The Differences in Neuroprotective Efficacy of Progesterone and Medroxyprogesterone Acetate Correlate with Their Effects on Brain-Derived Neurotrophic Factor Expression

Abstract

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.

Progesterone and the Spinal Cord: Good Friends in Bad Times

“…In addition, we also observed that PROG preserves the microtubule-associated protein 2 (MAP2) immunostaining in deafferentiated motoneurones, which may help to recover cytoskeleton organization [5] . Collectively, our results and those from a recent report [7] suggest that PROG-induced BDNF expression correlates with its neuroprotective effects and may help to understand the potential role of PROG to support and sustain normal cellular function after SCI.…”

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

“…PROG also has anti-inflammatory properties, and its action reduces the inflammatory response following brain damage [40,41]. By the activation of nuclear receptors, PROG increases the levels of brain-derived neurotrophic factor [42], a neurotrophic factor involved in neuroprotection and in maintaining neuron function [43]. PROG increases the expression of the mitochondrial antiapoptotic protein Bcl-2 [44] and was reported to decrease oxidative stress by increasing the levels of endogenous antioxidants such as glutathione, superoxide dismutase, and catalase [45].…”

Norgestrel may be a potential therapy for retinal degenerations

“…In our recent publication, we observed norgestrel-mediated induction of bFGF, a neurotrophic factor repeatedly associated with protection from lightinduced photoreceptor degeneration, in the retina. This result is not unprecedented in neuronal tissue, induction of BDNF expression has been observed in the CNS in response to progesterone [17]. Therefore, induction of neurotrophic factors could account for some of the potent pro-survival properties of norgestrel, complementing the growth factor-based therapies that are currently under development for the treatment of retinal disease.…”