astressin and Seizures

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.

Topics: Analysis of Variance; Animals; Chromatography, High Pressure Liquid; Corticotropin-Releasing Hormone; Hippocampus; Kainic Acid; Male; Microinjections; Neurons; Neuroprotective Agents; Peptide Fragments; Rats; Rats, Sprague-Dawley; Seizures

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).

Topics: Animals; Corticotropin-Releasing Hormone; Electroencephalography; Female; Neuroprotective Agents; Peptide Fragments; Pregnancy; Rats; Rats, Sprague-Dawley; Seizures