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β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease

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Abstract

Parkinson disease (PD) is a neurodegenerative disease characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) area. The present study was undertaken to evaluate the neuroprotective effect of β-caryophyllene (BCP) against rotenone-induced oxidative stress and neuroinflammation in a rat model of PD. In the present study, BCP was administered once daily for 4 weeks at a dose of 50 mg/kg body weight prior to a rotenone (2.5 mg/kg body weight) challenge to mimic the progressive neurodegenerative nature of PD. Rotenone administration results in oxidative stress as evidenced by decreased activities of superoxide dismutase, catalase, and depletion of glutathione with a concomitant rise in lipid peroxidation product, malondialdehyde. Rotenone also significantly increased pro-inflammatory cytokines in the midbrain region and elevated the inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum. Further, immunohistochemical analysis revealed loss of dopaminergic neurons in the SNc area and enhanced expression of ionized calcium-binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP), indicators of microglia activation, and astrocyte hypertrophy, respectively, as an index of inflammation. However, treatment with BCP rescued dopaminergic neurons and decreased microglia and astrocyte activation evidenced by reduced Iba-1 and GFAP expression. BCP in addition to attenuation of pro-inflammatory cytokines and inflammatory mediators such as COX-2 and iNOS, also restored antioxidant enzymes and inhibited lipid peroxidation as well as glutathione depletion. The findings demonstrate that BCP provides neuroprotection against rotenone-induced PD and the neuroprotective effects can be ascribed to its potent antioxidant and anti-inflammatory activities.

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References

  1. Gopalakrishna A, Alexander SA (2015) Understanding Parkinson disease: a complex and multifaceted illness. J Neurosci Nurs 47(6):320–326

    Article  PubMed  Google Scholar 

  2. Olanow CW, Tatton WG (1999) Etiology and pathogenesis of Parkinson's disease. Annu Rev Neurosci 22:123–144  

    Article  CAS  PubMed  Google Scholar 

  3. Niranjan R (2014) The role of inflammatory and oxidative stress mechanisms in the pathogenesis of Parkinson’s disease: focus on astrocytes. Mol Neurobiol 49(1):28–38

    Article  CAS  PubMed  Google Scholar 

  4. Taylor JM, Main BS, Crack PJ (2013) Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson’s disease. Neurochem Int 62(5):803–819

    Article  CAS  PubMed  Google Scholar 

  5. Al Dakheel A, Kalia LV, Lang AE (2014) Pathogenesis-targeted, disease-modifying therapies in Parkinson disease. Neurotherapeutics 11(1):6–23

    Article  CAS  Google Scholar 

  6. Jin H, Kanthasamy A, Ghosh A, Anantharam V, Kalyanaraman B, Kanthasamy AG (2014) Mitochondria-targeted antioxidants for treatment of Parkinson’s disease: preclinical and clinical outcomes. Biochim Biophys Acta 1842(8):1282–1294

    Article  CAS  PubMed  Google Scholar 

  7. Seidl SE, Santiago JA, Bilyk H, Potashkin JA (2014) The emerging role of nutrition in Parkinson’s disease. Front Aging Neurosci 6:36

    Article  PubMed  PubMed Central  Google Scholar 

  8. Song JX, Sze SC, Ng TB, Lee CK, Leung GP, Shaw PC, Tong Y, Zhang YB (2012) Anti-Parkinsonian drug discovery from herbal medicines: what have we got from neurotoxic models? J Ethnopharmacol 139(3):698–711

    Article  CAS  PubMed  Google Scholar 

  9. Mythri RB, Harish G, Bharath MM (2012) Therapeutic potential of natural products in Parkinson’s disease. Recent Pat Endocr Metab Immune Drug Discov 6(3):181–200

    Article  CAS  PubMed  Google Scholar 

  10. Hill AJ, Williams CM, Whalley BJ, Stephens GJ (2012) Phytocannabinoids as novel therapeutic agents in CNS disorders. Pharmacol Ther 133(1):79–97

    Article  CAS  PubMed  Google Scholar 

  11. Little JP, Villanueva EB, Klegeris A (2011) Therapeutic potential of cannabinoids in the treatment of neuroinflammation associated with Parkinson’s disease. Mini Rev Med Chem 11(7):582–590

    Article  CAS  PubMed  Google Scholar 

  12. 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 USA 105(26):9099–9104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chang HJ, Kim HJ, Chun HS (2007) Quantitative structure-activity relationship (QSAR) for neuroprotective activity of terpenoids. Life Sci 80(9):835–841

    Article  CAS  PubMed  Google Scholar 

  14. Abbas MA, Taha MO, Zihlif MA, Disi AM (2013) β-Caryophyllene causes regression of endometrial implants in a rat model of endometriosis without affecting fertility. Eur J Pharmacol 702(1–3):12–19

    Article  CAS  PubMed  Google Scholar 

  15. Bento AF, Marcon R, Dutra RC, Claudino RF, Cola M, Leite DF, Calixto JB (2011) β-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway. Am J Pathol 178(3):1153–1166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cho HI, Hong JM, Choi JW, Choi HS, Hwan Kwak J, Lee DU, Kook Lee S, Lee SM (2015) β-Caryophyllene alleviates d-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the TLR4 and RAGE signaling pathways. Eur J Pharmacol 764:613–621

    Article  CAS  PubMed  Google Scholar 

  17. Zheng X, Sun T, Wang X (2013) Activation of type 2 cannabinoid receptors (CB2R) promotes fatty acid oxidation through the SIRT1/PGC-1α pathway. Biochem Biophys Res Commun 436(3):377–381

    Article  CAS  PubMed  Google Scholar 

  18. 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(3):928–939

    Article  CAS  PubMed  Google Scholar 

  19. Liu H, Song Z, Liao D, Zhang T, Liu F, Zhuang K, Luo K, Yang L (2015) Neuroprotective effects of trans-caryophyllene against kainic acid induced seizure activity and oxidative stress in mice. Neurochem Res 40(1):118–123

    Article  CAS  PubMed  Google Scholar 

  20. Guo K, Mou X, Huang J, Xiong N, Li H (2014) Trans-caryophyllene suppresses hypoxia-induced neuroinflammatory responses by inhibiting NF-κB activation in microglia. J Mol Neurosci 54(1):41–48

    Article  CAS  PubMed  Google Scholar 

  21. Cheng Y, Dong Z, Liu S (2014) β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway. Pharmacology 94(1–2):1–12

    Article  CAS  PubMed  Google Scholar 

  22. Al Mansouri S, Ojha S, Al Maamari E, Al Ameri M, Nurulain SM, Bahi A (2014) The cannabinoid receptor 2 agonist, β-caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice. Pharmacol Biochem Behav 124:260–268

    Article  CAS  PubMed  Google Scholar 

  23. Assis LC, Straliotto MR, Engel D, Hort MA, Dutra RC, de Bem AF (2014) β-Caryophyllene protects the C6 glioma cells against glutamate-induced excitotoxicity through the Nrf2 pathway. Neuroscience 279:220–231

    Article  CAS  PubMed  Google Scholar 

  24. Belanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 14(6):724–738

    Article  CAS  PubMed  Google Scholar 

  25. Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JT (2009) A highly reproducible rotenone model of Parkinson’s disease. Neurobiol Dis 34(2):279–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fujikawa T, Kanada N, Shimada A, Ogata M, Suzuki I, Hayashi I, Nakashima K (2005) Effect of sesamin in Acanthopanax senticosus HARMS on behavioral dysfunction in rotenone-induced Parkinsonian rats. Biol Pharm Bull 28:169–172

    Article  CAS  PubMed  Google Scholar 

  27. Sherer TB, Betarbet R, Kim JH, Greenamyre JT (2003) Selective microglial activation in the rat rotenone model of Parkinson’s disease. Neurosci Lett 341:87–90

    Article  CAS  PubMed  Google Scholar 

  28. Ojha S, Javed H, Azimullah S, Abul Khair SB, Haque ME (2015) Neuroprotective potential of ferulic acid in the rotenone model of Parkinson’s disease. Drug Des Dev Ther 9:5499–5510

    Google Scholar 

  29. Messripour M, Messripour A (2013) Age related interaction of dopamine and serotonin synthesis in striatal synaptosomes. Biocell 37:17–21

    CAS  PubMed  Google Scholar 

  30. Pizzimenti S, Ciamporcero E, Daga M, Pettazzoni P, Arcaro A, Cetrangolo G, Minelli R, Dianzani C, Lepore A, Gentile F, Barrera G (2013) Interaction of aldehydes derived from lipid peroxidation and membrane proteins. Front Physiol 4:242

    Article  PubMed  PubMed Central  Google Scholar 

  31. Thakur P, Nehru B (2013) Anti-inflammatory properties rather than anti-oxidant capability is the major mechanism of neuroprotection by sodium salicylate in a chronic rotenone model of Parkinson’s disease. Neuroscience 231:420–431

    Article  CAS  PubMed  Google Scholar 

  32. Sutachan JJ, Casas Z, Albarracin SL, Stab BR, Samudio I, Gonzalez J, Morales L, Barreto GE (2012) Cellular and molecular mechanisms of antioxidants in Parkinson’s disease. Nutr Neurosci 15(3):120–126

    Article  CAS  PubMed  Google Scholar 

  33. Albarracin SL, Stab B, Casas Z, Sutachan JJ, Samudio I, Gonzalez J, Gonzalo L, Capani F, Morales L, Barreto GE (2012) Effects of natural antioxidants in neurodegenerative disease. Nutr Neurosci 15(1):1–9

    Article  CAS  PubMed  Google Scholar 

  34. Smeyne M, Smeyne RJ (2013) Glutathione metabolism and Parkinson’s disease. Free Radic Biol Med 62:13–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Calleja MA, Vieites JM, Montero-Meléndez T, Torres MI, Faus MJ, Gil A, Suárez A (2013) The antioxidant effect of β-caryophyllene protects rat liver from carbon tetrachloride-induced fibrosis by inhibiting hepatic stellate cell activation. Br J Nutr 109(3):394–401

    Article  CAS  PubMed  Google Scholar 

  36. Alvarez-González I, Madrigal-Bujaidar E, Castro-García S (2014) Antigenotoxic capacity of beta-caryophyllene in mouse, and evaluation of its antioxidant and GST induction activities. J Toxicol Sci 39(6):849–859

    Article  PubMed  Google Scholar 

  37. Babu RO, Moorkoth D, Azeez S, Eapen SJ (2012) Virtual screening and in vitro assay of potential drug like inhibitors from spices against glutathione-S-transferase of meloidogyne incognita. Bioinformation 8(7):319–325

    Article  PubMed  PubMed Central  Google Scholar 

  38. Doorn KJ, Lucassen PJ, Boddeke HW, Prins M, Berendse HW, Drukarch B, van Dam AM (2012) Emerging roles of microglial activation and non-motor symptoms in Parkinson’s disease. Prog Neurobiol 98(2):222–238

    Article  PubMed  Google Scholar 

  39. Mosley RL, Benner EJ, Kadiu I, Thomas M, Boska MD, Hasan K, Laurie C, Gendelman HE (2006) Neuroinflammation, oxidative stress and the pathogenesis of Parkinson’s disease. Clin Neurosci Res 6:261–281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sarkar S, Gough B, Raymick J, Beaudoin MA, Ali SF, Virmani A, Binienda ZK (2015) Histopathological and electrophysiological indices of rotenone-evoked dopaminergic toxicity: neuroprotective effects of acetyl-l-carnitine. Neurosci Lett 606:53–59

    Article  CAS  PubMed  Google Scholar 

  41. Swarnkar S, Goswami P, Kamat PK, Patro IK, Singh S, Nath C (2013) Rotenone-induced neurotoxicity in rat brain areas: a study on neuronal and neuronal supportive cells. Neuroscience 230:172–183

    Article  CAS  PubMed  Google Scholar 

  42. McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord 23(4):474–483

    Article  PubMed  Google Scholar 

  43. Littlejohn D, ManFAno E, Clarke M, Bobyn J, Moloney K, Hayley S (2010) Inflammatory mechanisms of neurodegeneration in toxin-based models of Parkinson’s disease. Parkinsons Dis 2011:713517

    Google Scholar 

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Acknowledgments

The research grants support from the United Arab Emirates University and the National Research Foundation, United Arab Emirates to MEH and SO are duly acknowledged. The authors would also like to acknowledge Mahmoud Hag Ali, Animal Research Facility controller for his help in animal care and welfare. The authors also acknowledge the proof read of the manuscript by Dr. Keith M Bagnall, Professor of Anatomy, College of Medicine and Health Sciences, UAE University, UAE.

Author contributions

All the authors provided important intellectual content, reviewed the content, and approved the final version for the manuscript. Contributed significantly, read, and approved the manuscript: HJ, MEH, and SO. Conceived and designed the experiments: HJ, MEH, and SO. Performed the experiments: HJ and AS. Analyzed the data: HJ, MEH, and SO. Contributed reagents/materials/analysis tools: MEH and SO. Wrote the paper: HJ, MEH, and SO.

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    Authors and Affiliations

    1. Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box: 17666, Al Ain, UAE

      Shreesh Ojha & Sheikh Azimullah

    2. Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, PO Box: 17666, Al Ain, UAE

      Hayate Javed & M. Emdadul Haque

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    1. Shreesh Ojha
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    Correspondence to M. Emdadul Haque.

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    There are no patents, products in development or marketed products to declare. The research grant funding organizations have no role in study design, data collection and analysis, decision to publish, or the preparation of the manuscript.

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    Shreesh Ojha and Hayate Javed have contributed equally to this work.

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    Ojha, S., Javed, H., Azimullah, S. et al. β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease. Mol Cell Biochem 418, 59–70 (2016). https://doi.org/10.1007/s11010-016-2733-y

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