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A Combined Treatment with Taurine and Intra-arterial Thrombolysis in an Embolic Model of Stroke in Rats: Increased Neuroprotective Efficacy and Extended Therapeutic Time Window

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Abstract

Combination treatment may target different pathophysiological events following cerebral ischemia thus enhancing the efficacy of treatment in thromboembolic stroke. Taurine confers a neuroprotective effect in the mechanical stroke model. This effect has not been assessed in an embolic stroke model. Here, we sought to evaluate the neuroprotective effect of taurine alone and in combination with thrombolytic therapy to investigate whether combined administration would extend the therapeutic time window without increasing the hemorrhagic transformation in a rat embolic stroke model. Rats were subjected to right embolic middle cerebral artery occlusion and then randomly assigned to the following groups: saline treatment alone at 4 h, urokinase, taurine treatment alone at 4, 6, or 8 h, and the combination of taurine and urokinase at 4, 6, or 8 h after the insult. Brain infarct volume, neurobehavioral outcome, regional cerebral blood flow, intracranial hemorrhage incidence were observed and evaluated. Posttreatment with taurine at 4 or 6 h, urokinase at 4 h or in combination at 4, 6, or 8 h significantly reduced infarct volume and improved neurobehavioral outcome. The combination treatment had better neurobehavioral outcome and smaller infarction volume than urokinase or taurine treatment alone. The clinical outcome correlated well with infarct volume. Together, the present study suggests that administration of taurine after stroke is neuroprotective, seemingly because it reduces the reperfusion damage of urokinase, leading to widen the therapeutic window for the thrombolytic effect of urokinase to 8 h. Thrombolysis can also enhance the neuroprotective effect of taurine. The reduction of inflammatory response, neuron death and inhibition of blood brain barrier (BBB) disruption may underlie the beneficial effects of combination of taurine and urokinase in the treatment of embolic stroke.

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References

  1. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 h after acute ischemic stroke. N Engl J Med. 2008;359:1317–29.

    Article  CAS  PubMed  Google Scholar 

  2. Macleod MR, Davis SM, Mitchell PJ, Gerraty RP, Fitt G, Hankey GJ, et al. Results of a multicentre, randomised controlled trial of intra-arterial urokinase in the treatment of acute posterior circulation ischaemic stroke. Cerebrovasc Dis. 2005;20:12–7.

    Article  CAS  PubMed  Google Scholar 

  3. Agarwal P, Kumar S, Hariharan S, Eshkar N, Verro P, Cohen B, et al. Hyperdense middle cerebral artery sign: can it be used to select intra-arterial versus intravenous thrombolysis in acute ischemic stroke? Cerebrovasc Dis. 2004;17:182–90.

    Article  PubMed  Google Scholar 

  4. Qureshi AI, Ezzeddine MA, Nasar A, Suri MF, Kirmani JF, Janjua N, et al. Is IV tissue plasminogen activator beneficial in patients with hyperdense artery sign? Neurology. 2006;66(8):1171–4.

    Article  CAS  PubMed  Google Scholar 

  5. Labiche LA, Al-Senani F. WojnerAW, et al. Is the benefit of early recanalization sustained at 3 months? A prospective cohort study. Stroke. 2003;34:695–8.

    Article  PubMed  Google Scholar 

  6. Alexandrov AV, Molina CA, Grotta JC, et al. Ultrasound enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med. 2004;351:2170–8.

    Article  CAS  PubMed  Google Scholar 

  7. Brott TG, Haley Jr EC, Levy DE, et al. Urgent therapy for stroke. Part 1. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke. 1992;23:632–40.

    CAS  PubMed  Google Scholar 

  8. Von Krummer R, Hacke W. Safety and efficacy of intravenous tissue plasminogen activator and heparin in acute middle cerebral artery stroke. Stroke. 1992;23:646–52.

    Google Scholar 

  9. Trouillas P, Nighoghossian N, Getenet JC, et al. Open trial of intravenous tissue plasminogen activator in acute carotid territory stroke: correlations of outcome with clinical and radiological data. Stroke. 1996;27:882–90.

    CAS  PubMed  Google Scholar 

  10. Mattle HP. Intravenous or intra-arterial thrombolysis? It’s time to find the right approach for the right patient. Stroke. 2007;38:2038–40.

    Article  PubMed  Google Scholar 

  11. Del Zoppo GJ, Higashida RT, Furlan AJ, et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke. 1998;29:4–11.

    PubMed  Google Scholar 

  12. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial pro-urokinase for acute ischemic stroke: the PROACT II study: a randomized controlled trial. JAMA. 1999;282:2003–11.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang L, Zhang ZG, Zhang CL, Zhang RL, Chopp M. Intravenous administration of a GPIIb/IIIa receptor antagonist extends the therapeutic window of intra-arterial tenecteplase-tissue plasminogen activator in a rat stroke model. Stroke. 2004;35:2890–095.

    Article  CAS  PubMed  Google Scholar 

  14. Sun M, Xu C. Neuroprotective mechanism of taurine due to up-regulating calpastatin and down-regulating calpain and caspase-3 during focal cerebral ischemia cellular and molecular neurobiology. Cell Mol Neurobiol. 2008;28:593–611.

    Article  PubMed  Google Scholar 

  15. Asahi M, Asahi K, Wang XY, Lo EH. Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2000;20:452–7.

    Article  CAS  PubMed  Google Scholar 

  16. Paxinos G, Watson C. The Rat Brain Stereotaxic Coordinates. 2nd ed. Orlando: Academic Press; 1986.

    Google Scholar 

  17. Shuaib A, Yang Y, Siddiqui M, Kalra J. Intraarterial urokinase produces significant attenuation of infarction volume in an embolic focal ischemia model. Exp Neurol. 1998;154:330–5.

    Article  CAS  PubMed  Google Scholar 

  18. Yang Y, Li Q, Shuaib A. Enhanced neuroprotection and reduced hemorrhagic incidence in focal cerebral ischemia of rat by low dose combination therapy of urokinase and topiramate. Neuropharmacology. 2000;39:881–8.

    Article  CAS  PubMed  Google Scholar 

  19. Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke. 1986;17:472–6.

    CAS  PubMed  Google Scholar 

  20. Lin TN, He YY, Wu G, Khan M, Hsu CY. Effects of brain edema on infarct volume in a focal cerebral ischemia model in rats. Stroke. 1993;24:117–21.

    CAS  PubMed  Google Scholar 

  21. Zhang JW, Gottschall PE. Zymographic measurement of gelatinase activity in brain tissue after detergent extraction and affinity-support purification. J Neurosci Methods. 1997;76:15–20.

    Article  CAS  PubMed  Google Scholar 

  22. Kleiner DE, Stetler-Stevenson WG. Quantitative zymography: detection of pictogram quantities of gelatinase. Anal Biochem. 1994;218:325–9.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang ZG, Chopp M. Measurement of myeloperoxidase immunoreactive cells in ischemic brain after transient middle cerebral artery occlusion in the rat. Neurosci Res Comm. 1997;20:85–91.

    Article  CAS  Google Scholar 

  24. Lima L, Obregon F, Cubillos S, Fazzino F, Jaimes I. Taurine as a micronutrient in development and regeneration of the central nervous system. Nutr Neurosci. 2001;4:439–43.

    CAS  PubMed  Google Scholar 

  25. Matsumoto K, Ueda S, Hashimoto T, Kuriyama K. Ischemic neuronal injury in the rat hippocampus following transient forebrain ischemia: evaluation using in vivo microdialysis. Brain Res. 1991;543:236–42.

    Article  CAS  PubMed  Google Scholar 

  26. Wu JY, Lin CT, Johanssen FF, Liu JW. Taurine neurons in rat hippocampal formation are relatively inert to cerebral ischemia. Adv Exp Med Biol. 1994;359:289–98.

    CAS  PubMed  Google Scholar 

  27. Shuaib A. The role of taurine in cerebral ischemia: studies in transient forebrain ischemia and embolic focal ischemia in rodents. Adv Exp Med Biol. 2003;526:421–31.

    CAS  PubMed  Google Scholar 

  28. Sanberg PR, Willow M. Dose-dependent effects of taurine on convulsions induced by hypoxia in the rat. Neurosci Lett. 1980;16:297–300.

    Article  CAS  PubMed  Google Scholar 

  29. Schurr A, Tseng MT, West CA, Rigor BM. Taurine improves the recovery of neuronal function following cerebral hypoxia: an in vitro study. Life Sci. 1987;40:2059–66.

    Article  CAS  PubMed  Google Scholar 

  30. Schuller-Levis GB, Park E. Taurine and its chloramine: modulators of immunity. Neurochem Res. 2004;29:117–26.

    Article  CAS  PubMed  Google Scholar 

  31. Guz G, Oz E, Lortlar N, Ulusu NN, Demirogullari B, Omeroglu S, et al. The effect of taurine on renal ischemia/reperfusion injury. Amino Acids. 2007;32:405–11.

    Article  CAS  PubMed  Google Scholar 

  32. Raschke P, Massoudy P, Becker BF. Taurine protects the heart from neutrophil-induced reperfusion injury. Free Radic Biol Med. 1995;19:461–71.

    Article  CAS  PubMed  Google Scholar 

  33. Giriş M, Depboylu B, Doğru-Abbasoğlu S, Erbil Y, Olgaç V, Aliş H, et al. Effect of taurine on oxidative stress and apoptosis-related protein expression in trinitrobenzene sulphonic acid-induced colitis. Clin Exp Immunol. 2008;152:102–10.

    Article  PubMed  Google Scholar 

  34. Marcinkiewicz J, Kurnyta M, Biedroń R, Bobek M, Kontny E, Maśliński W. Anti-inflammatory effects of taurine derivatives (taurine chloramine, taurine bromamine, and taurolidine) are mediated by different mechanisms. Adv Exp Med Biol. 2006;583:481–92.

    Article  CAS  PubMed  Google Scholar 

  35. Zhao RZ, Wang S, Kim HY, Storrie H, Rosen BR, Mooney DJ, et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med. 2006;12:441–5.

    Article  CAS  PubMed  Google Scholar 

  36. Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD, et al. Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol. 2005;289:H558–68.

    Article  CAS  PubMed  Google Scholar 

  37. Matsuo Y, Onodera H, Shiga Y, Nakamura M, Ninomiya M, Kihara T, et al. Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke. 1994;25:1469–75.

    CAS  PubMed  Google Scholar 

  38. Ogawa A, Mori E, Minematsu K, Taki W, Takahashi A, Nemoto S, et al. Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan. Stroke. 2007;38(10):2633–9.

    Article  CAS  PubMed  Google Scholar 

  39. Lee DH, Jo KD, Kim HG, Choi SJ, Jung SM, Ryu DS, et al. Local intraarterial urokinase thrombolysis of acute ischemic stroke with or without intravenous abciximab: a pilot study. J Vasc Interv Radiol. 2002;13(8):769–74.

    Article  PubMed  Google Scholar 

  40. Yu YY, Niu L, Gao L, Zhao ZW, Deng JP, Qu YZ, et al. Intraarterial thrombolysis and stent placement for acute basilar artery occlusion. J Vasc Interv Radiol. 2010;21(9):1359–63.

    Article  PubMed  Google Scholar 

  41. Arnold M, Fischer U, Schroth G, Nedeltchev K, Isenegger J, Remonda L, et al. Intra-arterial thrombolysis of acute iatrogenic intracranial arterial occlusion attributable to neuroendovascular procedures or coronary angiography. Stroke. 2008;39(5):1491–5.

    Article  PubMed  Google Scholar 

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Sources of funding

This work was supported by the Beijing Natural Science Foundation of China, NO: 7052018.

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  1. Department of Neurochemistry, Beijing Neurosurgical Institute, 6 Tiantan Xi Li, 100050, Beijing, People’s Republic of China

    Weihua Guan, Yumei Zhao & Chao Xu

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  1. Weihua Guan
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  3. Chao Xu
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Correspondence to Chao Xu.

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Guan, W., Zhao, Y. & Xu, C. A Combined Treatment with Taurine and Intra-arterial Thrombolysis in an Embolic Model of Stroke in Rats: Increased Neuroprotective Efficacy and Extended Therapeutic Time Window. Transl. Stroke Res. 2, 80–91 (2011). https://doi.org/10.1007/s12975-010-0050-4

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