Progesterone reverses 17beta-estradiol-mediated neuroprotection and BDNF induction in cultured hippocampal slices.
Due to the many similarities in mechanisms of action, targets and effects, progesterone (P4), estrogen and neurotrophins have been implicated in synaptic plasticity as well as in neuroprotection and neurodegeneration. In this study, we examined the interactions between 17beta-estradiol (E2) and P4 and brain-derived neurotrophic factor (BDNF) on both plasticity and excitotoxicity in rat cultured hippocampal slices. First, we evaluated the neuroprotective effects of E2 and P4 against N-methyl-D-aspartate (NMDA) toxicity in cultured rat hippocampal slices. As previously reported, pretreatment with 10 nm E2 (24 h) was neuroprotective against NMDA toxicity. However, P4 (10 nm) added 20 h after E2 treatment for 4 h reversed its protective effect. In addition, the same E2 treatment resulted in an increase in BDNF protein levels as well as in activation of its receptor, TrkB, while addition of P4 attenuated E2-mediated increase in BDNF and TrkB levels. Furthermore, E2-mediated neuroprotection was eliminated by a BDNF scavenger, TrkB-Fc. Our results indicate that E2 neuroprotective effects are mediated through the BDNF pathway and that, under certain conditions, P4 antagonizes the protective effect of estrogen.
Aguirre
Claudia C
CC
Neuroscience Graduate Program, University of Southern California, Los Angeles, CA 90089-2520, USA.
Baudry
Michel
M
D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions / Q000502:physiology; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D009924:Organ Culture Techniques; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011374:Progesterone; D004958:Estradiol; D020813:Receptor, trkB