Corticotropin-releasing hormone- mediated neuroprotection against oxidative stress is associated with the increased release of non-amyloidogenic amyloid beta precursor protein and with the suppression of nuclear factor-kappaB.
The neuropeptide CRH is the central regulator of the hypothalamic-pituitary-adrenal (HPA) stress response system and is implicated in various stress-related conditions. In the neurodegenerative disorder Alzheimer's disease (AD), levels of CRH are decreased. AD pathology is characterized by the deposition of the nonsoluble amyloid beta protein ( A beta), oxidative stress, and neuronal cell death. Employing primary neurons and clonal cells, we demonstrate that CRH has a neuroprotective activity in CRH-receptor type 1 (CRH-R1)-expressing neurons against oxidative cell death. The protective effect of CRH was blocked by selective and nonselective CRH-R1 antagonists and by protein kinase A inhibitors. Overexpression of CRH-R1 in clonal hippocampal cells lacking endogenous CRH-receptors established neuroprotection by CRH. The activation of CRH-R1 and neuroprotection are accompanied by an increased release of non-amyloidogenic soluble A beta precursor protein. At the molecular level CRH caused the suppression of the DNA- binding activity and transcriptional activity of the transcription factor NF-kappaB. Suppression of NF-kappaB by overexpression of a super-repressor mutant form of IkappaB-alpha, a specific inhibitor of NF-kappaB, led to protection of the cells against oxidative stress. These data demonstrate a novel cytoprotective effect of CRH that is mediated by CRH-R1 and downstream by suppression of NF-kappaB and indicate CRH as an endogenous protective neuropeptide against oxidative cell death in addition to its function in the HPA-system. Moreover, the protective function of CRH proposes a molecular link between oxidative stress-related degenerative events and the CRH-R1 system.[1]References
- Corticotropin-releasing hormone-mediated neuroprotection against oxidative stress is associated with the increased release of non-amyloidogenic amyloid beta precursor protein and with the suppression of nuclear factor-kappaB. Lezoualc'h, F., Engert, S., Berning, B., Behl, C. Mol. Endocrinol. (2000) [Pubmed]
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