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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  1. The observation that, in vitro, urocortin provides neuroprotection to vulnerable neurons may have some therapeutic implications in Alzheimer's disease (AD). However, these implications are not clear-cut, since other studies have shown that administering urocortin receptor antagonists can attenuate the neural damage in response to focal cerebral ischemia in vivo. While the authors did quantify the CNS expression of urocortin receptors, it would be of interest to know the tissue concentrations of urocortin relative to specific disease states, other growth factors, and age.

    There is evidence that AD is associated with aberrant entry of neurons into the cell cycle. Urocortin receptor expression is higher in the regressing corpus luteum than in the functioning corpus luteum, report Muramatsu et al. 2001. Urocortin has been shown to inhibit melanoma tumor growth (Carlson et al., 2001). In addition, it is not present in the colonic mucosa until after the fetal and neonatal period, the time of most rapid tissue development (Muramatsu et al., 2000). Conversely, urocortin receptor density in the CNS is greatest during early development (De Souza, 1995). Whether there is any correlation between urocortin's neuroprotective effect and possible inhibition of cell cycling could be an area for further investigation.

    References:

    . Urocortin and corticotropin-releasing factor receptor expression in normal cycling human ovaries. J Clin Endocrinol Metab. 2001 Mar;86(3):1362-9. PubMed.

    . Inhibition of mouse melanoma cell proliferation by corticotropin-releasing hormone and its analogs. Anticancer Res. 2001 Mar-Apr;21(2A):1173-9. PubMed.

    . Urocortin and corticotropin-releasing factor receptor expression in the human colonic mucosa. Peptides. 2000 Dec;21(12):1799-809. PubMed.

    . Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. Psychoneuroendocrinology. 1995;20(8):789-819. PubMed.

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Primary Papers

  1. . 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.