Interrelations between blood-brain barrier permeability and matrix metalloproteinases are differently affected by tissue plasminogen activator and hyperoxia in a rat model of embolic stroke

Rats underwent embolic middle cerebral artery occlusion (eMCAO) and treatment with normobaric (NBO) or hyperbaric oxygen (HBO), tPA, tPA+HBO, or no treatment. BBB-P was assessed by intravenously applied FITC-albumin at 4 or 24 hours. MMP-2/-9 and TIMP-1/-2 serum levels were determined at 5 or 25 hours. Time point-corrected partial correlations were used to explore interrelations of BBB-P in ischemic regions (extra-/intravasal FITC-albumin ratio) and related serum markers. BBB-P correlated positively with MMP-2 and MMP-9 in controls, whereas hyperoxia led to an inverse association, most pronounced for HBO/MMP-9 (r = -0.606; P < 0.05). As expected, positive coefficients were observed after treatment with tPA. Co-treatment with HBO attenuated and in part reversed this effect, but to a lower degree than HBO alone. Amongst MMPs and TIMPs, significant associations shifted from MMP-9 to -2 when comparing treatment with HBO/tPA and tPA+HBO. TIMPs were significantly interrelated after tPA, tPA+HBO, and interestingly, HBO alone.HBO was found to reverse the positively directed interrelation of BBB-P and MMPs after eMCAO, but this effect failed to sustain in the expected amount when HBO and tPA were given simultaneously.Multiple clinical trials have proven the efficacy of tissue plasminogen activator (tPA) in the treatment of acute focal cerebral ischemia [1]. Apart from its beneficial recanalizing actions, tPA has also detrimental effects contributing to blood-brain barrier (BBB) disruption in ischemia-affected brain tissue [2-4] with an increased risk of secondary hemorrhage and poor outcome [5,6]. Enzymes, e.g., matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), are considered as key factors regulating the BBB integrity [7,8]. Thereby, MMPs possess both destructive abilities in earlier phases of ischemia and regenerative properties (e.g., remodeling) in later phases [9], which implicate complex interactions in the time course of ischemic stroke. Interestingly, tP