From the Department of Neurosurgery, Neuroscience Institute, Penn State Hershey Medical Center (R.J., S.L., M.W., G.L.).
Department of Molecular and Cellular Physiology (A.Y.X., G.L.), Louisiana State University Health Sciences Center, Shreveport.
Stroke. 2018 Jul;49(7):1708-1718. doi: 10.1161/STROKEAHA.118.020747. Epub 2018 May 29.
Taurine (2-aminoethansulfolic amino acid) exerts neuroprotective actions in experimental stroke. Here, we investigated the effect of taurine in combination with delayed tPA (tissue-type plasminogen activator) on embolic stroke.
Rats subjected to embolic middle cerebral artery occlusion were treated with taurine (50 mg/kg) at 4 hours in combination with tPA (10 mg/kg) at 6 hours. Control groups consisted of ischemic rats treated with either taurine (50 mg/kg) or saline at 4 hours or tPA (10 mg/kg) alone at 2 or 6 hours after middle cerebral artery occlusion.
We found that combination treatment with taurine and tPA robustly reduced infarct volume and neurological deficits 3 days after stroke, whereas treatment with taurine alone had a less-significant protective effect. tPA alone at 6 hours had no effects on infarct volume but instead induced intracerebral hemorrhage. The combination treatment with taurine prevented tPA-associated hemorrhage and reduced intravascular deposition of fibrin/fibrinogen and platelets in downstream microvessels and hence improved microvascular patency. These protective effects are associated with profound inhibition of CD147 (cluster of differentiation 147)-dependent MMP-9 (matrix metalloproteinase-9) pathway in ischemic brain endothelium by taurine. Notably, targeted inhibition of CD147 by intracerebroventricular injection of the rat CD147 siRNA profoundly inhibited ischemia-induced and tPA-enhanced MMP-9 activity in ischemic brain endothelium and blocked tPA-induced cerebral hemorrhage. Finally, the combination treatment with taurine and tPA improved long-term outcome at least 45 days after stroke compared with saline-treated group.
Our results suggest that taurine in combination with tPA may be a clinically feasible approach toward future attempts at combination stroke therapy.
牛磺酸（2-氨基乙磺酸）在实验性中风中具有神经保护作用。在这里，我们研究了牛磺酸与延迟 tPA（组织型纤溶酶原激活物）联合应用于栓塞性中风的效果。
对栓塞性大脑中动脉闭塞的大鼠，在 4 小时时用牛磺酸（50mg/kg）联合在 6 小时时用 tPA（10mg/kg）治疗。对照组由在 4 小时时用牛磺酸（50mg/kg）或生理盐水、或在大脑中动脉闭塞后 2 小时或 6 小时时单独用 tPA（10mg/kg）治疗的缺血性大鼠组成。
我们发现，牛磺酸与 tPA 的联合治疗在中风后 3 天显著减少梗死体积和神经功能缺损，而单独用牛磺酸治疗的保护效果则不那么显著。6 小时时单独用 tPA 对梗死体积没有影响，但会引起脑出血。牛磺酸联合治疗可预防 tPA 相关的出血，并减少下游微血管内纤维蛋白/纤维蛋白原和血小板的血管内沉积，从而改善微血管通畅性。这些保护作用与牛磺酸在缺血性脑内皮细胞中对 CD147（分化群 147）依赖性 MMP-9（基质金属蛋白酶-9）途径的强烈抑制有关。值得注意的是，通过脑室内注射大鼠 CD147 siRNA 靶向抑制 CD147，可显著抑制缺血性脑内皮细胞中缺血诱导和 tPA 增强的 MMP-9 活性，并阻断 tPA 引起的脑出血。最后，与生理盐水处理组相比，牛磺酸与 tPA 的联合治疗在中风后至少 45 天改善了长期预后。
我们的结果表明，牛磺酸与 tPA 的联合应用可能是未来联合中风治疗尝试的一种可行的临床方法。
