Skip to main content

Advertisement

Log in

Panax notoginseng saponins administration modulates pro- /anti-inflammatory factor expression and improves neurologic outcome following permanent MCAO in rats

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Ischemic stroke, particularly permanent occlusion, accounts for the overwhelming majority of all strokes. In addition to the occlusion of arteries, the inflammatory response plays a pivotal role in the severity of the cerebral injury and its clinical prognosis. Here, panax notoginseng saponins (PNS) extracted from a traditional Chinese herbal medicine was administered following permanent middle cerebral artery occlusion (MCAO) in rats to explore the neuroprotective mechanisms against ischemic injury. The results showed that MCAO surgery was successful in producing an infarct and that PNS and nimodipine could ameliorate the neurological deficits. The expression levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) were increased, while the level of interleukin-10 (IL-10) was reduced in the infarct cortex 7 days after MCAO, as assessed by immunohistochemistry, western blotting and quantitative real-time PCR (qRT-PCR). PNS was able to markedly reduce the overexpression of IL-1β and TNF-α while significantly promoting the expression of IL-10, but did not affect the elevated expression of TGF-β1. Meanwhile, nimodipine was able to significantly reduce the expression of IL-1β and TNF-α, but had no obvious effect on IL-10 or TGF-β1. In addition, the serum levels of TNF-α, IL-10 and TGF-β1 were basically consistent with cerebral tissue results; however, the IL-1β levels did not differ. We conclude that PNS can directly down-regulate the overexpression of proinflammatory factors IL-1β and TNF-α while up-regulating the expression of anti-inflammatory factor IL-10 in the core region of the cerebral infarct, thereby preventing neurological damage in rats after permanent MCAO.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Agrawal NK, Kant S (2014) Targeting inflammation in diabetes: newer therapeutic options. World J Diabetes 5:697–710. doi:10.4239/wjd.v5.i5.697

    Article  PubMed  PubMed Central  Google Scholar 

  • Bachis A, Colangelo AM, Vicini S, Doe PP, De Bernardi MA, Brooker G, Mocchetti I (2001) Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity. J Neurosci Off J Soc Neurosci 21:3104–3112

    CAS  Google Scholar 

  • Bacigaluppi M, Comi G, Hermann DM (2010) Animal models of ischemic stroke. Part two: modeling cerebral ischemia. The open neurology journal 4:34–38. doi:10.2174/1874205X01004020034

    PubMed  PubMed Central  Google Scholar 

  • Barone FC et al. (1997) Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke; a journal of cerebral circulation 28:1233–1244

    Article  CAS  Google Scholar 

  • Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ (2001) Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci Off J Soc Neurosci 21:5528–5534

    CAS  Google Scholar 

  • Brea D, Sobrino T, Ramos-Cabrer P, Castillo J (2009) Inflammatory and neuroimmunomodulatory changes in acute cerebral ischemia Cerebrovascular diseases 27 Suppl 1:48–64 doi:10.1159/000200441

  • Buisson A, Lesne S, Docagne F, Ali C, Nicole O, MacKenzie ET (2003) Vivien D. Transforming growth factor-beta and ischemic brain injury Cellular and molecular neurobiology 23:539–550

    CAS  PubMed  Google Scholar 

  • Candelario-Jalil E et al. (2007) Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. The Journal of pharmacology and experimental therapeutics 323:488–498. doi:10.1124/jpet.107.127035

    Article  CAS  PubMed  Google Scholar 

  • Candelario-Jalil E, Yang Y, Rosenberg GA (2009) Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 158:983–994. doi:10.1016/j.neuroscience.2008.06.025

    Article  CAS  PubMed  Google Scholar 

  • Chin J, Angers A, Cleary LJ, Eskin A, Byrne JH (2002) Transforming growth factor beta1 alters synapsin distribution and modulates synaptic depression in Aplysia. J Neurosci Off J Soc Neurosci 22:RC220

    CAS  Google Scholar 

  • Chinese Pharmacopoeia Commission (2010) Pharmacopoeia of the People’s Republic of China. Beijing: Chinese Medical Science and Technology Press.

  • Chio CC, Lin JW, Chang MW, Wang CC, Kuo JR, Yang CZ, Chang CP (2010) Therapeutic evaluation of etanercept in a model of traumatic brain injury. J Neurochem 115:921–929. doi:10.1111/j.1471-4159.2010.06969.x

    Article  CAS  PubMed  Google Scholar 

  • Corbyn Z (2014) Statistics: a growing global burden. Nature 510:S2–S3. doi:10.1038/510S2a

    Article  CAS  PubMed  Google Scholar 

  • de Bilbao F, Arsenijevic D, Moll T, Garcia-Gabay I, Vallet P, Langhans W, Giannakopoulos P (2009) In vivo over-expression of interleukin-10 increases resistance to focal brain ischemia in mice. J Neurochem 110:12–22. doi:10.1111/j.1471-4159.2009.06098.x

    Article  PubMed  Google Scholar 

  • Dhandapani KM (2003) Brann DW. Transforming growth factor-beta: a neuroprotective factor in cerebral ischemia Cell biochemistry and biophysics 39:13–22. doi:10.1385/CBB:39:1:13

    CAS  PubMed  Google Scholar 

  • Doll DN, Rellick SL, Barr TL, Ren X, Simpkins JW (2015) Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity. J Neurochem 132:443–451. doi:10.1111/jnc.13008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dou L, Lu Y, Shen T, Huang X, Man Y, Wang S, Li J (2012) Panax notogingseng saponins suppress RAGE/MAPK signaling and NF-kappaB activation in apolipoprotein-E-deficient atherosclerosis-prone mice. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology 29:875–882. doi:10.1159/000315061

    Article  CAS  Google Scholar 

  • Doyle KP, Cekanaviciute E, Mamer LE, Buckwalter MS (2010) TGFbeta signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke. Journal of neuroinflammation 7:62. doi:10.1186/1742–2094–7-62

    Article  PubMed  PubMed Central  Google Scholar 

  • Flanders KC, Ren RF (1998) Lippa CF. Transforming growth factor-betas in neurodegenerative disease Progress in neurobiology 54:71–85

    CAS  PubMed  Google Scholar 

  • Frenkel D, Huang Z, Maron R, Koldzic DN, Hancock WW, Moskowitz MA, Weiner HL (2003) Nasal vaccination with myelin oligodendrocyte glycoprotein reduces stroke size by inducing IL-10-producing CD4+ T cells. J Immunol 171:6549–6555

    Article  CAS  PubMed  Google Scholar 

  • Galkina E, Ley K (2009) Immune and inflammatory mechanisms of atherosclerosis. Annual review of immunology 27:165–197. doi:10.1146/annurev.immunol.021908.132620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grilli M, Barbieri I, Basudev H, Brusa R, Casati C, Lozza G, Ongini E (2000) Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage. The European journal of neuroscience 12:2265–2272

    Article  CAS  PubMed  Google Scholar 

  • Gronberg NV, Johansen FF, Kristiansen U, Hasseldam H (2013) Leukocyte infiltration in experimental stroke. Journal of neuroinflammation 10:115. doi:10.1186/1742–2094–10-115

    Article  PubMed  PubMed Central  Google Scholar 

  • Grotta JC (2014) tPA for stroke: important progress in achieving faster treatment. Jama 311:1615–1617. doi:10.1001/jama.2014.3322

    Article  PubMed  Google Scholar 

  • He NW, Zhao Y, Guo L, Shang J, Yang XB (2012) Antioxidant, antiproliferative, and pro-apoptotic activities of a saponin extract derived from the roots of Panax notoginseng (Burk.) F.H. Chen Journal of medicinal food 15:350–359. doi:10.1089/jmf.2011.1801

    Article  CAS  PubMed  Google Scholar 

  • Hills NK, Johnston SC (2006) Why are eligible thrombolysis candidates left untreated? American journal of preventive medicine 31:S210–S216. doi:10.1016/j.amepre.2006.08.004

    Article  PubMed  Google Scholar 

  • Jiang M et al. (2014) Neuroprotective effects of bilobalide on cerebral ischemia and reperfusion injury are associated with inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation. Journal of neuroinflammation 11:167. doi:10.1186/s12974–014–0167-6

    Article  PubMed  PubMed Central  Google Scholar 

  • Jin R, Liu L, Zhang S, Nanda A, G L (2013) Role of inflammation and its mediators in acute ischemic stroke. Journal of cardiovascular translational research 6:834–851. doi:10.1007/s12265–013–9508-6

    Article  PubMed  Google Scholar 

  • Jordan J, Segura T, Brea D, Galindo MF, Castillo J (2008) Inflammation as therapeutic objective in stroke. Current pharmaceutical design 14:3549–3564

    Article  CAS  PubMed  Google Scholar 

  • Justin A, Sathishkumar M, Sudheer A, Shanthakumari S, Ramanathan M (2014) Non-hypotensive dose of telmisartan and nimodipine produced synergistic neuroprotective effect in cerebral ischemic model by attenuating brain cytokine levels. Pharmacology, biochemistry, and behavior 122:61–73. doi:10.1016/j.pbb.2014.03.009

    Article  CAS  PubMed  Google Scholar 

  • Kawabori M (2015) Yenari MA. Inflammatory responses in brain ischemia Current medicinal chemistry 22:1258–1277

    Article  CAS  PubMed  Google Scholar 

  • Killer M, Ladurner G, Kunz AB, Kraus J (2010) Current endovascular treatment of acute stroke and future aspects Drug discovery today 15:640–647. doi:10.1016/j.drudis.2010.04.007

    PubMed  Google Scholar 

  • Koton S, Schneider AL, Rosamond WD, Shahar E, Sang Y, Gottesman RF (2011) Coresh J (2014) Stroke incidence and mortality trends in US communities, 1987 to. Jama 312:259–268. doi:10.1001/jama.2014.7692

    Article  Google Scholar 

  • Lambertsen KL, Meldgaard M, Ladeby R, Finsen B (2005) A quantitative study of microglial-macrophage synthesis of tumor necrosis factor during acute and late focal cerebral ischemia in mice. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 25:119–135. doi:10.1038/sj.jcbfm.9600014

    Article  CAS  Google Scholar 

  • Lavine SD, Hofman FM, Zlokovic BV (1998) Circulating antibody against tumor necrosis factor-alpha protects rat brain from reperfusion injury. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 18:52–58. doi:10.1097/00004647-199801000-00005

    Article  CAS  Google Scholar 

  • Li X et al. (2007) Pharmacokinetic and absolute bioavailability study of total panax notoginsenoside, a typical multiple constituent traditional chinese medicine (TCM) in rats. Biological & pharmaceutical bulletin 30:847–851

    Article  CAS  Google Scholar 

  • Li H, Deng CQ, Chen BY, Zhang SP, Liang Y, XG L (2009) Total saponins of Panax notoginseng modulate the expression of caspases and attenuate apoptosis in rats following focal cerebral ischemia-reperfusion. Journal of ethnopharmacology 121:412–418. doi:10.1016/j.jep.2008.10.042

    Article  CAS  PubMed  Google Scholar 

  • Liang F (2013) Research of Daodi Chinese medicinal materials. Beijing University of Chinese Medicine, Ph.D.

    Google Scholar 

  • Liu L et al. (2014) Panax notoginseng saponins promotes stroke recovery by influencing expression of Nogo-A, NgR and p75NGF, in vitro and in vivo. Biological & pharmaceutical bulletin 37:560–568

    Article  CAS  Google Scholar 

  • Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke; a journal of cerebral circulation 20:84–91

    Article  CAS  Google Scholar 

  • McColl BW, Rothwell NJ, Allan SM (2007) Systemic inflammatory stimulus potentiates the acute phase and CXC chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1- and neutrophil-dependent mechanisms. J Neurosci Off J Soc Neurosci 27:4403–4412. doi:10.1523/JNEUROSCI.5376-06.2007

    Article  CAS  Google Scholar 

  • Meistrell ME 3rd et al. (1997) Tumor necrosis factor is a brain damaging cytokine in cerebral ischemia Shock (Augusta, Ga). 8:341–348

  • Meng L, Wei Y, Wei S, Huang Y, Li X, Huang J (2008) Effects of panax notoginseng saponins on serum TNF - α and IL - 6 levels in patients with acute cerebral infarction. Chinese Journal of Rehabilitation Medicine 23:205–207

    CAS  Google Scholar 

  • Murray KN, Parry-Jones AR, Allan SM (2015) Interleukin-1 and acute brain injury. Front Cell Neurosci 9:18. doi:10.3389/fncel.2015.00018

    Article  PubMed  PubMed Central  Google Scholar 

  • Nathaniel TI, Williams-Hernandez A, Hunter LA, Liddy C, Peffley DM, Umesiri FE, Imeh-Nathaniel A (2015) Tissue hypoxia during ischemic stroke: Adaptive clues from hypoxia-tolerant animal models Brain research bulletin 114:1–12 doi:10.1016/j.brainresbull.2015.02.006

  • Ng TB (2006) Pharmacological activity of sanchi ginseng (Panax notoginseng). The Journal of pharmacy and pharmacology 58:1007–1019. doi:10.1211/jpp.58.8.0001

    Article  CAS  PubMed  Google Scholar 

  • Pang L, Ye W, Che XM, Roessler BJ, Betz AL, Yang GY (2001) Reduction of inflammatory response in the mouse brain with adenoviral-mediated transforming growth factor-ss1 expression. Stroke; a journal of cerebral circulation 32:544–552

    Article  CAS  Google Scholar 

  • Parry-Jones AR, Liimatainen T, Kauppinen RA, Grohn OH, Rothwell NJ (2008) Interleukin-1 exacerbates focal cerebral ischemia and reduces ischemic brain temperature in the rat. Magnetic resonance in medicine 59:1239–1249. doi:10.1002/mrm.21531

    Article  PubMed  Google Scholar 

  • Pradillo JM et al. (2012) Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 32:1810–1819. doi:10.1038/jcbfm.2012.101

    Article  CAS  Google Scholar 

  • Ruocco A et al. (1999) A transforming growth factor-beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxic and ischemic brain injury. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 19:1345–1353. doi:10.1097/00004647-199912000-00008

    Article  CAS  Google Scholar 

  • Sadana P, Coughlin L, Burke J, Woods R, Mdzinarishvili A (2015) Anti-edema action of thyroid hormone in MCAO model of ischemic brain stroke: Possible association with AQP4 modulation. Journal of the neurological sciences. doi:10.1016/j.jns.2015.04.042

    PubMed  Google Scholar 

  • Spera PA, Ellison JA, Feuerstein GZ, Barone FC (1998) IL-10 reduces rat brain injury following focal stroke. Neurosci Lett 251:189–192

    Article  CAS  PubMed  Google Scholar 

  • Stroemer RP, Rothwell NJ (1998) Exacerbation of ischemic brain damage by localized striatal injection of interleukin-1beta in the rat. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 18:833–839. doi:10.1097/00004647-199808000-00003

    Article  CAS  Google Scholar 

  • Tarkowski E, Rosengren L, Blomstrand C, Wikkelso C, Jensen C, Ekholm S, Tarkowski A (1995) Early intrathecal production of interleukin-6 predicts the size of brain lesion in stroke. Stroke; a journal of cerebral circulation 26:1393–1398

    Article  CAS  Google Scholar 

  • Thompson JW, Narayanan SV, Koronowski KB, Morris-Blanco K, Dave KR (2015) Perez-Pinzon MA. Signaling pathways leading to ischemic mitochondrial neuroprotection Journal of bioenergetics and biomembranes 47:101–110. doi:10.1007/s10863–014–9574-8

    CAS  PubMed  Google Scholar 

  • Tuttolomondo A, Pecoraro R, Pinto A (2014) Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date. Drug design, development and therapy 8:2221–2238. doi:10.2147/DDDT.S67655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uzayisenga R, Ayeka PA, Wang Y (2014) Anti-diabetic potential of panax notoginseng saponins (PNS): a review. Phytotherapy research: PTR 28:510–516. doi:10.1002/ptr.5026

    Article  PubMed  Google Scholar 

  • Wang X, Barone FC, Aiyar NV, Feuerstein GZ (1997) Interleukin-1 receptor and receptor antagonist gene expression after focal stroke in rats Stroke; a journal of cerebral circulation 28:155–161; discussion 161–152

  • Wang JF, Li Y, Song JN (2014a) Pang HG. Role of hydrogen sulfide in secondary neuronal injury Neurochemistry international 64:37–47. doi:10.1016/j.neuint.2013.11.002

    CAS  PubMed  Google Scholar 

  • Wang P et al. (2014b) Panax notoginseng saponins (PNS) inhibits breast cancer metastasis. Journal of ethnopharmacology 154:663–671. doi:10.1016/j.jep.2014.04.037

    Article  CAS  PubMed  Google Scholar 

  • Yaidikar L, Thakur S (2015) Punicalagin attenuated cerebral ischemia-reperfusion insult via inhibition of proinflammatory cytokines, up-regulation of Bcl-2, down-regulation of Bax, and caspase-3. Molecular and cellular biochemistry 402:141–148. doi:10.1007/s11010–014-2321-y

    Article  CAS  PubMed  Google Scholar 

  • Yamasaki Y, Matsuura N, Shozuhara H, Onodera H, Itoyama Y, Kogure K (1995) Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats Stroke; a journal of cerebral circulation 26:676–680; discussion 681

  • Zhang G (2011) Clinical research of panax notoginseng saponins (Xuesaitong) on serum TNF- α, IL-1β and IL-6 levels in patients with acute cerebral infarction. Prevention and Treatment of Cardio -Cerebral -Vascular Disease 11:378–380

    Google Scholar 

  • Zhang J, Fang XY (2004) [The historical condition in the spread of Sanqi (Panax notoginseng) in the Ming Dynasty] Zhonghua yi shi za zhi 34:16–20

  • Zhang J et al. (2012a) Core-shell hybrid liposomal vesicles loaded with panax notoginsenoside: preparation, characterization and protective effects on global cerebral ischemia/reperfusion injury and acute myocardial ischemia in rats. International journal of nanomedicine 7:4299–4310. doi:10.2147/IJN.S32385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Yang J, Zhang C, Jiang X, Zhou H, Liu M (2012b) Calcium antagonists for acute ischemic stroke. The Cochrane database of systematic reviews 5:CD001928. doi:10.1002/14651858.CD001928.pub2

    Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 30772803 and 81173235). The authors would like to thank the key laboratory of Dongzhimen Hospital for providing the necessary facilities to ensure the completion of the research.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lingqun Zhu.

Ethics declarations

Conflict of interest

The authors declare that there is no potential conflict of interest.

Additional information

Xiaowei Shi and Wenjing Yu contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, X., Yu, W., Liu, L. et al. Panax notoginseng saponins administration modulates pro- /anti-inflammatory factor expression and improves neurologic outcome following permanent MCAO in rats. Metab Brain Dis 32, 221–233 (2017). https://doi.org/10.1007/s11011-016-9901-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-016-9901-3

Keywords

Navigation