Skip to main content
SpringerLink
Log in

Piperine suppresses cerebral ischemia–reperfusion-induced inflammation through the repression of COX-2, NOS-2, and NF-κB in middle cerebral artery occlusion rat model

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The pathophysiological mechanisms leading to neuronal injury in middle cerebral artery occlusion (MCAO) model of cerebral stroke are complex and multifactorial that form the bases of behavioral deficits and inflammation mediated damage. The present study demonstrates the effect of piperine pretreatment (10 mg/kg b wt, once daily p.o. for 15 days) on cerebral ischemia-induced inflammation in male Wistar rats. The right middle cerebral artery was occluded for 2 h followed by reperfusion for 22 h. A maximum infarct volume (57.80 %) was observed in ischemic MCAO group. However, piperine administration prior to ischemia showed a significant reduction in infarct volume (28.29 %; p < 0.05) and neuronal loss (12.72 %; p < 0.01). As a result of piperine pretreatment, a significant improvement in behavioral outputs of MCAO rats (p < 0.05–0.01) was observed. Piperine successfully reduced the level of proinflammatory cytokines IL-1β, IL-6 and TNF-α, in ischemic group (p < 0.01). Ischemic group brain has shown edematous morphology with vacuolated architecture and pyknotic nuclei in H & E staining which was successfully ameliorated by piperine administration. Moreover, piperine also succeeded in lowering the expression of COX-2, NOS-2, and NF-κB (p < 0.01). Both cytosolic and nuclear NF-κB were down-regulated in ischemic group pre-administered with piperine (p < 0.01). The present study suggests that piperine is able to salvage the ischemic penumbral zone neurons by virtue of its anti-inflammatory property, thereby limiting ischemic cell death.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Liang X, Lin L, Woodling NS, Wang Q, Anacker C, Pan T, Merchant M, Andreasson K (2011) Signaling via the prostaglandin E2 receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia. J Clin Invest. doi:10.1172/JCI46279

  2. Ishrat T, Sayeed I, Atif F, Stein DG (2009) Effects of progesterone administration on infarct volume and functional deficits following permanent focal cerebral ischemia in rats. Brain Res 1257:94–101

    Article  PubMed  CAS  Google Scholar 

  3. Mehta SL, Manhas N, Raghubir R (2007) Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 54:34–66

    Article  PubMed  CAS  Google Scholar 

  4. Hicks A, Jolkkonen J (2009) Challenges and possibilities of intravascular cell therapy in stroke. Acta Neurobiol Exp 69:1–11

    Google Scholar 

  5. Ridder DA, Schwaninger M (2009) NF-kappaB signaling in cerebral ischemia. Neuroscience 158:995–1006

    Article  PubMed  CAS  Google Scholar 

  6. Tu XK, Yang WZ, Shi SS, Wang CH, Zhang GL, Ni TR, Chen CM, Wang R, Jia JW, Song QM (2010) Spatiotemporal distribution of inflammatory reaction and expression of TLR2/4 signaling pathway in rat brain following permanent focal cerebral ischemia. Neurochem Res 35:1147–1155

    Article  PubMed  CAS  Google Scholar 

  7. Mohammadi MT, Shid-Moosavi SM, Dehghani GA (2011) Contribution of nitric oxide synthase (NOS) in blood–brain barrier disruption during acute focal cerebral ischemia in normal rat. Pathophysiology. doi:10.1016/j.pathophys.2011.07.003

  8. Wang T, Qin L, Liu B, Liu Y, Wilson B, Eling TE, Langenbach R, Taniura S, Hong JS (2004) Role of reactive oxygen species in LPS-induced production of prostaglandin E2 in microglia. J Neurochem 88:939–947

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  10. Yousuf S, Atif F, Hoda N et al (2007) Oral supplementation of majun baladar ameliorates antioxidant enzyme activities in cerebral ischaemic damage. Basic Clin Pharmacol Toxicol 101:246–253

    Article  PubMed  CAS  Google Scholar 

  11. Cai F, Li C, Wu J, Min Q, Ouyang C, Zheng M, Ma S, Yu W, Lin F (2007) Modulation of the oxidative stress and nuclear factor κB activation by theaflavin 3,3′-gallate in the rats exposed to cerebral ischemia–reperfusion. Folia Biol (Praha) 53:164–172

    CAS  Google Scholar 

  12. Wattanathorn J, Chonpathompikunlert P, Muchimapura S, Priprem A, Tankamnerdthai O (2008) Piperine, the potential functional food for mood and cognitive disorders. Food Chem Toxicol 46:3106–3110

    Article  PubMed  CAS  Google Scholar 

  13. Khan MM, Ahmad A, Ishrat T, Khuwaja G, Srivastawa P, Khan MB, Raza SS, Javed H, Vaibhav K, Khan A, Islam F (2009) Rutin protects the neural damage induced by transient focal ischemia in rats. Brain Res 1292:123–135

    Article  PubMed  CAS  Google Scholar 

  14. Diwan V, Poudyal H, Brown L (2011) Piperine attenuates cardiovascular, liver and metabolic changes in high carbohydrate, high fat-fed rats. Cell Biochem Biophys. doi:10.1007/s12013-011-9306-1

  15. Pradeep CR, Kuttan G (2004) Piperine is a potent inhibitor of nuclear factor-kappaB (NF-kappaB), c-Fos, CREB, ATF-2 and proinflammatory cytokine gene expression in B16F-10 melanoma cells. Int Immunopharmacol 4:1795–1803

    Article  PubMed  CAS  Google Scholar 

  16. Pathak N, Khandelwal S (2009) Immunomodulatory role of piperine in cadmium induced thymic atrophy and splenomegaly in mice. Environ Toxicol Pharmacol 28:52–60

    Article  PubMed  CAS  Google Scholar 

  17. Li S, Wang C, Wang M, Li W, Matsumoto K, Tang Y (2007) Antidepressant like effects of piperine in chronic mild stress treated mice and its possible mechanisms. Life Sci 80:1373–1381

    Article  PubMed  CAS  Google Scholar 

  18. Szallasi A (2005) Piperine: researchers discover new flavor in an ancient spice. Trends Pharmacol Sci 26:437–439

    PubMed  CAS  Google Scholar 

  19. Rauscher FM, Sanders RA, Watkins JB III (2000) Effects of piperine on antioxidant pathways in tissues from normal and streptozotocin-induced diabetic rats. J Biochem Mol Toxicol 14:329–334

    Article  PubMed  CAS  Google Scholar 

  20. Li S, Wang C, Li W, Koike K, Nikaido T, Wang MW (2007) Antidepressant-like effects of piperine and its derivative, antiepilepsirine. J Asian Nat Prod Res 9:421–430

    Article  PubMed  CAS  Google Scholar 

  21. Sarkisian MR, Frenkel M, Li W, Oborski JA, LoTurco JJ (2001) Altered interneuron development in the cerebral cortex of the flathead mutant. Cereb Cortex 11:734–743

    Article  PubMed  CAS  Google Scholar 

  22. Li S-Y, Yang D, Yeung C-M, Yu W-Y, Chang RC-C et al (2011) Lycium barbarum polysaccharides reduce neuronal damage, blood–retinal barrier disruption and oxidative stress in retinal ischemia/reperfusion injury. PLoS ONE 6(1):e16380. doi:10.1371/journal.pone.0016380

    Article  PubMed  CAS  Google Scholar 

  23. Bederson JB, Pitts LH, Tsuji M et al (1986) Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17:472–476

    Article  PubMed  CAS  Google Scholar 

  24. Moran PM, Higgins LS, Cordel B, Moser PC (1995) Age related learning deficits in transgenic mice expressing the 721-amino acid isoforms of human beta-amyloid precursor protein. Proc Natl Acad Sci USA 92:5341–5345

    Article  PubMed  CAS  Google Scholar 

  25. Sommer B, Barbieri S, Hofele K et al (2000) Mouse models of alpha-synucleinopathy and Lewy pathology. Exp Gerontol 35:1389–1403

    Article  PubMed  CAS  Google Scholar 

  26. Yasuda Y, Shimoda T, Uno K, Tateishi N, Furuya S, Tsuchihashi Y, Kawai Y, Naruse S, Fujita S (2011) Temporal and sequential changes of glial cells and cytokine expression during neuronal degeneration after transient global ischemia in rats. J Neuroinflamm 8:70. doi:10.1186/1742-2094-8-70

    Article  CAS  Google Scholar 

  27. Whiteley W, Chong WL, Sengupta A, Sandercock P (2009) Blood markers for the prognosis of ischemic stroke: a systematic review. Stroke 40:e380–e389

    Article  PubMed  Google Scholar 

  28. Oto J, Suzue A, Inui D, Fukuta Y, Hosotsubo K, Torii M, Nagahiro S, Nishimura M (2008) Plasma proinflammatory and anti-inflammatory cytokine and catecholamine concentrations as predictors of neurological outcome in acute stroke patients. J Anesth 22:207–212

    Article  PubMed  Google Scholar 

  29. Fiskum G (2000) Mitochondrial participation in ischemic and traumatic neural cell death. J Neurotrauma 17:843–855

    Article  PubMed  CAS  Google Scholar 

  30. Plesnila N, Zhu C, Culmsee C, Gröger M, Moskowitz MA, Blomgren K (2004) Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab 24:458–466

    Article  PubMed  Google Scholar 

  31. Kataoka H, Kim SW, Plesnila N (2004) Leukocyte–endothelium interactions during permanent focal cerebral ischemia in mice. J Cereb Blood Flow Metab 24:668–676

    Article  PubMed  Google Scholar 

  32. Maddahi A, Edvinsson L (2010) Cerebral ischemia induces microvascular proinflammatory cytokine expression via the MEK/ERK pathway. J Neuroinflamm 7:14. doi:10.1186/1742-2094-7-14

    Article  Google Scholar 

  33. Chapman KZ, Dale VQ, Dénes A, Bennett G, Rothwell NJ, Allan SM, McColl BW (2009) A rapid and transient peripheral inflammatory response precedes brain inflammation after experimental stroke. J Cereb Blood Flow Metab 11:1764–1768

    Article  Google Scholar 

  34. Denes A, Thornton P, Rothwell NJ, Allan SM (2010) Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation. Brain Behav Immun 24:708–723

    Article  PubMed  CAS  Google Scholar 

  35. Sieber MW, Claus RA, Witte OW, Frahm C (2011) Attenuated inflammatory response in aged mice brains following stroke. PLoS ONE 6:e26288. doi:10.1371/journal.pone.0026288

    Article  PubMed  CAS  Google Scholar 

  36. Chan SJ, Wong WF, Wong PT, Bian JS (2010) Neuroprotective effects of andrographolide in a rat model of permanent cerebral ischaemia. Br J Pharmacol 161:668–679

    Article  PubMed  CAS  Google Scholar 

  37. Emsley HC, Smith CJ, Georgiou RF, Vail A, Tyrrell PJ, Barberan EM, Rothwell NJ, Hopkins SJ (2005) Correlation of systemic inflammatory response with infarct volume in acute ischemic stroke patients. Stroke 36:228–229

    Article  PubMed  Google Scholar 

  38. Krakauer T (2004) Molecular therapeutic targets in inflammation: cyclooxygenase and NF-kappaB. Curr Drug Targets Inflamm Allergy 3:317–324

    Article  PubMed  CAS  Google Scholar 

  39. Yokota C, Kaji T, Kuge Y, Inoue H, Tamaki N, Minematsu K (2004) Temporal and topographic profiles of cyclooxygenase-2 expression during 24 h of focal brain ischemia in rats. Neurosci Lett 357:219–222

    Article  PubMed  CAS  Google Scholar 

  40. Clancy RM, Abramson SB (1995) Nitric oxide—a novel mediator of inflammation. Proc Soc Exp Biol Med 210:93–101

    PubMed  CAS  Google Scholar 

  41. Sasaki T, Kitagawa K, Yamagata K et al (2004) Amelioration of hippocampal neuronal damage after transient forebrain ischemia in cyclooxygenase-2-deficient mice. J Cereb Blood Flow Metab 24:107–113

    Article  PubMed  CAS  Google Scholar 

  42. Madrigal JL, García-Bueno B, Moro MA, Lizasoain I, Lorenzo P, Leza JC (2003) Relationship between cyclooxygenase-2 and nitric oxide synthase-2 in rat cortex after stress. Eur J Neurosci 18:1701–1705

    Article  PubMed  Google Scholar 

  43. Weinberg JB (2000) Nitric oxide synthase 2 and cyclooxygenase 2 interactions in inflammation. Immunol Res 22:319–341

    Article  PubMed  CAS  Google Scholar 

  44. Mattson MP, Camandola S (2001) NF-κB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 107:247–254

    Article  PubMed  CAS  Google Scholar 

  45. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS (2001) Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 480–481:243–268

    PubMed  Google Scholar 

  46. Khajuria A, Thusu N, Zutshi U (2002) Piperine modulates permeability characteristics of intestine by inducing alterations in membrane dynamics: influence on brush border membrane fluidity, ultrastructure and enzyme kinetics. Phytomedicine 9:224–231

    Article  PubMed  CAS  Google Scholar 

  47. Srinivasan K (2007) Black pepper and its pungent principle-piperine: a review of diverse physiological effects. Crit Rev Food Sci Nutr 47:735–748

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors sincerely acknowledge UGC, Govt. of India for providing financial support. Moreover, we thank Dr. Anurag Agrawal, Mr. Tanveer Ahmad and Mr. Manish Kumar (Centre of Excellence for Translational Research in Asthma & Lung disease, Institute of Genomics and Integrative Biology, A unit of C.S.I.R., Mall Road, New Delhi 110007, India) for their valuable suggestion and help in microscopic imaging. We highly appreciate Mr. Dharamvir Singh, Mr. S. Abdul Fitr and Late Mr. Anil Kumar for their technical assistance.

Conflict of interest

The authors declare that there is no conflict of interest. No author has any financial interest or conflict of interest involved with this study.

Author information

Author notes

  1. Pallavi Shrivastava

    Present address: Department Neurology, Robert Wood Johanson Medical School, UMDNJ, New Jersey, USA

  2. Mohd. Moshahid Khan

    Present address: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA

  3. Gulrana Khuwaja, Farah Islam & Fakhrul Islam

    Present address: Neuroscience and Toxicology Unit, Faculty of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia

Authors and Affiliations

  1. Neurotoxicology Laboratory, Department of Medical Elementology & Toxicology (DST-FIST and UGC-SAP-DRS II Funded Department), Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, 110062, India

    Kumar Vaibhav, Pallavi Shrivastava, Hayate Javed, Andleeb Khan, Md. Ejaz Ahmed, Rizwana Tabassum, Mohd. Moshahid Khan, Gulrana Khuwaja, M. Saeed Siddiqui & Fakhrul Islam

  2. Neuroscience and Toxicology Unit, Faculty of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia

    Mohammed M. Safhi

  3. Department of Biotechnology, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India

    Farah Islam

Authors
  1. Kumar Vaibhav
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pallavi Shrivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hayate Javed
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andleeb Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Md. Ejaz Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rizwana Tabassum
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohd. Moshahid Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gulrana Khuwaja
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Farah Islam
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M. Saeed Siddiqui
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mohammed M. Safhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Fakhrul Islam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fakhrul Islam.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vaibhav, K., Shrivastava, P., Javed, H. et al. Piperine suppresses cerebral ischemia–reperfusion-induced inflammation through the repression of COX-2, NOS-2, and NF-κB in middle cerebral artery occlusion rat model. Mol Cell Biochem 367, 73–84 (2012). https://doi.org/10.1007/s11010-012-1321-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-012-1321-z

Keywords

Search

Navigation