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

BACKGROUND: In ischemic stroke, blood-brain barrier (BBB) regulations, typically involving matrix metalloproteinases (MMPs) and inhibitors (TIMPs) as mediators, became interesting since tissue plasminogen activator (tPA)-related BBB breakdown with risk of secondary hemorrhage was considered to involve these mediators too. Despite high clinical relevance, detailed interactions are purely understood. After a pilot study addressing hyperoxia as potential neuroprotective co-treatment to tPA, we analyzed interrelations between BBB permeability (BBB-P), MMPs and TIMPs. FINDINGS: 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. CONCLUSIONS: 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.