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Introduction: Inter-alpha Inhibitor Proteins (IAIP) are a family of endogenous plasma and extracellular matrix molecules. IAIPs have been shown to down-regulate inflammation, inhibit destructive serine proteases, and bind extracellular histones to neutralize cytotoxicity. Interestingly, many of these factors also regulate neuroprotection after stroke. In our initial studies, we found that IAIP treatment was neuroprotective in the middle cerebral artery occlusion model. Here, we analyzed if stroke alters IAIP using plasma samples from both mice and human stroke patients, and we investigated whether IAIP could provide neuroprotection using multiple stroke models.Methods: C57BL/6 mice were subjected to stroke with an autologous thromboembolic clot followed by reperfusion using t-PA. A separate cohort underwent the permanent occlusion model. Mice were randomized to receive IAIP or vehicle at 6h and 18h after stroke onset. Infarct was assessed 48h after reperfusion with t-PA, or 72h after permanent occlusion. Plasma samples from stroke patients and vascular risk factor matched controls were used for changes in IAIP levels using ELISA. Statistics were performed by two-sample t-test or Wilcoxon rank-sum test. P <0.05 considered significant.Results: IAIP treatment significantly reduced total injury size (t-PA alone 22±2% vs. t-PA+IAIP 13±3%; n=4-5/grp). Protection was also seen after permanent occlusion (vehicle 59.4±3.9% vs IAIP 39.5±5.9%; n=6-8/gp, p<.05), showing efficacy of IAIP in two different models. IAIP treatment improved survival rates (82% with IAIP vs 63% with vehicle) and neurological scores compared to vehicle group (p<0.05). Mean IAIP levels were significantly lower (stroke patients 134.4 ug/ml; n=51 vs controls 157.5 ug/ml; n=40), in parallel, increased IAIP-Histone complexes were seen in these patients. Similar changes were identified in mouse samples.Conclusions: Our results show that delayed IAIP treatment can significantly reduce cell death in both permanent ischemia and/or in combination with t-PA. IAIP could potentially represent an important, novel treatment for stroke. Our studies in combination with t-PA further strengths this clinical translatability and to design personalized dosing based on IAIP levels.