CRH (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 (A) 25-35 toxicity. At low CRH concentrations (10^-8 M), neuroprotective effects can only be observed in cerebellar and hippocampal cultures, while 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) PKA inhibitor. Western blot analysis, carried out using phospho-specific antibodies directed against MAPK, CREB and GSK3 also resulted in brain-specific differences concerning intracellular signaling. Correlating with cell survival, low CRH concentrations resulted in activation of the CREB pathway and inactivation of GSK3 in cerebellar and hippocampal cultures, while higher concentrations additionally resulted in activated CREB and inactivated GSK3 in cortical cultures. In contrast, MAPK activation only occurred in cortical neurons. Differences in signaling were found to be independent of receptor expression as RT-PCR analysis indicated no region specific-differences in CRHR1 mRNA expression.