Low concentrations of the hormone urocortin protects cultured hippocampal neurons from a number of toxic agents, including Aβ, according to an article in the current Journal of Neuroscience. Mark Mattson and colleagues at the National Institute on Aging and Johns Hopkins University, both in Baltimore, Maryland, also describe the receptor and associated signaling cascades that appear to mediate this effect.
Urocortin, like other members of the corticotropin-releasing hormone (CRH) family, regulate neuroendocrine, autonomic, and immunologic responses to stress. In the nervous system, urocortin is only found in a few areas, among them the hippocampus, whose neurons are particularly vulnerable to stress-induced damage. Mattson and colleagues found that picomolar concentrations of urocortin were potent protectors of cultured rat hippocampal neurons, helping to defend against both oxidative challenges (Aβ 25-35, 4hydroxynonenal, ferrous sulfate) and excitotoxic ones (glutamate). In comparison, CRH was 10-fold less potent at protecting the same neurons, and urocortin II had no beneficial effect.
Further investigation revealed that the neuroprotective effects of urocortin are mediated by the G-protein-coupled receptor CRHR1, and subsequent activation of a signaling pathway involving cAMP-dependent protein kinase, protein kinase C, and mitogen-activated protein kinase.
"This is the first demonstration of a biological activity of urocortin in hippocampal neurons, suggesting a role for the peptide in adaptive responses of hippocampal neurons to potentially lethal oxidative and excitotoxic insults," write the authors.—Hakon Heimer
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- Pedersen WA, Wan R, Zhang P, Mattson MP. Urocortin, but not urocortin II, protects cultured hippocampal neurons from oxidative and excitotoxic cell death via corticotropin-releasing hormone receptor type I. J Neurosci. 2002 Jan 15;22(2):404-12. PubMed.