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Potential advantages of Chinese medicine Taohong Siwu Decoction (桃红四物汤) combined with tissue-plasminogen activator for alleviating middle cerebral artery occlusion-induced embolic stroke in rats

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Abstract

Objective

To investigate whether combination treatment with Taohong Siwu Decoction (桃红四物汤, TSD) and recombinant tissue-type plasminogen activator (rt-PA) potentiate in reducing infarct volume and alleviate thromboembolic stroke in an in vivo rat model.

Method

Adult male Wistar rats were subjected to embolic middle cerebral artery occlusion (MCAO) and treated with rt-PA (4 and 8 mg/kg) alone (n=5), TSD [0.7 g/(kg·day)] alone (n=5), combination of rt-PA and TSD, 24 h after stroke. Rats were sacrificed at 14 days after treatment and lesion volumes were measured. To investigate the underlying mechanism of neuroprotective effect of the combination treatment, cleaved caspase-3, tumor necrosis factor alpha (TNF-α), hypoxia-inducible factor (HIF)-1α, and inducible nitric oxide synthase (iNOS) immunostaining were performed.

Results

Combination treatment significantly reduced infarct volume of cerebral ischemic regions compared with treatment of rt-PA and TSD alone and that of the saline control group (P<0.01). A combined treatment of rt-PA (4 mg/kg) with TSD [0.7 g/(kg·day)] significantly increased cerebral blood flow in a time (100 and 120 min) dependent manner (P<0.05). Interestingly, despite treatment of rt-PA (4 mg/kg) alone significantly reduced the expressions of HIF-1α, TNF-α, and iNOS in ischemic regions, reduction of these expressions were more potentiated when combined with TSD (P<0.05). Combination treatment also reduced apoptosis as measured by a significant reduction in active caspase-3 expression in the ischemic brain compared with the MCAO group (P<0.01).

Conclusions

A combination of low-dose rt-PA and TSD after embolic stroke reduced infarct volume, improved cerebral blood flow and provided neuroprotection and these effects were associated with reduction of apoptosis and attenuation of HIF-1α, TNF-α and iNOS expression. These results provide a positive contribution to better understand the therapeutic value of the combination of TSD with rt-PA in ischemic stroke and may support further clinical evaluation.

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References

  1. Wang L, Zhou GB, Liu P, Song JH, Liang Y, Yan XJ, et al. Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia. Proc Natl Acad Sci USA 2008;105:4826–483.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Gong X, Sucher NJ. Stroke therapy in traditional Chinese medicine (TCM): prospects for drug discovery and development. Phytomed 2002;9:478–484.

    Article  CAS  Google Scholar 

  3. Yang JM. Therapeutic effect observation of 154 cases of coronary artery disease angina using Taohongsiwutang (THSW). China J Mod Med (Chin) 2007;17:2268–2275.

    Google Scholar 

  4. Qi ZX, Du CB. Local microcirculation changes in rabbits with glucocorticoid-induced avascular necrosis of femoral head following Taohongsiwu Decoction treatment. J Clin Rehab Tissue Eng Res 2008;12:2104–2107.

    Google Scholar 

  5. Yepes M, Roussel BD, Ali C, Vivien D. Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends Neurosci 2008; 32:48–55.

    Article  PubMed  Google Scholar 

  6. Turley KR, Toledo-Pereyra LH, Kothari RU. Molecular mechanisms in the pathogenesis and treatment of acute ischemic stroke. J Invest Surg 2005;18:207–218.

    Article  PubMed  Google Scholar 

  7. Derex L, Nighoghossian N. Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update. J Neurol Neurosurg Psychiat 2010;79:1093–1099.

    Article  Google Scholar 

  8. Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metabol 2001;21:2–14.

    Article  CAS  Google Scholar 

  9. Krueger K, Busch E. Protocol of a thromboembolic stroke model in the rat: review of the experimental procedure and comparison of models. Invest Radiol 2002;37:600–608.

    Article  PubMed  Google Scholar 

  10. Lee EJ, Chen HY, Wu TS, Chen TY, Ayoub IA, Maynard KI. Acute administration of Ginkgo biloba extract (EGb 761) affords neuroprotection against permanent and transient focal cerebral ischemia in Sprague-Dawley rats. J Neurosci Res 2002;68:636–645.

    Article  PubMed  CAS  Google Scholar 

  11. Hsiao G, Lin KH, Chang Y, Chen TL, Tzu NH, Chou DS, et al. Protective mechanisms of inosine in platelet activation and cerebral ischemic damage. Arterioscler Thromb Vasc Biol 2005;25:1998–2004.

    Article  PubMed  CAS  Google Scholar 

  12. Rodrigo J, Alonso D, Fernandez AP, Serrano J, Richart A, Lopez JC, et al. Neuronal and inducible nitric oxide synthase expression and protein nitration in rat cerebellum after oxygen and glucose deprivation. Brain Res 2001;909:20–45.

    Article  PubMed  CAS  Google Scholar 

  13. Cai YF, Fu Y, Guo JW, You JS, Wang LX, Liang WX, et al. Randomized multi-center control clinical study on acute ischemic stroke treatment with traditional Chinese medicine. J Chin Med Mater (Chin) 2007;30:1192–1195.

    Google Scholar 

  14. Qiu J. Back to the future for Chinese herbal medicines. Nat Rev Drug Discov 2007;6:506–507.

    Article  PubMed  CAS  Google Scholar 

  15. Wu CJ, Chen JT, Yen TL, Jayakumar T, Chou DS, Hsiao G, et al. Neuroprotection by the traditional Chinese medicine, Tao-Hong-Si-Wu-Tang, against middle cerebral artery occlusion-induced cerebral ischemia in rats. Evid Based Complement Alternat Med 2011;2011:1–9.

    Google Scholar 

  16. Overgaard K. Thrombolytic therapy in experimental embolic stroke. Cerebrovasc Brain Metabol Rev 1994;6:257–286.

    CAS  Google Scholar 

  17. Ginsberg MD, Busto R. Rodent models of cerebral ischemia. Stroke 1989;20:1627–1642.

    Article  PubMed  CAS  Google Scholar 

  18. Sharp FR, Bernaudin M. HIF1 and oxygen sensing in the brain. Nat Rev Neurosci 2004;5:437–448.

    Article  PubMed  CAS  Google Scholar 

  19. Shi H. Hypoxia inducible factor 1 as a therapeutic target in ischemic stroke. Curr Med Chem 2009;16:4593–4600.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Sheldon RA, Osredkar D, Lee CL, Jiang X, Mu D, Ferriero DM. HIF-1 alpha-deficient mice have increased brain injury after neonatal hypoxiaischemia. Dev Neurosci 2009;31:452–458.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Melillo G, Musso T, Sica A, Taylor LS, Cox GW, Varesio LA. Hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J Exp Med 1995;182:1683–1693.

    Article  PubMed  CAS  Google Scholar 

  22. Moro AM, Alba JD, Leza JC, Lorenzo P, Fernandez AP, Bentura ML, et al. Neuronal expression of inducible nitric oxide synthase after oxygen and glucose deprivation in rat forebrain slices. Eur J Neurosci 1998;10:445–456.

    Article  PubMed  CAS  Google Scholar 

  23. Iadecola C, Zhang F, Casey R, Nagayama M, Ross ME. Delayed reduction of ischemia brain injury and neurological deficits in mice lacking the nitric oxide synthase gene. J Neurosci 1997;17:9157–9164.

    PubMed  CAS  Google Scholar 

  24. Takano H, Manchikalapudi S, Tang XL, Qiu Y, Rizvi A, Jadoon AK, et al. Nitric oxide synthase is the mediator of late preconditioning against myocardial infarction in conscious rabbits. Circulation 1998; 98:441–449.

    Article  PubMed  CAS  Google Scholar 

  25. Iadecola C, Xu X, Zhang F, El-Fakahany EE, Ross ME. Marked induction of calcium-independent nitric oxide synthase activity after focal cerebral ischemia. J Cereb Blood Flow Metab 1995;15:52–59.

    Article  PubMed  CAS  Google Scholar 

  26. Savitz SI, Erhardt JA, Anthony JV, Gupta G, Li X, Barone FC, et al. The novel betablocker, carvedilol, provides neuroprotection in transient focal stroke. J Cereb Blood Flow Metabol 2000;20:1197–1204.

    Article  CAS  Google Scholar 

  27. Manabat C, Han BH, Wendland M, Derugin N, Fox CK, Choi J, et al. Reperfusion differentially induces caspase-3 activation in ischemic core and penumbra after stroke in immature brain. Stroke 2003;34:207–213.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Le DA, Wu Y, Huang Z, Matsushita K, Plesnila N, Augustinack JC, et al. Caspase activation and neuroprotection in caspase-3-deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proc Natl Acad Sci USA 2002;99:15188–15193.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Xu J, Culman J, Blume A, Brecht S, Gohlke P. Chronic treatment with a low dose of lithium protects the brain against ischemic injury by reducing apoptotic death. Stroke 2003;34:1287–1292.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  31. Luo Y, Cao G, Pei W, O’Horo C, Graham SH, Chen J. Induction of caspase-activated deoxyribonuclease activity after focal cerebral ischemia and reperfusion. J Cereb Blood Flow Metabol 2002;22:15–20.

    Article  CAS  Google Scholar 

  32. Vila N, Filella X, Deulofeu R, Ascaso C, Abellana R, Chamorroe A. Cytokine-induced inflammation and long-term stroke functional outcome. J Neurol Sci 1999;162:185–188.

    Article  PubMed  CAS  Google Scholar 

  33. Ferrarese C, Mascarucci P, Zoia C, Cavarretta R, Frigo M, Begni B, et al. Increased cytokine release from peripheral blood cells after acute stroke. J Cereb Blood Flow Metabol 1999;19:1004–1009.

    Article  CAS  Google Scholar 

  34. Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, et al. Tumour necrosis factor α. A mediator of focal ischemic brain injury. Stroke 1997;28:1233–1244.

    CAS  Google Scholar 

  35. Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ, Sutto-Tyrrell K, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation 2003;108:2317–2322.

    Article  PubMed  CAS  Google Scholar 

  36. Gupta S. Molecular steps of tumor necrosis factor receptor-mediated apoptosis. Curr Mol Med 2001;1:317–324.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan, 110, China

    Ting-Lin Yen  (顏廷霖), Chao-Chien Chang  (張釗監) & Joen-Rong Sheu  (許準榕)

  2. Department of Pharmacology, Taipei Medical University, Taipei, Taiwan, 110, China

    Ting-Lin Yen  (顏廷霖), Kuan-Hung Lin  (林冠宏), Thanasekaran Jayakumar, Song-Chow Lin  (林松洲) & Joen-Rong Sheu  (許準榕)

  3. Department of Cardiology, Cathay General Hospital, Taipei, Taiwan, 106, China

    Eng-Thiam Ong  (王榮添) & Chao-Chien Chang  (張釗監)

  4. Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, 111, China

    Kuan-Hung Lin  (林冠宏)

  5. Department of Anatomy, College of Medicine, Taipei Medical University, Taipei, Taiwan, 110, China

    Tsorng-Han Fong  (馮琮涵)

Authors
  1. Ting-Lin Yen  (顏廷霖)
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  2. Eng-Thiam Ong  (王榮添)
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  3. Kuan-Hung Lin  (林冠宏)
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  4. Chao-Chien Chang  (張釗監)
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  5. Thanasekaran Jayakumar
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  6. Song-Chow Lin  (林松洲)
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  7. Tsorng-Han Fong  (馮琮涵)
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  8. Joen-Rong Sheu  (許準榕)
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Corresponding authors

Correspondence to Tsorng-Han Fong  (馮琮涵) or Joen-Rong Sheu  (許準榕).

Additional information

Supported by grants from the National Science Council of Taiwan (No. NSC97-2320-B-038-016-MY3 and NSC100-2320-B-038-021-MY3), the Committee on Chinese Medicine and Pharmacy (No. CCMP100-RD-009), and the Cathay General Hospital, Taipei Medical University (No. 99CGH-TMU-01-2 and CGH-MR-10023)

These authors contributed equally to this work

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Yen, TL., Ong, ET., Lin, KH. et al. Potential advantages of Chinese medicine Taohong Siwu Decoction (桃红四物汤) combined with tissue-plasminogen activator for alleviating middle cerebral artery occlusion-induced embolic stroke in rats. Chin. J. Integr. Med. (2014). https://doi.org/10.1007/s11655-014-1847-x

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  • DOI: https://doi.org/10.1007/s11655-014-1847-x

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