RESUMO
Whereas hormone therapy is used for the treatment of menopausal symptoms, its efficacy in helping reduce the risk of other diseases such as Alzheimer's disease has been questioned in view of the results of recent clinical trials that appeared inconsistent with numerous basic research studies that supported the beneficial effects of hormones. One possible explanation of this discrepancy may lie in the choice of hormone used. For example, we and others found that progesterone is neuroprotective whereas medroxyprogesterone acetate (MPA), the synthetic progestin used in hormone therapy, is not. Because our data suggest that progesterone-induced protection is associated with the induction of brain-derived neurotrophic factor (BDNF) levels and, importantly, can be blocked by inhibiting the neurotrophin signaling, we determined whether progesterone and medroxyprogesterone acetate differed in their ability to regulate BDNF levels in the explants of the cerebral cortex. We found that progesterone elicited an increase in both BDNF mRNA and protein levels, whereas medroxyprogesterone acetate did not. Furthermore, using both a pharmacological inhibitor of the progesterone receptor (PR) and PR knockout mice, we determined that the effects of progesterone were mediated by the classical PR. Our results underscore the fact that not all progestins have equivalent effects on the brain and suggest that the selection of the appropriate progestin may influence the success of hormone therapy formulations used in treating the menopause and/or reducing the risk for diseases associated with the postmenopausal period.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/biossíntese , Acetato de Medroxiprogesterona/farmacologia , Progesterona/farmacologia , Receptores de Progesterona/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ácido Glutâmico/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo , Receptores de Progesterona/efeitos dos fármacosRESUMO
The higher prevalence and risk for Alzheimer's disease in women relative to men has been partially attributed to the precipitous decline in gonadal hormone levels that occurs in women following the menopause. Although considerable attention has been focused on the consequence of estrogen loss, and thus estrogen's neuroprotective potential, it is important to recognize that the menopause results in a precipitous decline in progesterone levels as well. In fact, progesterone is neuroprotective, although the precise mechanisms involved remain unclear. Based on our previous observation that progesterone elicits the phosphorylation of ERK and Akt, key effectors of the neuroprotective mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3-K) pathways, respectively, we determined whether activation of either of these pathways was necessary for progesterone-induced protection. With organotypic explants (slice culture) of the cerebral cortex, we found that progesterone protected against glutamate-induced toxicity. Furthermore, these protective effects were inhibited by either the MEK1/2 inhibitor UO126 or the PI3-K inhibitor LY294002, supporting the requirement for both the MAPK and PI3-K pathways in progesterone-induced protection. In addition, at a concentration and duration of treatment consistent with our neuroprotection data, progesterone also increased the expression of brain-derived neurotrophic factor (BDNF), at the level of both protein and mRNA. This induction of BDNF may be relevant to the protective effects of progesterone, in that inhibition of Trk signaling, with K252a, inhibited the protective effects of progesterone. Collectively, these data suggest that progesterone is protective via multiple and potentially related mechanisms. (c) 2007 Wiley-Liss, Inc.