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Brain Region-Specific Neuroprotective Action and Signaling of Corticotropin-Releasing Hormone in Primary Neurons

Independent Research Group Neurodegeneration, Max Planck Institute of Psychiatry, 80804 Munich, Germany; and Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz, 55099 Mainz, Germany

Address all correspondence and requests for reprints to: Christian Behl, Ph.D., Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz, 55099 Mainz, Germany. E-mail: cbehl{at}uni-mainz.de.

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 ß 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)3ß 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 GSK3ß in cerebellar and hippocampal cultures, but higher concentrations additionally resulted in activated CREB and inactivated GSK3ß 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.

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