Effects of Kudiezi Injection on Serum Inflammatory Biomarkers in Patients with Acute Cerebral Infarction

Xuemei Liu, Xianglan Jin, Baoxin Chen, Xiaohan Liu, Xiao Liang, Xiaolei Fang, Hongyun Wu, Xiaoyu Fu, Hong Zheng, Xiao Ding, Na Duan, Yunling Zhang, Xuemei Liu, Xianglan Jin, Baoxin Chen, Xiaohan Liu, Xiao Liang, Xiaolei Fang, Hongyun Wu, Xiaoyu Fu, Hong Zheng, Xiao Ding, Na Duan, Yunling Zhang

Abstract

Background: Kudiezi injection is a traditional Chinese medicine for acute cerebral infarction, but the exact mechanisms are poorly understood.

Objective: To investigate the mechanisms of Kudiezi injection on the inflammatory response in the treatment of acute cerebral infarction.

Methods: This was a prospective study of patients with acute cerebral infarction within 48 h of onset and treated between July 2012 and July 2016 at three hospitals in China. The patients were randomized to routine treatments (control group) versus routine treatments and Kudiezi injection (Kudiezi group). The National Institutes of Health Stroke Score was assessed on days 1, 3, 5, 7, and 14. The patients were tested for serum levels of pro- and anti-inflammatory cytokines (S100 calcium-binding protein B, neuron-specific enolase, interleukin-6, interleukin-10, interleukin-18, and matrix metaloproteinase-9; by enzyme-linked immunosorbent assay) immediately after admission and on days 3, 5, and 14.

Results: Stroke scores were improved in both groups from days 1 to 14. On days 5 and 7, stroke scores in the Kudiezi group were lower than in the control group (P < 0.05). Compared with controls, the Kudiezi group had lower serum S100 calcium-binding protein B on day 14; higher interleukin-6 and interleukin-10 on day 3; lower interleukin-6 and interleukin-18 on day 5; and lower interleukin-18 and matrix metaloproteinase-9 on day 14.

Conclusion: Kudiezi injection could lead to early reduction of interleukin-6, interleukin-18, matrix metaloproteinase-9, neuron-specific enolase, and S100 calcium-binding protein B levels and increases of interleukin-10 levels in patients with acute ischemic stroke. This trial is registered with ClinicalTrials.gov NCT01636154.

Figures

Figure 1
Figure 1
Patient flowchart.
Figure 2
Figure 2
NIHSS score after acute ischemic stroke. NIHSS scores were decreased in both groups from day 1 to day 14. There were no differences between the two groups, except on days 5 and 7. n = 28/group. ∗P < 0.05 versus day 1. NIHSS: National Institutes of Health Stroke Scale.
Figure 3
Figure 3
Serum NSE and S100B levels in acute ischemic stroke patients. (a) NSE levels. (b) S100B levels. n = 28/group. ∗P < 0.05, ∗∗P < 0.01, t-test, versus the control group at the same time point. NSE: neuron-specific enolase; S100B: S100 calcium-binding protein B; KDZ: Kudiezi injection.
Figure 4
Figure 4
Serum inflammatory markers in acute ischemic stroke patients. (a) IL-6 levels. (b) IL-18 levels. (c) IL-10 levels. (d) MMP-9 levels. n = 28/group. ∗P < 0.05, ∗∗P < 0.01, t-test, versus the control group on the same time point. IL: interleukin; MMP: matrix metalloproteinase; KDZ: Kudiezi injection.

References

    1. Iadecola C., Anrather J. The immunology of stroke: from mechanisms to translation. Nature Medicine. 2011;17(7):796–808. doi: 10.1038/nm.2399.
    1. Jafarinaveh H. R., Allahtavakoli M., Rezazadeh H., et al. Proinflammatory cytokines in the embolic model of cerebral ischemia in rat. Iranian Journal of Allergy, Asthma, and Immunology. 2014;13(2):125–130.
    1. Park S. Y., Kim J., Kim O. J., et al. Predictive value of circulating interleukin-6 and heart-type fatty acid binding protein for three months clinical outcome in acute cerebral infarction: multiple blood markers profiling study. Critical Care. 2013;17(2, article R45) doi: 10.1186/cc12564.
    1. Bustamante A., Sobrino T., Giralt D., et al. Prognostic value of blood interleukin-6 in the prediction of functional outcome after stroke: a systematic review and meta-analysis. Journal of Neuroimmunology. 2014;274(1-2):215–224. doi: 10.1016/j.jneuroim.2014.07.015.
    1. Kang H. J., Bae K. Y., Kim S. W., et al. Effects of interleukin-6, interleukin-18, and statin use, evaluated at acute stroke, on post-stroke depression during 1-year follow-up. Psychoneuroendocrinology. 2016;72:156–160. doi: 10.1016/j.psyneuen.2016.07.001.
    1. Protti G. G., Gagliardi R. J., Forte W. C. N., Sprovieri S. R. S. Interleukin-10 may protect against progressing injury during the acute phase of ischemic stroke. Arquivos de Neuro-Psiquiatria. 2013;71(11):846–851. doi: 10.1590/0004-282X20130168.
    1. Rodríguez-Yáñez M., Castellanos M., Sobrino T., et al. Interleukin-10 facilitates the selection of patients for systemic thrombolysis. BMC Neurology. 2013;13(1):p. 62. doi: 10.1186/1471-2377-13-62.
    1. Nash D. L., Bellolio M. F., Stead L. G. S100 as a marker of acute brain ischemia: a systematic review. Neurocritical Care. 2008;8(2):301–307. doi: 10.1007/s12028-007-9019-x.
    1. Wunderlich M. T., Lins H., Skalej M., Wallesch C. W., Goertler M. Neuron-specific enolase and tau protein as neurobiochemical markers of neuronal damage are related to early clinical course and long-term outcome in acute ischemic stroke. Clinical Neurology and Neurosurgery. 2006;108(6):558–563. doi: 10.1016/j.clineuro.2005.12.006.
    1. Mir I. N., Chalak L. F. Serum biomarkers to evaluate the integrity of the neurovascular unit. Early Human Development. 2014;90(10):707–711. doi: 10.1016/j.earlhumdev.2014.06.010.
    1. Zhang B., Wang Y. National 'Tenth five-Year' scientific and technological projects "comprehensive treatment program of acute stroke"-- clinical study on treatment of ischemic stroke with dish Mai Ling Kudiezi injection. Guide to Chinese Medicine. 2006;2006(1):112–117.
    1. Zhai Q. Effect of Kudiezi injection in treating middle-aged and young patients with acute cerebral infarction and its influence on Interleukin-6 and C-reactive protein. Hebei Journal of Traditional Chinese Medicine. 2011;33(6):900–902.
    1. Zhou Y., Liu D. Effect of Kudiezi injection on serum inflammatory factors, efficacy and quality of life in patients with acute cerebral infarction. Chinese Archives of Traditional Chinese Medicine. 2016;34(4):900–903.
    1. Sun L., Liu R. R., Zhao W., Li Y. B., Zhang Y. J. Determination of four amino acids in Kudiezi injection. Tianjin Journal of Traditional Chinese Medicine. 2015;2015(2):106–109.
    1. Liu R.-R., Zhang X.-P., Wang F., et al. Rapid screening and identification of sesquiterpene lactones in Kudiezi injection based on high-performance liquid chromatography coupled with linear ion trap-orbitrap mass spectrometry. Chinese Journal of Natural Medicines. 2018;16(2):150–160. doi: 10.1016/S1875-5364(18)30042-6.
    1. Yin P., Liu Y., Zhang J., Cai W., Li Y., Lu J. Rapid content determination of four flavones in Ku-die-zi injection by UPLC-ESI-MS/MS. World Science and Technology - Modernization of Traditional Chinese Medicine. 2015;2015(1):119–123.
    1. Liu S.-Y., Cai W., Wang F., et al. UHPLC-LTQ-Orbitrap-based metabolomics coupled with metabolomics pathway analysis method for exploring the protection mechanism of Kudiezi injection in a rat anti-ischemic cerebral reperfusion damage model. Chinese Journal of Natural Medicines. 2017;15(12):955–960. doi: 10.1016/S1875-5364(18)30013-X.
    1. Chen F.-Q., Li Q., Pan C.-S., et al. Kudiezi injection® alleviates blood–brain barrier disruption after ischemia-reperfusion in rats. Microcirculation. 2016;23(6):426–437. doi: 10.1111/micc.12288.
    1. Liu X., Zhang X., Wang F., et al. Improvement in cerebral ischemia–reperfusion injury through the TLR4/NF-κB pathway after Kudiezi injection in rats. Life Sciences. 2017;191:132–140. doi: 10.1016/j.lfs.2017.10.035.
    1. Liang X., Zhang Y., Wang X., et al. Effects of heat-clearing and blood-activating combination on acute cerebral ischemia of heat toxin pattern in rats via NF-κB signaling pathway. Journal of Beijing University Traditional Chinese Medicine. 2015;38:377–382.
    1. Wang J. Qing heat and activating blood component treat acute cerebral infarction by TLR4-NOX4 signaling pathway in rats, [M.S. thesis] Beijing University of Chinese Medicine; 2015.
    1. Wang F., Zhang Y., Liu X., et al. Study on the differential proteins of Kudiezi injection on rats with Huoxue syndrome of ischemic stroke. China Journal of Chinese Material Medicine. 2014;39(10):1874–1879.
    1. Liu Y., Zhu L., Zhang Y., Zheng H., Liu X. Effect of Kudiezi injection on the expression of nuclear factor-κB and adhesion molecules after high glucose injury in human brain microvascular endothelial cells. China Journal of Traditional Chinese Medicine and Pharmacy. 2010;25(2):204–207.
    1. Kopani M., Celec P., Danisovic L., Michalka P., Biro C. Oxidative stress and electron spin resonance. Clinica Chimica Acta. 2006;364(1-2):61–66. doi: 10.1016/j.cca.2005.05.016.
    1. Liu X., Tao Y., Wang F., et al. Kudiezi injection mitigates myocardial injury induced by acute cerebral ischemia in rats. BMC Complementary and Alternative Medicine. 2017;17(1):p. 8. doi: 10.1186/s12906-016-1514-1.
    1. Chinese Medical Association Neurology Branch Cerebrovascular Disease Study Group. Chinese treatment guidelines of the acute ischemic stroke 2010. Chinese Journal of Neurology. 2010;43:146–154.
    1. Goldstein L. B., Bertels C., Davis J. N. Interrater reliability of the NIH stroke scale. Archives of Neurology. 1989;46(6):660–662. doi: 10.1001/archneur.1989.00520420080026.
    1. Hu Y. Y., Dong X. Q., Yu W. H., Zhang Z. Y. Change in plasma S100B level after acute spontaneous basal ganglia hemorrhage. Shock. 2010;33(2):134–140. doi: 10.1097/SHK.0b013e3181ad5c88.
    1. Alatas Ö. D., Gürger M., Ateşçelik M., et al. Neuron-specific enolase, S100 calcium-binding protein B, and heat shock protein 70 levels in patients with intracranial hemorrhage. Medicine. 2015;94(50):p. 1. doi: 10.1097/01.md.0000476046.44577.d5.
    1. Brunswick A. S., Hwang B. Y., Appelboom G., Hwang R. Y., Piazza M. A., Connolly E. S., Jr. Serum biomarkers of spontaneous intracerebral hemorrhage induced secondary brain injury. Journal of the Neurological Sciences. 2012;321(1-2):1–10. doi: 10.1016/j.jns.2012.06.008.
    1. Raabe A., Kopetsch O., Woszczyk A., et al. Serum S-100B protein as a molecular marker in severe traumatic brain injury. Restorative Neurology and Neuroscience. 2003;21(3-4):159–169.
    1. Meric E., Gunduz A., Turedi S., Cakir E., Yandi M. The prognostic value of neuron-specific enolase in head trauma patients. The Journal of Emergency Medicine. 2010;38(3):297–301. doi: 10.1016/j.jemermed.2007.11.032.
    1. Lamers K. J. B., Vos P., Verbeek M. M., Rosmalen F., van Geel W. J. A., van Engelen B. G. M. Protein S-100B, neuron-specific enolase (NSE), myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) and blood of neurological patients. Brain Research Bulletin. 2003;61(3):261–264. doi: 10.1016/S0361-9230(03)00089-3.
    1. González-García S., González-Quevedo A., Fernández-Concepción O., et al. Short-term prognostic value of serum neuron specific enolase and S100B in acute stroke patients. Clinical Biochemistry. 2012;45(16-17):1302–1307. doi: 10.1016/j.clinbiochem.2012.07.094.
    1. van Exel E., Gussekloo J., de Craen A. J. M., Bootsma-van der Wiel A., Frolich M., Westendorp R. G. J. Inflammation and stroke: the Leiden 85-plus study. Stroke. 2002;33(4):1135–1138. doi: 10.1161/01.STR.0000014206.05597.9E.
    1. Wang Q., Tang X., Yenari M. The inflammatory response in stroke. Journal of Neuroimmunology. 2007;184(1-2):53–68. doi: 10.1016/j.jneuroim.2006.11.014.
    1. Mihara M., Hashizume M., Yoshida H., Suzuki M., Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clinical Science (London, England) 2012;122(4):143–159. doi: 10.1042/CS20110340.
    1. Vila N., Reverter J. C., Yague J., Chamorro A. Interaction between interleukin-6 and the natural anticoagulant system in acute stroke. Journal of Interferon & Cytokine Research. 2000;20(3):325–329. doi: 10.1089/107999000312478.
    1. Perini F., Morra M., Alecci M., Galloni E., Marchi M., Toso V. Temporal profile of serum anti-inflammatory and pro-inflammatory interleukins in acute ischemic stroke patients. Neurological Sciences. 2001;22(4):289–296. doi: 10.1007/s10072-001-8170-y.
    1. Kohno K., Kurimoto M. Interleukin 18, a cytokine which resembles IL-1 structurally and IL-12 functionally but exerts its effect independently of both. Clinical Immunology and Immunopathology. 1998;86(1):11–15. doi: 10.1006/clin.1997.4475.
    1. Yang L., Zhang Z., Sun D., Xu Z., Zhang X., Li L. The serum interleukin-18 is a potential marker for development of post-stroke depression. Neurological Research. 2010;32(4):340–346. doi: 10.1179/016164110X12656393665080.
    1. Pan Y., Tang R., Huang J., Wei Y. Detection of IL-18 and CRP in stroke patients. Chinese Journal of Laboratory Diagnosis. 2010;14(1):93–95.
    1. Hedtjarn M., Leverin A. L., Eriksson K., Blomgren K., Mallard C., Hagberg H. Interleukin-18 involvement in hypoxic-ischemic brain injury. The Journal of Neuroscience. 2002;22(14):5910–5919. doi: 10.1523/JNEUROSCI.22-14-05910.2002.
    1. Sapojnikova N., Kartvelishvili T., Asatiani N., et al. Correlation between MMP-9 and extracellular cytokine HMGB1 in prediction of human ischemic stroke outcome. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2014;1842(9):1379–1384. doi: 10.1016/j.bbadis.2014.04.031.
    1. Montaner J., Alvarez-Sabin J., Molina C., et al. Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke. 2001;32(8):1759–1766. doi: 10.1161/01.STR.32.8.1759.
    1. Graham C. A., Chan R. W. Y., Chan D. Y. S., Chan C. P. Y., Wong L. K. S., Rainer T. H. Matrix metalloproteinase 9 mRNA: an early prognostic marker for patients with acute stroke. Clinical Biochemistry. 2012;45(4-5):352–355. doi: 10.1016/j.clinbiochem.2011.12.006.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel