Effects of PS-519 combined with thrombolytic therapy in embolic stroke in rat
We evaluated the effect of a proteasome inhibitor (PS-519) which blocks the activation of NF-kB, alone or combination with thrombolysis, on ischemic cell damage after embolic stroke in rat. Male Wistar rats (n=44) were subjected to embolic middle cerebral artery (MCA) occlusion. Animals were randomly assigned into seven groups: PS-519 treatment groups (n=6 each group) were infused intravenously with PS-519(1.0 mg/kg) at 2 h, 4 h, or 6 h after MCA occlusion, respectively. Combination treatment groups (n=6 each group) PS-519(1.0 mg/kg) followed by rtPA (10 mg/kg) were administered at 2 h, 4 h, or 6 h after MCA occlusion. A control group (n=8) was administered saline at 2 h after MCA occlusion. Rats were sacrificed 7 days after MCA occlusion, infarct volume and gross hemorrhage were measured. In PS-519 treatment groups: infarct volume was significantly (p<0.05) reduced by PS-519 treatment at 2 (19”3.5%) and 4 h (22“3.1%) after MCA occlusion when compared with the control group (34”3.5%). However, no significant reduction of lesion volume was found in the 6 hour treated group (34“2.5%). In the combination treatment groups: infarction volume was significantly (p<0.05) reduced in all three groups compared with control: 2 h (18”4.3%), 4 h (21“3.6%), 6 h (21”4.4%). None of treated rats and 25% of control rats had intracerebral gross hemorrhage. Significant reductions (p<0.05) in neurological deficit and body weight loss were found in all treated groups except the group that treated with PS-519 alone at 6 h. Our results demonstrate that administration of PS-519 alone, or combination with rtPA significantly reduces ischemic cell damage. Moreover, combination treatment with PS-519 and rtPA expands the therapeutic window to at least 6 h after embolic stroke. This suggests that combination therapy might lead to improved neurological outcome beyond that which would occur with neuroprotective treatment or thrombolytics alone.