Effects of nonpeptide V(1) vasopressin receptor antagonist SR-49059 on infarction volume and recovery of function in a focal embolic stroke model.
OBJECTIVE
Cerebral edema develops very early after the onset of focal cerebral ischemia and may be a major factor in early disability after an acute ischemic stroke. There have been very limited studies on the usefulness of antiedemic agents as neuroprotective agents in the setting of focal cerebral ischemia. We tested the neuroprotective effects of a new potent nonpeptide vasopressin receptor V(1) antagonist, SR-49059, in a focal embolic stroke model in rats.


METHODS
Focal ischemic injury was induced by embolizing a preformed clot into the middle cerebral artery (MCA). Infarction volume was measured at 48 hours after the MCA occlusion. Neurological deficits, ischemic brain edema, seizure activity, and mortality and hemorrhage rates were also documented.


RESULTS
Treatment with SR-49059 (2 mg/kg), initiated immediately after MCA occlusion, significantly reduced infarction volume (P<0.05) measured at 48 hours after the arterial occlusion. In animals in which the treatment was delayed for 1 hour after MCA occlusion, infarction volume was also reduced significantly (P<0.05). Infarction volume in the rats that received the drug at 3 or 6 hours after MCA occlusion was not different from that in the vehicle-treated group. Treatment with SR-49059, when started early after the arterial occlusion, also reduced neurological deficits and ischemic brain edema. Injection of drug at a higher dose (30 mg/kg) also reduced infarction volume and improved functional recovery but was not superior to the lower dose (2 mg/kg) when the drug was administrated at 1 hour after MCA occlusion.


CONCLUSIONS
Our data show that the selective vasopressin receptor antagonist SR-49059 is a potent neuroprotective agent when used early after onset of arterial occlusion in an embolic focal ischemia model in rats. Further studies are needed in stroke models to better understand its neuroprotective properties when used alone or in combination with thrombolysis.
Shuaib
Ashfaq
A
Stroke Research Laboratory, Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta, Canada. ashfaq.shuaib@ualberta.ca
Xu Wang
Chen
C
Yang
Tao
T
Noor
Raza
R
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001522:Behavior, Animal / Q000187:drug effects; D001929:Brain Edema / Q000473:pathology / Q000517:prevention & control; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006727:Hormone Antagonists / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy; D020766:Intracranial Embolism / Q000150:complications / Q000188:drug therapy*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome
D065092:Antidiuretic Hormone Receptor Antagonists; D006727:Hormone Antagonists; D007211:Indoles; D018696:Neuroprotective Agents; D011759:Pyrrolidines; C082134:relcovaptan