Neuroprotective effects of the CRF1 antagonist R121920 after permanent focal ischemia in the rat.

Abstract

The neuroprotective effects of a systemically active, highly selective, corticotropin-releasing factor-1 (CRF1) receptor antagonist, R121920 ((7-(dipropylamino)-2,5-dimethyl-3- [2-(dimethylamino)-5-pyridyl] pyrazolo [1,5-a] pyrimidine), was assessed in two rat models of permanent focal cerebral ischemia, where the middle cerebral artery (MCA) was occluded either through the subtemporal approach or using the intraluminal suture technique. R121920 rapidly crossed the blood-brain barrier after intravenous (IV) bolus administration (10 mg/kg), with peak brain concentrations at 5 minutes (2.26 +/- 0.40 microg/mL), which were approximately 2-fold greater than those in plasma (0.98 +/- 0.24 microg/mL). Treatment with R121920 (10 mg/kg IV followed by 5 mg/kg subcutaneously at hourly intervals for 4 hours) significantly (P < 0.001) reduced total (by 40%) and cortical (by 37%) infarct volume at 24 hours after subtemporal MCA occlusion (MCAO). In the intraluminal suture MCAO model, IV administration of R121920 (10 mg/kg) at the time of ischemia onset (and at multiple times thereafter) reduced both hemispheric infarct volume (by 34%, P < 0.001) and brain swelling (by 50%, P < 0.001) when assessed at 24 hours. In this model of focal ischemia, significant reduction (P < 0.05) in both outcome measures was obtained when R121920 administration was delayed up to 1 hour after MCAO. These results further define the antiischemic properties of selective CRF 1 antagonists in two experimental models of permanent focal cerebral ischemia.

• Authors: K B Mackay, H Bozigian, D E Grigoriadis, S A Loddick, G Verge, A C Foster
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 21 Issue 10 Pg. 1208-14 (Oct 2001) ISSN: 0271-678X [Print] United States
• PMID: 11598498 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Neuroprotective Agents
• Receptors, Corticotropin-Releasing Hormone
• CRF receptor type 1

Topics

• Animals
• Brain Edema (physiopathology, prevention & control)
• Brain Ischemia (physiopathology)
• Male
• Middle Cerebral Artery (pathology)
• Neuroprotective Agents (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Corticotropin-Releasing Hormone (antagonists & inhibitors)