Effects of Nonpeptide V ₁ Vasopressin Receptor Antagonist SR-49059 on Infarction Volume and Recovery of Function in a Focal Embolic Stroke Model

Abstract

Background and Purpose-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 (PϽ0.05) 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 (PϽ0.05). 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. (Stroke. 2002;33:3033-3037.)

Proliferating Progenitor Cells: A Required Cellular Element for Induction of Ischemic Tolerance in the Brain

“…The volume of infarct was calculated using the following formula: infarct volume = (volume of left hemisphereÀ(volume of right hemisphere Àmeasured infarct volume))/volume of left hemisphere. The brain swelling was determined using the following formula: swelling (edema) = (volume of right hemisphereÀvolume of left hemisphere)/volume of left hemisphere (Shuaib et al, 2002).…”

Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat

“…The method for quantification of infarct volume was performed exactly as previously reported [25,66,78]. Briefly, after completing the neurological evaluation and the rotarod test at 3 days after transient FCI, the animals were sacrificed under deep anesthesia and brains were removed, frozen and coronally sectioned into six 2-mm-thick slices (from rostral to caudal, first to sixth).…”

Real-Time Monitoring of Changes in Brain Extracellular Sodium and Potassium Concentrations and Intracranial Pressure after Selective Vasopressin-1a Receptor Inhibition following Focal Traumatic Brain Injury in Rats

“…Further, experimental models of intracerebral hemorrhage, middle cerebral artery occlusion, ischemia, and cold and traumatic brain injury have demonstrated that V1aR inhibition reduces brain edema. [22][23][24][25][26][27][28][29][30][31] The underlying mechanism of this response has been attributed to either modulation of vasopressin in the brain parenchyma 17 or its interaction with aquaporin-4 (AQP4). AQP4 is the predominant water channel in the brain and has a significant role in the pathophysiology of brain edema.…”