2 and progestins are abolished and even reversed. Indeed, we demonstrate that the mechanism, by which steroids promote survival in neural cells, depends on activation of Nitric Oxide Synthase (NOS) since the pharmacological blocking of NOS prevents prosurvival effects induced by sex steroids. These data are relevant to the role of perimenopausal E2 use on protection against excitotoxic stimuli confirming at the bench the importance of the timing for estrogen therapy to prevent neurodegenerative diseases as shown in the last clinical trials.