Abstract T P214: A Multifunctional Nitroxylated Albumin for Early Treatment of Stroke

Abstract

Objective: To determine if early treatment with a multifunctional nitroxylated albumin (MNA) in a rat embolic model of ischemic stroke can overcome the time limitation of tPA with better efficacy than human serum albumin (HSA). Background: A recently published clinical trial in JAMA concluded that the treatment time has a profound influence on outcome to stroke victims. We have published a series of animal studies to show the antioxidant activities including superoxide dismutase and catalase mimic properties of MNA support its development as an early stroke treatment Methods: Early treatment of MNA was tested for the reduction of infarction and hemorrhage with delayed tPA treatment in a rat embolic model of ischemic stroke. Thirty animals were used. In anesthetized rat, a catheter was inserted into the middle cerebral artery (MCA) at its origin followed by injection into MCA of a 25 mm clot to cause occlusion. Two hours following occlusion, 10 ml/kg of MNA (n=10) was given and 4 hours following occlusion 10 mg/kg of tPA was given. As controls, HSA (n=10) plus tPA or saline (n=10) plus tPA was administered using the identical protocol. After 14 days animals were anesthetized and euthanized. Their brains slices were examined for the volume of cerebral tissue infarction and evidence of hemorrhagic transformation. Results: The results show that the level of infarction with tPA treatment at 4 hours was about 38%. Co-treatment with HSA at 2 hours and tPA at 4 hours did not cause a significant decrease in infarct volume compared to saline plus tPA. However, treatment at 2 hours with MNA and 4 hours with tPA resulted in a significant reduction in infarct volume (p<0.01). About 22 % of the brain slices exhibited microscopic hemorrhage with saline plus tPA group. There was no significant difference comparing HSA and saline groups. However, microscopic hemorrhage was significantly reduced in rats that were treated with MNA at 2 hours (p<0.01 and p<0.05, MNA vs. saline and HSA, respectively). In addition, the conjunctive treatment with MNA completely prevented gross hemorrhage. Conclusions: MNA treatment data in rat embolic stroke model supports its development as an early stroke treatment drug, which may fill the void of recently failed HSA stroke trials.