Taurine Reduces tPA (Tissue-Type Plasminogen Activator)-Induced Hemorrhage and Microvascular Thrombosis After Embolic Stroke in Rat

Abstract

Many neuroprotective agents, some promising, have been tested as adjunctive therapy with tPA to reduce its Background and Purpose-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. Methods-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. Results-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. Conclusions-Our results suggest that taurine in combination with tPA may be a clinically feasible approach toward future attempts at combination stroke therapy. Visual Overview-An online visual overview is available for this article.

Combined Treatment With 2-(2-Benzofu-Ranyl)-2-Imidazoline and Recombinant Tissue Plasminogen Activator Protects Blood–Brain Barrier Integrity in a Rat Model of Embolic Middle Cerebral Artery Occlusion

“…And rt-PA also mediates neuronal destruction through plasmin proteolysis (Tsirka et al, 1995;Tsirka et al, 1996). Delayed rt-PA can also cause secondary thrombus formation in downstream microvessels (Jin et al, 2018). Consistent with this literature, we found that 2-BFI + rt-PA (8 h) was unable to rescue BBB integrity in our study, as the negative effects of rt-PA treatment at 8 h blocked the majority of the beneficial effects of 2-BFI.…”

“…LOX inhibitor LOXBlock-1 have all shown promise as adjuvant therapies that can be combined with rt-PA (Zhang et al, 2009;Chen et al, 2017;Jin et al, 2018). An effective postischemic neuroprotective agent would permit the benefits of rt-PA and block all the negative effects, including reduced rt-PA neurotoxicity, reduced risk of hemorrhage, decreased reperfusion injury, amplified neuroprotective effect and increased therapeutic time window.…”

Alterations of gut microbiota contribute to the progression of unruptured intracranial aneurysms

“…In addition, taurine showed a considerable decrease in UIA patients compared with controls. Taurine has been shown to reduce inflammatory injury in various diseases and to play a protective role in acute ischemic stroke 29 , traumatic brain injury 30 , subarachnoid hemorrhage 31 , and aortic aneurysm formation 32 . Depletion of the taurine transport system has been reported in the microbiome in atherosclerotic cardiovascular disease 7 .…”

PI3Kγ (Phosphoinositide 3-Kinase-γ) Inhibition Attenuates Tissue-Type Plasminogen Activator–Induced Brain Hemorrhage and Improves Microvascular Patency After Embolic Stroke

“…Spontaneously hypertensive rats (SHRs, male, 12–15 week-old, weighing 270–310g, from Charles River Laboratories) were subjected to embolic middle cerebral artery occlusion (MCAO) according to the standard operating procedure in our laboratory [18, 21].…”