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

The neuroprotective effects of a systemically active, highly selective, cor ticotropin-releasing factor-1 (CRF1) receptor antagonist, R121920 ((7-(dipr opylamino)-2,5-dimethyl-3- [2-(dimethylamino)-5-pyridyl] pyrazolo [1,5-a] p yrimidine), was assessed in two rat models of permanent focal cerebral isch emia, where the middle cerebral artery (MCA) was occluded either through th e subtemporal approach or using the intraluminal suture technique. R121920 rapidly crossed the blood-brain barrier after intravenous (IV) bolus admini stration (10 mg/kg), with peak brain concentrations at 5 minutes (2.26 +/- 0.40 mug/mL), which were approximately 2-fold greater than those in plasma (0.98 +/- 0.24 mug/mL). Treatment with R121920 (10 mg/kg IV followed by 5 m g/kg subcutaneously at hourly intervals for 4 hours) significantly (P < 0.0 01) reduced total (by 40%) and cortical (by 37%) infarct volume at 24 hours after subtemporal MCA occlusion (MCAO). In the intraluminal suture MCAO mo del, 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 del ayed up to 1 hour after MCAO. These results further define the antiischemic properties of selective CRF1 antagonists in two experimental models of per manent focal cerebral ischemia.