The effect of 'Astressin', a novel antagonist of corticotropin releasing hormone (CRH), on CRH-induced seizures in the infant rat: comparison with two other antagonists.
Corticotropin releasing hormone (CRH) has both neuroendocrine effects, promoting ACTH release from the anterior pituitary, and neurotransmitter properties, acting on specific neuronal populations. A recently designed CRH analogue has been shown to be highly potent in preventing activation of pituitary CRH receptors. The efficacy of this compound, 'Astressin', in blocking the effects of CRH in the central nervous system (CNS) has not been determined. CRH induces prolonged amygdala-origin seizures in neonatal and infant rats. This model was used in the current study, to compare Astressin to alpha-helical CRH-(9-41), and to [D-Phe12, Nle21.38, C-MeLeu37]CRH-(12-41), i.e. D-Phe-CRH-(12-41). Astressin (3 or 10 micrograms) was infused into the cerebral ventricles of infant rats prior to CRH infusion. Both doses of the analogue significantly delayed the onset of CRH-induced seizures when given 15, but not 30 min before CRH. No effect of the lower Astressin dose on seizure duration was demonstrated; the higher dose prevented seizures in 2/12 rats, and delayed seizure onset in the others (22.7 +/- 5 min vs 10.1 +/- 1.3 min). In the same paradigm, 10 micrograms of alpha-helical CRH-(9-41) and 5 micrograms of D-Phe-CRH-(12-41) had comparable effects on seizure latency and duration. Electroencephalograms confirmed the behavioral effects of Astressin. Therefore, in a CNS model of CRH-mediated neurotransmission, the potency of Astressin is not substantially higher than that of alpha-helical CRH (9-41) and D-Phe-CRH-(12-41).
Baram
T Z
TZ
Department of Pediatrics, University of California, Irvine 92717, USA.
Koutsoukos
Y
Y
Schultz
L
L
Rivier
J
J
D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
D018696:Neuroprotective Agents; D010446:Peptide Fragments; C104416:astressin; D003346:Corticotropin-Releasing Hormone