title: Pgrmc1/BDNF Signaling Plays a Critical Role in Mediating Glia-Neuron Cross Talk.
abstract: Progesterone (P4) exerts robust cytoprotection in brain slice cultures (containing both neurons and glia), yet such protection is not as evident in neuron-enriched cultures, suggesting that glia may play an indispensable role in P4's neuroprotection. We previously reported that a membrane-associated P4 receptor, P4 receptor membrane component 1, mediates P4-induced brain-derived neurotrophic factor (BDNF) release from glia. Here, we sought to determine whether glia are required for P4's neuroprotection and whether glia's roles are mediated, at least partially, via releasing soluble factors to act on neighboring neurons. Our data demonstrate that P4 increased the level of mature BDNF (neuroprotective) while decreasing pro-BDNF (potentially neurotoxic) in the conditioned media (CMs) of cultured C6 astrocytes. We examined the effects of CMs derived from P4-treated astrocytes (P4-CMs) on 2 neuronal models: 1) all-trans retinoid acid-differentiated SH-SY5Y cells and 2) mouse primary hippocampal neurons. P4-CM increased synaptic marker expression and promoted neuronal survival against H2O2. These effects were attenuated by Y1036 (an inhibitor of neurotrophin receptor [tropomysin-related kinase] signaling), as well as tropomysin-related kinase B-IgG (a more specific inhibitor to block BDNF signaling), which pointed to BDNF as the key protective component within P4-CM. These findings suggest that P4 may exert its maximal protection by triggering a glia-neuron cross talk, in which P4 promotes mature BDNF release from glia to enhance synaptogenesis as well as survival of neurons. This recognition of the importance of glia in mediating P4's neuroprotection may also inform the design of effective therapeutic methods for treating diseases wherein neuronal death and/or synaptic deficits are noted.
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Fen
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Trinh
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Renqi
authors.initials: R
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Zhenglan
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Cunningham
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Meharvan
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Chang
authors.initials: C
authors.lastname: Su
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D053778:Thiazolidines / Q000494:pharmacology
chemical_list: C547152:3-((5E)-4-oxo-5-((5-(4-sulfamoylphenyl)-2-furyl)methylene)-2-thioxo-thiazolidin-3-yl)propanoic acid; D019208:Brain-Derived Neurotrophic Factor; D008565:Membrane Proteins; C508868:PGRMC1 protein, mouse; D011422:Propionates; D011980:Receptors, Progesterone; D053778:Thiazolidines; D011374:Progesterone