Influence of corticotrophin releasing factor on neuronal cell death in vitro and in vivo.
Several studies have demonstrated that antagonists of the corticotrophin releasing factor (CRF) receptor markedly inhibit experimentally induced excitotoxic, ischaemic and traumatic brain injury in the rat, and that CRF expression is elevated in response to experimentally induced stroke or traumatic brain injury. CRF is also induced by the pro-inflammatory cytokine interleukin 1 (IL-1), which participates in various forms of neurodegeneration. The aim of this study was to test the hypothesis that CRF is toxic directly in vivo or in vitro. In primary cultures of rat cortical neurons, exposure to CRF (10 pM-100 nM) for 24 h failed to cause cell death directly, or to modify the neurotoxic effects of N-methyl-D-aspartate (NMDA). Similarly, infusion of CRF (0.3-5 microg) into specific brain regions of the rat did not induce cell death and did not significantly alter the neuronal damage produced by infusion of excitatory amino acids. These data demonstrate that CRF is not directly neurotoxic, and suggest that either CRF mediates neuronal damage by indirect actions (e.g. on the vasculature) and/or that CRF is not the endogenous ligand which contributes to neurodegeneration through activation of CRF receptors.
Craighead
M W
MW
School of Biological Sciences, 1.124 Stopford Building, University of Manchester, Oxford Road, M13 9PT, Manchester, UK. mqbbssmwc@man.ac.uk
Boutin
H
H
Middlehurst
K M
KM
Allan
S M
SM
Brooks
N
N
Kimber
I
I
Rothwell
N J
NJ
D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D003346:Corticotropin-Releasing Hormone; D007770:L-Lactate Dehydrogenase