Abstract T P232: Combination Therapy With Taurine Plus Tissue Plasminogen Activator in a Rat Model of Embolic Stroke

Abstract

Background: Tissue plasminogen activator (tPA) is the only FDA-approved therapy for acute ischemic stroke, but it has narrow therapeutic window (within 4.5h) and increased risks of intracerebral hemorrhage. Taurine, an endogenous 2-aminoethansulfolic amino acid, exhibits a plethora of physiological functions. It has been found to protect against ischemic brain injury in animal models of stroke by diverse mechanisms. Strikingly, published data show that the therapeutic window of taurine was at least 8h after the onset of ischemic stroke, thus potentially allowing for delayed or more effective thrombolysis. In this study we investigated whether combination therapy with taurine plus tPA can block hemorrhagic transformation and thus extend the time window of tPA after delayed tPA treatment for ischemic stroke. Methods and Results: Male adult rats (330-380g) were subjected to embolic middle cerebral artery occlusion and then randomized into different treatment groups: saline injected at 4h; taurine (50 mg/kg) at 4h, tPA (10 mg/kg) at 6h, and combination therapy with taurine at 4h plus tPA at 6h after the onset of ischemia. Delayed 6-hour tPA did not decrease infarction but instead worsened brain hemorrhage. Combining taurine with delayed 6-hour tPA reduced tissue infarction, attenuated blood-brain barrier disruption by reduced degradation of tight junction proteins (claudin-5 and collagen IV), and ameliorated brain hemorrhage. These protective effects are correlated with decreased brain matrix metallopeptidase-9 activity possibly through inactivation of NF-kB and CD147 (a potent inducer of MMPs) in the postischemic brain, particularly in the cerebral microvessels (using structurally intact microvessels isolated from the brain). Conclusion: The present study demonstrates for the first time that combination therapy with taurine may attenuate delayed tPA-associated hemorrhagic transformation and extend tPA treatment time windows in a clinically relevant thromboembolic stroke model. Inhibition of MMP-9 in brain microvessels via inactivation of NF-κB and CD147 signaling may underlie the protective mechanisms of taurine.