Skip to main content

Advertisement

Log in

Trans-Caryophyllene Suppresses Hypoxia-Induced Neuroinflammatory Responses by Inhibiting NF-κB Activation in Microglia

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Microglia cells have been reported to mediate hypoxia-induced inflammation through the production of proinflammatory cytokines, including interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and IL-6. Given the fact that the activation of the type 2 cannabinoid receptor (CB2R) provides antioxidative and anti-inflammatory results, it is suspected that its selective agonist, trans-caryophyllene (TC), may have protective effects against hypoxia-induced neuroinflammatory responses. In this study, TC was found to significantly inhibit hypoxia-induced cytotoxicity as well as the release of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6, through activation of BV2 microglia following hypoxic exposure (1 % O2, 24 h). Furthermore, TC significantly inhibited hypoxia-induced generation of reactive oxygen species (ROS) in mitochondria as well as the activation of nuclear factor kappa B (NF-κB) in microglia. Importantly, TC’s effects on inhibiting the activation of NF-κB and the secretion of inflammatory cytokines can be abolished by muting the CB2R using small RNA interference. These observations indicate that TC suppresses the hypoxia-induced neuroinflammatory response through inhibition of NF-κB activation in microglia. Therefore, TC may be beneficial in preventing hypoxia-induced neuroinflammation.

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

  • Aso E, Juvés S, Maldonado R, Ferrer I (2013) CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AβPP/PS1 mice. J Alzheimers Dis 35:847–858

    PubMed  Google Scholar 

  • Cabral GA, Griffin-Thomas L (2009) Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev Mol Med 11:e3

    Article  PubMed Central  PubMed  Google Scholar 

  • Cao Z, Mulvihill MM, Mukhopadhyay P, Xu H, Erdélyi K, Hao E, Holovac E, Haskó G, Cravatt BF, Nomura DK, Pacher P (2013) Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice. Gastroenterology 144:808–817

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Carlson BW, Carlson JR, Neelon VJ, Hartman M (2008) Tailoring protocols to successfully recruit and retain older adults in a longitudinal study of sleep and cognition. Res Gerontol Nurs 1:232–237

    Article  PubMed Central  PubMed  Google Scholar 

  • Chamorro A, Hallenbeck J (2006) The harms and benefits of inflammatory and immune responses in vascular disease. Stroke 37:291–293

    Article  PubMed Central  PubMed  Google Scholar 

  • Chang HJ, Kim HJ, Chun HS (2007) Quantitative structure-activity relationship (QSAR) for neuroprotective activity of terpenoids. Life Sci 80:835–841

    Article  CAS  PubMed  Google Scholar 

  • Choi IY, Ju C, Anthony Jalin AM, da Lee I, Prather PL, Kim WK (2013) Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury. Am J Pathol 182:928–939

    Article  CAS  PubMed  Google Scholar 

  • Gerhard A, Neumaier B, Elitok E, Glatting G, Ries V, Tomczak R, Ludolph AC, Reske SN (2000) In vivo imaging of activated microglia using [11C]PK11195 and positron emission tomography in patients after ischemic stroke. NeuroReport 11:2957–2960

    Article  CAS  PubMed  Google Scholar 

  • Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, Altmann KH, Karsak M, Zimmer A (2008) Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci U S A 105:9099–9104

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Girard S, Brough D, Lopez-Castejon G, Giles J, Rothwell NJ, Allan SM (2013) Microglia and macrophages differentially modulate cell death after brain injury caused by oxygen-glucose deprivation in organotypic brain slices. Glia 61:813–824

    Article  PubMed Central  PubMed  Google Scholar 

  • Glezer I, Simard AR, Rivest S (2007) Neuroprotective role of the innate immune system by microglia. Neuroscience 147:867–883

    Article  CAS  PubMed  Google Scholar 

  • Habib P, Slowik A, Zendedel A, Johann S, Dang J, Beyer C (2013) Regulation of hypoxia-induced inflammatory responses and M1–M2 phenotype switch of primary rat microglia by sex steroids. J Mol Neurosci

  • Heneka MT, O’Banion MK, Terwel D, Kummer MP (2010) Neuroinflammatory processes in Alzheimer’s disease. J Neural Transm 117:919–947

    Article  CAS  PubMed  Google Scholar 

  • Imai F, Suzuki H, Oda J, Ninomiya T, Ono K, Sano H, Sawada M (2007) Neuroprotective effect of exogenous microglia in global brain ischemia. J Cereb Blood Flow Metab 27:488–500

    Article  CAS  PubMed  Google Scholar 

  • Kigerl KA, Gendel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29:13435–13444

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318

    Article  CAS  PubMed  Google Scholar 

  • Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7:97

    Article  PubMed Central  PubMed  Google Scholar 

  • Lalancette-Hébert M, Gowing G, Simard A, Weng YC, Kriz J (2007) Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 27:2596–2605

    Article  PubMed  Google Scholar 

  • Liu SF, Malik AB (2006) NF-κB activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol 290:L622–L645

    CAS  PubMed  Google Scholar 

  • Montecucco F, Lenglet S, Braunersreuther V, Burger F, Pelli G, Bertolotto M, Mach F, Steffens S (2009) CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mol Cell Cardiol 46:612–620

    Article  CAS  PubMed  Google Scholar 

  • Mukhopadhyay P, Rajesh M, Pan H, Patel V, Mukhopadhyay B, Bátkai S, Gao B, Haskó G, Pacher P (2010) Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy. Free Radic Biol Med 48:457–467

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nakajima K, Kohsaka S (2001) Microglia: activation and their significance in the central nervous system. J Biochem 130:169–175

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi H, Wu Z (2009) Microglia-aging: roles of microglial lysosome- and mitochondria-derived reactive oxygen species in brain aging. Behav Brain Res 201:1–7

    Article  CAS  PubMed  Google Scholar 

  • Nurmi A, Lindsberg PJ, Koistinaho M, Zhang W, Juettler E, Karjalainen-Lindsberg ML, Weih F, Frank N, Schwaninger M, Koistinaho J (2004) Nuclear factor-κB contributes to infarction after permanent focal ischemia. Stroke 35:987–991

    Article  PubMed  Google Scholar 

  • Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180

    CAS  PubMed  Google Scholar 

  • Pertwee RG (2009) Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol 156:397–411

    CAS  PubMed Central  PubMed  Google Scholar 

  • Qin ZH, Tao LY, Chen X (2007) Dual roles of NF-κB in cell survival and implications of NF-κB inhibitors in neuroprotective therapy. Acta Pharmacol Sin 28:1859–1872

    Article  CAS  PubMed  Google Scholar 

  • Rathnasamy G, Ling EA, Kaur C (2011) Iron and iron regulatory proteins in amoeboid microglial cells are linked to oligodendrocyte death in hypoxic neonatal rat periventricular white matter through production of proinflammatory cytokines and reactive oxygen/nitrogen species. J Neurosci 31:17982–17995

    Article  CAS  PubMed  Google Scholar 

  • Salehi P, Sonboli A, Khaligh P, Mirzajani F (2012) Essential oil composition and antioxidant activity of different extracts of Nepeta betonicifolia C.A. Meyer and Nepeta saccharata Bunge. Nat Prod Res 26:736–743

    Article  CAS  PubMed  Google Scholar 

  • Shi H, Sheng B, Zhang F, Wu C, Zhang R, Zhu J, Xu K, Kuang Y, Jameson SC, Lin Z, Wang Y, Chen J, Jain MK, Atkins GB (2013) Kruppel-like factor 2 protects against ischemic stroke by regulating endothelial blood brain barrier function. Am J Physiol Heart Circ Physiol 304:H796–H805

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sivakumar V, Foulds WS, Luu CD, Ling EA, Kaur C (2011) Retinal ganglion cell death is induced by microglia derived pro-inflammatory cytokines in the hypoxic neonatal retina. J Pathol 224:245–260

    Article  CAS  PubMed  Google Scholar 

  • Toledano MB, Leonard WJ (1991) Modulation of transcription factor NF-κB binding activity by oxidation-reduction in vitro. Proc Natl Acad Sci U S A 88:4328–4332

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yang Q, Yang ZF, Liu SB, Zhang XN, Hou Y, Li XQ, Wu YM, Wen AD, Zhao MG (2010) Neuroprotective effects of hydroxysafflor yellow A against excitotoxic neuronal death partially through down-regulation of NR2B-containing NMDA receptors. Neurochem Res 35:1353–1360

    Article  CAS  PubMed  Google Scholar 

  • Zarruk JG, Fernández-López D, García-Yébenes I, García-Gutiérrez MS, Vivancos J, Nombela F, Torres M, Burguete MC, Manzanares J, Lizasoain I, Moro MA (2012) Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection. Stroke 43:211–219

    Article  CAS  PubMed  Google Scholar 

  • Zawadzka M, Dabrowski M, Gozdz A, Szadujkis B, Sliwa M, Lipko M, Kaminska B (2012) Early steps of microglial activation are directly affected by neuroprotectant FK506 in both in vitro inflammation and in rat model of stroke. J Mol Med (Berl) 90:1459–1471. doi:10.1007/s00109-012-0925-9

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hongge Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guo, K., Mou, X., Huang, J. et al. Trans-Caryophyllene Suppresses Hypoxia-Induced Neuroinflammatory Responses by Inhibiting NF-κB Activation in Microglia. J Mol Neurosci 54, 41–48 (2014). https://doi.org/10.1007/s12031-014-0243-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-014-0243-5

Keywords

Navigation