Neurochemical Research

, Volume 35, Issue 9, pp 1323–1332

Protective Effects of the Synthetic Cannabinoids CP55,940 and JWH-015 on Rat Brain Mitochondria upon Paraquat Exposure

  • Carlos Velez-Pardo
  • Marlene Jimenez-Del-Rio
  • Silvia Lores-Arnaiz
  • Juanita Bustamante
Original Paper


The effects of cannabinoids in mitochondria after acute oxidative stress insult are not fully established. We investigated the ability of CP55,940 and JWH-015 to scavenge reactive oxygen species and their effect on mitochondria permeability transition (MPT) in either a mitochondria-free superoxide anion generation system, intact rat brain mitochondria or in sub-mitochondrial particles (SMP) treated with paraquat (PQ). Oxygen consumption, mitochondrial membrane potential (Δψm) and MPT were determined as parameters of mitochondrial function. It is found that both cannabinoids effectively attenuate mitochondrial damage against PQ-induced oxidative stress by scavenging anion superoxide radical (O2∙−) and hydrogen peroxide (H2O2), maintaining Δψm and by avoiding Ca2+-induced mitochondrial swelling. Understanding the mechanistic action of cannabinoids on mitochondria might provide new insights into more effective therapeutic approaches for oxidative stress related disorders.


CP55,940 Cannabinoids JWH-015 Mitochondria Oxidative stress Paraquat 


  1. 1.
    Elsohly MA, Slade D (2005) Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 78:539–548CrossRefPubMedGoogle Scholar
  2. 2.
    Smita K, Sushil-Kumar V, Premendran JS (2007) Anandamide: an update. Fundam Clin Pharmacol 21:1–8CrossRefPubMedGoogle Scholar
  3. 3.
    Padgett LW (2005) Recent developments in cannabinoid ligands. Life Sci 77:1767–1798CrossRefPubMedGoogle Scholar
  4. 4.
    Szabo B (2008) Pharmacology of cannabinoid receptors. Biotrend Rev 2:1–13Google Scholar
  5. 5.
    Sagredo O, García-Arencibia M, de Lago E, Finetti S, Decio A, Fernández-Ruiz J (2007) Cannabinoids and neuroprotection in basal ganglia disorders. Mol Neurobiol 36:82–91CrossRefPubMedGoogle Scholar
  6. 6.
    Martínez-Orgado J, Fernández-López D, Lizasoain I, Romero J (2007) The seek of neuroprotection: introducing cannabinoids. Recent Patents CNS Drug Discov 2:131–139CrossRefGoogle Scholar
  7. 7.
    de Lago E, Fernández-Ruiz J (2007) Cannabinoids and neuroprotection in motor-related disorders. CNS Neurol Disord Drug Targets 6:377–387CrossRefPubMedGoogle Scholar
  8. 8.
    Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (−)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95:8268–8273CrossRefPubMedGoogle Scholar
  9. 9.
    Chen Y, Buck J (2000) Cannabinoids protect cells from oxidative cell death: a receptor-independent mechanism. J Pharmacol Exp Ther 293:807–812PubMedGoogle Scholar
  10. 10.
    Marsicano G, Moosmann B, Hermann H, Lutz B, Behl C (2002) Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J Neurochem 80:448–456CrossRefPubMedGoogle Scholar
  11. 11.
    Lastres-Becker I, Fernandez-Ruiz J (2006) An overview of Parkinson’s disease and the cannabinoid system and possible benefits of cannabinoid-based treatments. Curr Med Chem 13:3705–3718CrossRefPubMedGoogle Scholar
  12. 12.
    Nagayama T, Sinor AD, Simon RP, Chen J, Graham SH, Jin K, Greenberg DA (1999) Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci 19:2987–2995PubMedGoogle Scholar
  13. 13.
    Kim SH, Won SJ, Mao XO, Jin K, Greenberg DA (2005) Involvement of protein kinase A in cannabinoid receptor-mediated protection from oxidative neuronal injury. J Pharmacol Exp Ther 313:88–94CrossRefPubMedGoogle Scholar
  14. 14.
    Velez-Pardo C, Jimenez-Del-Rio M (2006) Avoidance of Aβ[25–35]/(H2O2)-induced apoptosis in lymphocytes by the cannabinoid agonists CP55,940 and JWH-015 via receptor-independent and PI3 K-dependent mechanisms: role of NF-κB and p53. Med Chem 2:471–479CrossRefPubMedGoogle Scholar
  15. 15.
    Garcia-Arencibia M, Gonzalez S, de Lago E, Ramos JA, Mechoulam R, Fernandez-Ruiz J (2007) Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties. Brain Res 1134:162–170CrossRefPubMedGoogle Scholar
  16. 16.
    Jimenez-Del-Rio M, Daza-Restrepo A, Velez-Pardo C (2008) The cannabinoid CP55,940 prolongs survival and improves locomotor activity in Drosophila melanogaster against paraquat: implications in Parkinson’s disease. Neurosci Res 61:404–411CrossRefPubMedGoogle Scholar
  17. 17.
    Jimenez-Del-Rio M, Velez-Pardo C (2008) Paraquat induces apoptosis in human lymphocytes: Protective and rescue effects of glucose, cannabinoids and Insulin-like growth factor-1. Growth Factors 26:49–60CrossRefGoogle Scholar
  18. 18.
    Halestrap AP (2009) What is the mitochondrial permeability transition pore? J Mol Cell Cardiology 46:821–831CrossRefGoogle Scholar
  19. 19.
    Lemasters JJ, Theruvath TP, Zhong Z, Nieminen AL (2009) Mitochondrial calcium and the permeability transition in cell death. Biochim Biophys Acta 1787:1395–1401CrossRefPubMedGoogle Scholar
  20. 20.
    Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7:65–74CrossRefPubMedGoogle Scholar
  21. 21.
    Lores-Arnaiz S, Coronel MF, Boveris A (1999) Nitric oxide, superoxide and hydrogen peroxide production in brain mitochondria after haloperidol treatment. Nitric Oxide: Biol Chem 3:235–243CrossRefGoogle Scholar
  22. 22.
    Boveris A (1984) Determination of the production of superoxide radicals and hydrogen peroxide in mitochondria. Meth Enzymol 105:429–435CrossRefPubMedGoogle Scholar
  23. 23.
    Boveris A, Oshino N, Chance B (1972) The cellular production of hydrogen peroxide. Biochem J 128:617–627PubMedGoogle Scholar
  24. 24.
    Chance B, Williams GR (1956) The respiratory chain and oxidative phosphorylation. Adv Enzymol 17:65–134Google Scholar
  25. 25.
    Estabrook RW (1967) Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios. Meth Enzymol 10:41–47CrossRefGoogle Scholar
  26. 26.
    Mattiasson G, Friberg H, Hansson M, Elmér E, Wieloch T (2003) Flow cytometric analysis of mitochondria from CA1 and CA3 regions of rat hippocampus reveals differences in permeability transition pore activation. J Neurochem 87:532–544CrossRefPubMedGoogle Scholar
  27. 27.
    Bustamante J, Di Libero E, Fernandez-Cobo M, Monti N, Cadenas E, Boveris A (2004) Kinetic analysis of thapsigargin–induced thymocyte apoptosis. Free Rad Biol Med 37:1490–1498CrossRefPubMedGoogle Scholar
  28. 28.
    Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidatrion of epinephrineand a simple assay for superoxide dismutase. J Biol Med 10:3170–3175Google Scholar
  29. 29.
    Gogvadze V, Robertson JD, Zhivotovsky B, Orrenius S (2002) Cytochrome c release occurs via Ca2+ dependent and Ca2+ independent mechanisms that are regulated by Bax. Proc Natl Acad Sci USA 99:1259–1263CrossRefPubMedGoogle Scholar
  30. 30.
    Bustamante J, Nutt L, Orrenius S, Gogvadze V (2005) Arsenic stimulates release of cytochrome c from isolated mitochondria via induction of mitochondrial permeability transition. Toxicol Appl Pharmacol 207(2 Suppl):110–116CrossRefPubMedGoogle Scholar
  31. 31.
    Czerniczyniec A, Bustamante J, Lores-Arnaiz S (2006) Modulation of brain mitochondrial function by deprenyl. Neurochem Int 48:235–241CrossRefPubMedGoogle Scholar
  32. 32.
    Bernardi P, Scorrano L, Colonia R, Petronilli V, Di Lisa F (1999) Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur J Biochem 264:687–701CrossRefPubMedGoogle Scholar
  33. 33.
    Hunter DR, Haworth RA (1979) The Ca++-induced membrane transition in mitochondria. I. The protective mechanisms. Arch Biochem Biophys 195:453–459CrossRefPubMedGoogle Scholar
  34. 34.
    Cafiso DS (1994) Alamethicin a peptide model for voltage gaiting and protein-membrane interactions. Ann Rev Biophys Biomol Struct 23:141–165CrossRefGoogle Scholar
  35. 35.
    Hansson MJ, Persson T, Friberg H, Keep MF, Rees A, Wieloch T, Elmer E (2003) Powerful cyclosporine inhibition of calcium-induced permeability transition in brain mitochondria. Brain Res 960:99–111CrossRefPubMedGoogle Scholar
  36. 36.
    Costa B, Parolaro D, Colleoni M (1996) Chronic cannabinoid, CP-55, 940, administration alters biotransformation in the rat. Eur J Pharmacol 313:17–24CrossRefPubMedGoogle Scholar
  37. 37.
    Cochemé HM, Murphy MP (2008) Complex I is the major site of mitochondrial superoxide production by paraquat. J Biol Chem 283:1786–1798CrossRefPubMedGoogle Scholar
  38. 38.
    Loschen G, Azzi A, Richter C, Flohé L (1974) Superoxide radicals as precursors of mitochondrial hydrogen peroxide. FEBS Lett 42:68–72CrossRefPubMedGoogle Scholar
  39. 39.
    Forman HJ, Kennedy JA (1974) Role of superoxide radical in mitochondrial dehydrogenase reactions. Biochem Biophys Res Commun 60:1044–1050CrossRefPubMedGoogle Scholar
  40. 40.
    Prabhakar NR, Kumar GK (2004) Oxidative stress in the systemic and cellular responses to intermittent hypoxia. Biol Chem 385:217–221CrossRefPubMedGoogle Scholar
  41. 41.
    Gray JP, Heck DE, Mishin PJS, Hong JY, Thiruchelvam M, Cory-Slechta DA, Laskin DL, Laskin JD (2007) Paraquat increases cyanide-insensitive respiration in murine lung epithelial cells by activating an NAD(P)H:paraquat oxidoreductase. J Biol Chem 282:7939–7949CrossRefPubMedGoogle Scholar
  42. 42.
    Sarafian TA, Kouyoumjian S, Khoshaghideh F, Tashkin DP, Roth MD (2003) Delta 9-tetrahydrocannabinol disrupts mitochondrial function and cell energetics. Am J Physiol Lung Cell Mol Physiol 284:L298–L306PubMedGoogle Scholar
  43. 43.
    Athanasiou A, Clarke AB, Turner AE, Kumaran NM, Vakilpour S, Smith PA, Bagiokou D, Bradshaw TD, Westwell AD, Fang L, Lobo DN, Constantinescu CS, Calabrese V, Loesch A, Alexander SP, Clothier RH, Kendall DA, Bates TE (2007) Cannabinoid receptor agonists are mitochondrial inhibitors: a unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death. Biochem Biophys Res Commun 364:131–137CrossRefPubMedGoogle Scholar
  44. 44.
    Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29:2053–2063CrossRefPubMedGoogle Scholar
  45. 45.
    Costantini P, Petronilli V, Colonna R, Bernardi P (1995) On the effects of paraquat on isolated mitochondria. Evidence that paraquat causes opening of the cyclosporin A-sensitive permeability transition pore synergistically with nitric oxide. Toxicology 99((1–2)):77–88CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Carlos Velez-Pardo
    • 1
  • Marlene Jimenez-Del-Rio
    • 1
  • Silvia Lores-Arnaiz
    • 2
  • Juanita Bustamante
    • 2
  1. 1.School of Medicine, Biomedical Research Institute, Neuroscience Research GroupUniversity of AntioquiaMedellinColombia
  2. 2.Laboratory of Free Radical Biology, School of Pharmacy and BiochemistryUniversity of Buenos AiresBuenos AiresArgentina

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