Piperine pre-treatment has immunomodulatory effects in hippocampal local model of demyelination

authors:

avatar roshanbakhsh roshanbakhsh , avatar Mahmoud Elahdadi Salmani , avatar Simin Namvar Ashdash , avatar seyed Raheleh Ahmadian , avatar Fereshteh Pourabdolhossein ORCID , *

Koomesh: Vol.23, issue 1; 155-165
published online: December 02, 2021
article type: Research Article
received: April 04, 2020
accepted: July 02, 2020

how to cite: roshanbakhsh R, Elahdadi Salmani M, Namvar Ashdash S, Ahmadian S R, Pourabdolhossein F. Piperine pre-treatment has immunomodulatory effects in hippocampal local model of demyelination. koomesh. 2021;23(1):e153251. 

Abstract

Introduction: Inflammatory processes has an important role in the Multiple Sclerosis (MS)’s pathophysiology. Therefore, hampering the inflammatory factors could be an effective strategy in MS treatment. Piperine (the main alkaloid of black piper) has immunomodulatory and anti-inflammatory properties. In this study the pre-treatment effects of piperine on the gene expression level of inflammatory and anti-inflammatory cytokines, growth factors and myelin repair was investigated. Materials and Methods: Adult male Wistar rats (200–250 g) in 4 experimental groups (1: Control, 2: LPC, 3: LPC+vehicle, 4: LPC+PP 5) were studied (n=8). The pre-treatment with piperine (5 mg/kg) started 2 weeks before demyelination induction by bilateral injection of lysolecithin into the CA1 regions of the hippocampus, until the end of experiment. Myelin repair process was analyzed with myelin specific staining. The evaluation of astrocyte activation was done by immunohistochemistry and the gene expression analysis for IL-1β, TNF-α, NF-kB, FOXP3, IL-10, BDNF and NGF in the hippocampal tissue was done by Real-time PCR technique. Results: Pre-treatment with piperine significantly decreased the extent of demyelination and increased myelin optical density. Moreover, glial activation and expression level of inflammatory cytokines (IL-1β, TNF-α, NF-kB) were significantly decreased in the pre-treatment groups with piperine and the level of anti-inflammatory cytokines (FOXP3, IL-10) increased in the hippocampal tissue. The increased expression level of BDNF and NGF was also observed in the piperine pre-treated group. Conclusion: Piperine improved myelin repair process through reduction of inflammatory cytokines, glial activation and enhancement of anti-inflammatory cytokines and growth factors

References

  • 1.

    Lassmann H. Review: the architecture of inflammatory demyelinating lesions: implications for studies on pathogenesis. Neuropathol Appl Neurobiol 2011; 37: 698-710.

  • 2.

    Dutta R, Chomyk AM, Chang A, Ribaudo MV, Deckard SA, Doud MK, et al. Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors. Annal Neurol 2013; 73:45-637.

  • 3.

    Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000; 343: 938-952.

  • 4.

    Pak F, Nafariyeh T, Asghari N, Shokrollahy M, Kokhaei P. Immunopathology of multiple sclerosis. Koomesh 2013; 14: 117-129. (Persian).

  • 5.

    Miljkovic D, Spasojevic I. Multiple sclerosis: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 2013; 19: 2286-2334.

  • 6.

    Belbasis L, Bellou V, Evangelou E, Ioannidis JP, Tzoulaki I. Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. Lancet Neurol 2015; 14: 263-273.

  • 7.

    Kakalacheva K, Munz C, Lunemann JD. Viral triggers of multiple sclerosis. Biochim Biophys Acta 2011; 1812: 132-140.

  • 8.

    Oreja-Guevara C, Ramos-Cejudo J, Aroeira LS, Chamorro B, Diez-Tejedor E. TH1/TH2 Cytokine profile in relapsing-remitting multiple sclerosis patients treated with Glatiramer acetate or Natalizumab. BMC Neurol 2012; 12: 95.

  • 9.

    Hedegaard CJ, Krakauer M, Bendtzen K, Lund H, Sellebjerg F, Nielsen CH. T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis. Immunology 2008; 125: 161-169.

  • 10.

    Lewin GR, Barde YA. Physiology of the neurotrophins. Annu Rev Neurosci 1996; 19: 289-317.

  • 11.

    Lee BH, Kim YK. The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig 2010; 7: 231-235.

  • 12.

    Djalali S, Holtje M, Grosse G, Rothe T, Stroh T, Grosse J, et al. Effects of brain-derived neurotrophic factor (BDNF) on glial cells and serotonergic neurones during development. J Neurochemistry 2005; 92: 27-616.

  • 13.

    Lykissas MG, Batistatou AK, Charalabopoulos KA, Beris AE. The role of neurotrophins in axonal growth, guidance, and regeneration. Curr Neurovasc Res 2007; 4: 143-151.

  • 14.

    Acosta CM, Cortes C, MacPhee H, Namaka MP. Exploring the role of nerve growth factor in multiple sclerosis: implications in myelin repair. CNS Neurol Disord Drug Targets 2013; 12: 1242-1256.

  • 15.

    Maillart E. Treatment of progressive multiple sclerosis: Challenges and promising perspectives. Rev Neurol (Paris) 2018; 174: 441-448.

  • 16.

    Dubois-Dalcq M, Ffrench-Constant C, Franklin RJ. Enhancing central nervous system remyelination in multiple sclerosis. Neuron 2005; 48: 9-12.

  • 17.

    Chitnis T, Imitola J, Khoury SJ. Therapeutic strategies to prevent neurodegeneration and promote regeneration in multiple sclerosis. Curr Drug Targets Immune Endocr Metabol Disord 2005; 5: 11-26.

  • 18.

    Mohajeri M, Sadeghizadeh M, Najafi F, Javan M. Polymerized nano-curcumin attenuates neurological symptoms in EAE model of multiple sclerosis through down regulation of inflammatory and oxidative processes and enhancing neuroprotection and myelin repair. Neuropharmacology 2015; 99: 156-167.

  • 19.

    Gorgani L, Mohammadi M, Najafpour GD, Nikzad M. Sequential microwave-ultrasound-assisted extraction for isolation of piperine from black pepper (Piper nigrum L.). Food Bioproc Technol 2017; 10: 2199-2207.

  • 20.

    Meghwal M, Goswami TK. Piper nigrum and piperine: an update. Phytother Res 2013; 27: 1121-1130.

  • 21.

    Kakarala M, Dubey SK, Tarnowski M, Cheng C, Liyanage S, Strawder T, et al. Ultra-low flow liquid chromatography assay with ultraviolet (UV) detection for piperine quantitation in human plasma. J Agric Food Chem 2010; 58: 6594-6599.

  • 22.

    Ali Y, Alam MS, Hamid H, Husain A, Bano S, Dhulap A, et al. Design, synthesis and biological evaluation of piperic acid triazolyl derivatives as potent anti-inflammatory agents. Eur J Med Chem 2015; 92: 490-500.

  • 23.

    Doucette CD, Greenshields AL, Liwski RS, Hoskin DW. Piperine blocks interleukin-2-driven cell cycle progression in CTLL-2 T lymphocytes by inhibiting multiple signal transduction pathways. Toxicol Lett 2015; 234: 1-12.

  • 24.

    Levine JM, Reynolds R. Activation and proliferation of endogenous oligodendrocyte precursor cells during ethidium bromide-induced demyelination. Exp Neurol 1999; 160: 333-347.

  • 25.

    Nait-Oumesmar B, Decker L, Lachapelle F, Avellana-Adalid V, Bachelin C, Baron-Van Evercooren A. Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur J Neurosci 1999; 11: 4357-4366.

  • 26.

    Stangel M, Hartung HP. Remyelinating strategies for the treatment of multiple sclerosis. Prog Neurobiol 2002; 68: 76-361.

  • 27.

    Denic A, Johnson AJ, Bieber AJ, Warrington AE, Rodriguez M, Pirko I. The relevance of animal models in multiple sclerosis research. Pathophysiology 2011; 18: 21-29.

  • 28.

    Mousavi Majd A, Ebrahim Tabar F, Afghani A, Ashrafpour S, Dehghan S, Gol M, et al. Inhibition of GABA A receptor improved spatial memory impairment in the local model of demyelination in rat hippocampus. Behav Brain Res 2018; 336: 111-121.

  • 29.

    Goudarzvand M, Javan M, Mirnajafi-Zadeh J, Mozafari S, Tiraihi T. Vitamins E and D3 attenuate demyelination and potentiate remyelination processes of hippocampal formation of rats following local injection of ethidium bromide. Cell Mol Neurobiol 2010; 30: 289-299.

  • 30.

    Khezri S, Dasht Bozorgi N, Rahmani F. The effect of caffeine on the myelin repair following experimental demyelination induction in the adult rat hippocampus. J Cell Mol Res 2016; 11: 15-24. (Persian).

  • 31.

    Chonpathompikunlert P, Wattanathorn J, Muchimapura S. Piperine, the main alkaloid of Thai black pepper, protects against neurodegeneration and cognitive impairment in animal model of cognitive deficit like condition of Alzheimer's disease. Food Chem Toxicol 2010; 48: 798-802.

  • 32.

    Bae GS, Kim MS, Jung WS, Seo SW, Yun SW, Kim SG, et al. Inhibition of lipopolysaccharide-induced inflammatory responses by piperine. Eur Pharmacol 2010; 642: 62-154.

  • 33.

    Paxinos G, Koutcherov Y, Halliday GM, Watson C, Wang H. Atlas of the developing mouse brain: At e17. 5, po, and: Academic press 2007.

  • 34.

    Pourabdolhossein F, Mozafari S, Morvan-Dubois G, Mirnajafi-Zadeh J, Lopez-Juarez A, Pierre-Simons J, et al. Nogo receptor inhibition enhances functional recovery following lysolecithin-induced demyelination in mouse optic chiasm. PloS One 2014; 9: e106378.

  • 35.

    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science (New York, NY) 2003; 299: 1057-1061.

  • 36.

    Deloire-Grassin MS, Brochet B, Quesson B, Delalande C, Dousset V, Canioni P, et al. In vivo evaluation of remyelination in rat brain by magnetization transfer imaging. J Neurol Sci 2000; 178: 10-16.

  • 37.

    Plemel JR, Michaels NJ, Weishaupt N, Caprariello AV, Keough MB, Rogers JA, et al. Mechanisms of lysophosphatidylcholine-induced demyelination: A primary lipid disrupting myelinopathy. Glia 2018; 66: 327-347.

  • 38.

    Yazdi A, Baharvand H, Javan M. Enhanced remyelination following lysolecithin-induced demyelination in mice under treatment with fingolimod (FTY720). Neuroscience 2015; 311: 34-44.

  • 39.

    Roshanbakhsh H, Elahdadi Salmani M, Dehghan S, Nazari A, Javan M, Pourabdolhossein F. Piperine ameliorated memory impairment and myelin damage in lysolecethin induced hippocampal demyelination. Life Sci 2020; 253: 117671.

  • 40.

    Amirifalah Z, Mokhtari-Dizaji M, Javan M. Visual evoked potential frequency content: Effect of lysolecithin induced demyelination in rat optic chiasm. Koomesh 2018; 20: 105-114. (Persian).

  • 41.

    Shaterpour M, Shaki F, Ghasemi M, Jafari-Sabet M, Ziar A, Ataee R. The protective effect of curcumin against lithium-induced nephrotoxicity in rats. Pharmac Biomed Res 2017; 3: 33-38.

  • 42.

    Qureshi GA, Parvez SH. Oxidative stress and neurodegenerative disorders: Elsevier 2007.

  • 43.

    Vaibhav K, Shrivastava P, Javed H, Khan A, Ahmed ME, Tabassum R, et al. Piperine suppresses cerebral ischemia-reperfusion-induced inflammation through the repression of COX-2, NOS-2, and NF-kappaB in middle cerebral artery occlusion rat model. Mol Cell Biochem 2012; 367: 73-84.

  • 44.

    Ying X, Yu K, Chen X, Chen H, Hong J, Cheng S, et al. Piperine inhibits LPS induced expression of inflammatory mediators in RAW 264.7 cells. Cell Immunol 2013; 285: 49-54.

  • 45.

    Singh S, Jamwal S, Kumar P. Piperine enhances the protective effect of curcumin against 3-NP induced neurotoxicity: possible neurotransmitters modulation mechanism. Neurochem Res 2015; 40: 1758-1766.

  • 46.

    Sabina EP, Nagar S, Rasool M. A role of piperine on monosodium urate crystal-induced inflammationan experimental model of gouty arthritis. Inflammation 2011; 34: 184-192.

  • 47.

    Lassmann H, Raine CS, Antel J, Prineas JW. Immunopathology of multiple sclerosis: report on an international meeting held at the Institute of Neurology of the University of Vienna. J Neuroimmunology 1998; 86: 213-217.

  • 48.

    Holley J, Gveric D, Newcombe J, Cuzner ML, Gutowski NJ. Astrocyte characterization in the multiple sclerosis glial scar. Neuropathol Appl Neurobiol 2003; 29: 434-444.

  • 49.

    Miron VE, Boyd A, Zhao J-W, Yuen TJ, Ruckh JM, Shadrach JL, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 2013; 16: 1211-1218.

  • 50.

    Ousman SS, David S. Lysophosphatidylcholine induces rapid recruitment and activation of macrophages in the adult mouse spinal cord. Glia 2000; 30: 92-104.

  • 51.

    Shrivastava P, Vaibhav K, Tabassum R, Khan A, Ishrat T, Khan MM, et al. Anti-apoptotic and anti-inflammatory effect of Piperine on 6-OHDA induced Parkinson's rat model. J Nutr Biochem 2013; 24: 680-687.

  • 52.

    Bang JS, Oh DH, Choi HM, Sur BJ, Lim SJ, Kim JY, et al. Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1beta-stimulated fibroblast-like synoviocytes and in rat arthritis models. Arthritis Res Ther 2009; 11: R49.

  • 53.

    Bi Y, Qu PC, Wang QS, Zheng L, Liu HL, Luo R, et al. Neuroprotective effects of alkaloids from Piper longum in a MPTP-induced mouse model of Parkinson's disease. Pharm Biol 2015; 53: 1516-1524.

  • 54.

    Liu T, Zhang L, Joo D, Sun SC. NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2017; 2: 17023.

  • 55.

    Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001; 27: 68-73.

  • 56.

    Kim CH. FOXP3 and its role in the immune system. Adv Exp Med Biol 2009; 665: 17-29.

  • 57.

    Oda JM, Hirata BK, Guembarovski RL, Watanabe MA. Genetic polymorphism in FOXP3 gene: imbalance in regulatory T-cell role and development of human diseases. J Genetics 2013; 92: 163-171.

  • 58.

    Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunology (Baltimore, Md: 1950) 2008; 180: 5771-5777.

  • 59.

    Salmaggi A, Dufour A, Eoli M, Corsini E, La Mantia L, Massa G, et al. Low serum interleukin-10 levels in multiple sclerosis: further evidence for decreased systemic immunosuppression? J Neurology 1996; 243: 13-17.

  • 60.

    Correale J, Gilmore W, McMillan M, Li S, McCarthy K, Le T, et al. Patterns of cytokine secretion by autoreactive proteolipid protein-specific T cell clones during the course of multiple sclerosis. J Immunology (Baltimore, Md: 1950) 1995; 154: 2959-2968.

  • 61.

    Saraiva M, O'Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010; 10: 170-181.

  • 62.

    Linker R, Gold R, Luhder F. Function of neurotrophic factors beyond the nervous system: inflammation and autoimmune demyelination. Crit Rev Immunol 2009; 29: 43-68.

  • 63.

    Van't Veer A, Du Y, Fischer TZ, Boetig DR, Wood MR, Dreyfus CF. Brain-derived neurotrophic factor effects on oligodendrocyte progenitors of the basal forebrain are mediated through trkB and the MAP kinase pathway. J Neurosci Res 2009; 87: 69-78.

  • 64.

    VonDran MW, Singh H, Honeywell JZ, Dreyfus CF. Levels of BDNF impact oligodendrocyte lineage cells following a cuprizone lesion. J Neurosci 2011; 31: 14182-14190.

  • 65.

    Fletcher JL, Wood RJ, Nguyen J, Norman EML, Jun CMK, Prawdiuk AR, et al. Targeting TrkB with a Brain-Derived Neurotrophic Factor Mimetic Promotes Myelin Repair in the Brain. J Neurosci 2018; 38: 7088-7099.

  • 66.

    Tongiorgi E, Sartori A, Baj G, Bratina A, Di Cola F, Zorzon M, et al. Altered serum content of brain-derived neurotrophic factor isoforms in multiple sclerosis. J Neurol Sci 2012; 320: 161-165.

  • 67.

    Kalinowska-Lyszczarz A, Losy J. The role of neurotrophins in multiple sclerosis-pathological and clinical implications. Int J Mol Sci 2012; 13: 13713-13725.

  • 68.

    Lindsay RM. Nerve growth factors (NGF, BDNF) enhance axonal regeneration but are not required for survival of adult sensory neurons. J Neurosci 1988; 8: 405-2394.