title: Time-dependent changes in CRH concentrations and release in discrete brain regions following global ischemia: effects of MK-801 pretreatment.
abstract: The excitatory actions of corticotropin-releasing hormone (CRH) in the brain and the neuroprotective effects of CRH antagonists in models of ischemia suggest a role for this peptide in the cascade of events leading to cellular damage. The present study aimed to characterize endogenous activation of CRH in discrete brain regions following global ischemia. Time-dependent changes in CRH concentrations were assessed in 10 brain regions including hippocampal, parahippocampal, and hypothalamic regions as well as the amygdala and the frontal cortex at three post-ischemic intervals: 4, 24, and 72 h (Experiment 1). The impact of pretreatment with a neuroprotective dose of the NMDA antagonist (5R,10S)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801; hydrogen maleate) on 24-h ischemia-induced CRH concentrations in the 10 brain regions was also determined (Experiment 2). In vivo microdialysis was used to assess dynamic fluctuations in CRH release at the dorsal hippocampus (CA1 pyramidal layer) and central nucleus of the amygdala (CeA; Experiment 3). Our findings revealed a rapid elevation of CRH concentrations at the piriform cortex (Pir) and hypothalamic nuclei following global ischemia. This was followed by decreased CRH concentrations at the amygdala, the frontal cortex (FC), the CA3, and the hypothalamus 24-h post-ischemia. MK-801 reversed the decreases in the hypothalamic nuclei but not in the other brain regions. Seventy-two hours post-ischemia, CRH levels returned to control values in all regions except the dentate gyrus (DG) where elevated CRH levels were observed. In vivo, a significant increase in CRH release in response to global ischemia was found at the CeA with no alterations at the CA1. These findings support brain region-specific ischemia-induced CRH alterations and suggest that CRH actions to mediate neuronal damage at the hippocampal CA1 layer may be indirect.
authors.affiliation: University of Michigan, Department of Psychiatry, VA Medical Center, Ann Arbor, MI, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Khan
authors.forename: Marc
authors.initials: M
authors.lastname: Milot
authors.forename: Jacinthe
authors.initials: J
authors.lastname: Lecompte-Collin
authors.forename: Hélène
authors.initials: H
authors.lastname: Plamondon
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000517:prevention & control*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D007511:Ischemia / Q000378:metabolism*; D008297:Male; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016291:Dizocilpine Maleate; D003346:Corticotropin-Releasing Hormone