title: Progesterone increases brain-derived neuroptrophic factor expression and protects against glutamate toxicity in a mitogen-activated protein kinase- and phosphoinositide-3 kinase-dependent manner in cerebral cortical explants.
abstract: 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.
authors.affiliation: Department of Pharmacology and Neuroscience and the Institute for Aging and Alzheimer's Disease Research, The Center FOR HER, University of North Texas Health Science Center, Fort Worth, Texas 76107-2699, USA.
authors.forename: Paramjit
authors.initials: P
authors.lastname: Kaur
authors.forename: Parmeet K
authors.initials: PK
authors.lastname: Jodhka
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Underwood
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Bowles
authors.forename: Nancyellen C
authors.initials: NC
authors.lastname: de Fiebre
authors.forename: Christopher M
authors.initials: CM
authors.lastname: de Fiebre
authors.forename: Meharvan
authors.initials: M
authors.lastname: Singh
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D018698:Glutamic Acid; D011374:Progesterone; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases