Astressin, a novel and potent CRF antagonist, is neuroprotective in the hippocampus when administered after a seizure.
Corticotropin-releasing factor (CRF), the principle hypothalamic regulator of the adrenocortical axis, also functions as a neurotransmitter. In this latter role, CRF causes electrophysiological activation and epileptiform activity in various brain regions. That finding, coupled with the observation that CRF mRNA is induced in endangered brain regions following necrotic insults, suggests that the peptide might contribute to necrotic neuron loss. Supporting that, a number of studies have shown that CRF antagonists decrease ischemic or excitotoxic damage to neurons. In the present report, we demonstrate the considerable neuroprotective potential of a novel and potent CRF antagonist, astressin, against kainic acid-induced excitotoxic seizures. Intracerebroventricular infusion of the peptide both 30 min before and 10 min after seizures decreased damage in some hippocampal cell fields by as much as 84%, a magnitude of protection greater than reported for other CRF antagonists against other models of necrotic neuronal injury. Administration of astressin was done against both local microinfusion (0.035 microgram) or systemic infusion (10 mg/kg body weight) of the excitotoxin; furthermore, the peptide protected even if administered only 10 min following excitotoxin exposure. This fulfills a critical prerequisite for any eventual therapeutic use of CRF antagonists, namely that they need not be administered in anticipation of a neurological insult.
Maecker
H
H
Department of Biological Sciences, Stanford University, CA 94305, USA.
Desai
A
A
Dash
R
R
Rivier
J
J
Vale
W
W
Sapolsky
R
R
D000704:Analysis of Variance; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology*; D007608:Kainic Acid; D008297:Male; D008845:Microinjections; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; 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; D007608:Kainic Acid