Hormonal preparation of neural cells influences the protective action of sex steroid against glutamate.

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

Toronto, Canada, June 2-5,

Congreso; The Endocrine Society’s 89th Annual Meeting ENDO 07.; 2007

The Endocrine Society’s

The hormone replacement therapy (HRT) has been largely used in the past to restore a hormonal environment which protects brain from damages. Estrogen and progesterone are potent regulator of brain function and several in vitro studies show neuroprotective action exerted by sex steroid on defending neural cells against toxic stimuli action. However, last clinical trials have completely challenged these issues and nowadays HRT has been reconsidered. To address controversies between basic science and evidence-based medicine of HRT, we used in vitro models which recreate a steroid deprived or an 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 restoring for the protection against excitotoxic stimuli, confirming at the bench the importance of the timing for estrogen therapy to prevent neurodegeneration as shown in the last clinical trials.