title: Brain region-specific neuroprotective action and signaling of corticotropin-releasing hormone in primary neurons.
abstract: CRH regulates the body's response to stressful stimuli by modulating the activity of the hypothalamic pituitary axis. In primary cultures and cell lines, CRH also acts as a potent neuroprotective factor in response to a number of toxins. Using primary neuronal cultures from the cerebellum, cerebral cortex, and hippocampus, we demonstrate that CRH exerts a brain region-specific neuroprotective effect on amyloid beta 25-35 toxicity. At low CRH concentrations (10(-8) M), neuroprotective effects can be observed only in cerebellar and hippocampal cultures, but a higher CRH concentration (10(-7) M) additionally led to the protection of cortical neurons. These neuroprotective effects were inhibited by H89, a specific protein kinase A inhibitor. Western blot analysis, carried out using phospho-specific antibodies directed against MAPK, cAMP response element-binding protein (CREB), and glycogen synthase kinase (GSK)3 beta also resulted in brain legion-specific differences regarding intracellular signaling. Correlating with cell survival, low CRH concentrations resulted in activation of the CREB pathway and inactivation of GSK3 beta in cerebellar and hippocampal cultures, but higher concentrations additionally resulted in activated CREB and inactivated GSK3 beta in cortical cultures. In contrast, MAPK activation occurred only in cortical neurons. Differences in signaling were found to be independent of receptor expression levels because RT-PCR analysis indicated no region-specific differences in CRHR1 mRNA expression.
authors.affiliation: Independent Research Group Neurodegeneration, Max Planck Institute of Psychiatry, 80804 Munich, Germany; Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz, 55099 Mainz, Germany.
authors.forename: Nadhim
authors.initials: N
authors.lastname: Bayatti
authors.forename: Jürgen
authors.initials: J
authors.lastname: Zschocke
authors.forename: Christian
authors.initials: C
authors.lastname: Behl
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000166:cytology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002540:Cerebral Cortex / Q000166:cytology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity; D010766:Phosphorylation; D011247:Pregnancy; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016875:tau Proteins / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D016229:Amyloid beta-Peptides; D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; C074636:amyloid beta-protein (25-35); D016875:tau Proteins; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D000071679:Glycogen Synthase Kinase 3 beta; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3