Skip to main content
SpringerLink
Log in

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

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

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.

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

Similar content being viewed by others

References

  1. Elsohly MA, Slade D (2005) Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 78:539–548

    Article  CAS  PubMed  Google Scholar 

  2. Smita K, Sushil-Kumar V, Premendran JS (2007) Anandamide: an update. Fundam Clin Pharmacol 21:1–8

    Article  CAS  PubMed  Google Scholar 

  3. Padgett LW (2005) Recent developments in cannabinoid ligands. Life Sci 77:1767–1798

    Article  CAS  PubMed  Google Scholar 

  4. Szabo B (2008) Pharmacology of cannabinoid receptors. Biotrend Rev 2:1–13

    Google Scholar 

  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 36:82–91

    Article  CAS  PubMed  Google Scholar 

  6. Martínez-Orgado J, Fernández-López D, Lizasoain I, Romero J (2007) The seek of neuroprotection: introducing cannabinoids. Recent Patents CNS Drug Discov 2:131–139

    Article  Google Scholar 

  7. de Lago E, Fernández-Ruiz J (2007) Cannabinoids and neuroprotection in motor-related disorders. CNS Neurol Disord Drug Targets 6:377–387

    Article  PubMed  Google Scholar 

  8. Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (−)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95:8268–8273

    Article  CAS  PubMed  Google Scholar 

  9. Chen Y, Buck J (2000) Cannabinoids protect cells from oxidative cell death: a receptor-independent mechanism. J Pharmacol Exp Ther 293:807–812

    CAS  PubMed  Google Scholar 

  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 80:448–456

    Article  CAS  PubMed  Google Scholar 

  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 13:3705–3718

    Article  CAS  PubMed  Google Scholar 

  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 19:2987–2995

    CAS  PubMed  Google Scholar 

  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 313:88–94

    Article  CAS  PubMed  Google Scholar 

  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 2:471–479

    Article  CAS  PubMed  Google Scholar 

  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 1134:162–170

    Article  CAS  PubMed  Google Scholar 

  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 61:404–411

    Article  CAS  PubMed  Google Scholar 

  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 26:49–60

    Article  Google Scholar 

  18. Halestrap AP (2009) What is the mitochondrial permeability transition pore? J Mol Cell Cardiology 46:821–831

    Article  CAS  Google Scholar 

  19. Lemasters JJ, Theruvath TP, Zhong Z, Nieminen AL (2009) Mitochondrial calcium and the permeability transition in cell death. Biochim Biophys Acta 1787:1395–1401

    Article  CAS  PubMed  Google Scholar 

  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 7:65–74

    Article  CAS  PubMed  Google Scholar 

  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 3:235–243

    Article  Google Scholar 

  22. Boveris A (1984) Determination of the production of superoxide radicals and hydrogen peroxide in mitochondria. Meth Enzymol 105:429–435

    Article  CAS  PubMed  Google Scholar 

  23. Boveris A, Oshino N, Chance B (1972) The cellular production of hydrogen peroxide. Biochem J 128:617–627

    CAS  PubMed  Google Scholar 

  24. Chance B, Williams GR (1956) The respiratory chain and oxidative phosphorylation. Adv Enzymol 17:65–134

    CAS  Google Scholar 

  25. Estabrook RW (1967) Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios. Meth Enzymol 10:41–47

    Article  CAS  Google Scholar 

  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 87:532–544

    Article  CAS  PubMed  Google Scholar 

  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 37:1490–1498

    Article  CAS  PubMed  Google Scholar 

  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 10:3170–3175

    Google Scholar 

  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 99:1259–1263

    Article  PubMed  Google Scholar 

  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):110–116

    Article  PubMed  Google Scholar 

  31. Czerniczyniec A, Bustamante J, Lores-Arnaiz S (2006) Modulation of brain mitochondrial function by deprenyl. Neurochem Int 48:235–241

    Article  CAS  PubMed  Google Scholar 

  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 264:687–701

    Article  CAS  PubMed  Google Scholar 

  33. Hunter DR, Haworth RA (1979) The Ca++-induced membrane transition in mitochondria. I. The protective mechanisms. Arch Biochem Biophys 195:453–459

    Article  CAS  PubMed  Google Scholar 

  34. Cafiso DS (1994) Alamethicin a peptide model for voltage gaiting and protein-membrane interactions. Ann Rev Biophys Biomol Struct 23:141–165

    Article  CAS  Google Scholar 

  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 960:99–111

    Article  CAS  PubMed  Google Scholar 

  36. Costa B, Parolaro D, Colleoni M (1996) Chronic cannabinoid, CP-55, 940, administration alters biotransformation in the rat. Eur J Pharmacol 313:17–24

    Article  CAS  PubMed  Google Scholar 

  37. Cochemé HM, Murphy MP (2008) Complex I is the major site of mitochondrial superoxide production by paraquat. J Biol Chem 283:1786–1798

    Article  PubMed  Google Scholar 

  38. Loschen G, Azzi A, Richter C, Flohé L (1974) Superoxide radicals as precursors of mitochondrial hydrogen peroxide. FEBS Lett 42:68–72

    Article  CAS  PubMed  Google Scholar 

  39. Forman HJ, Kennedy JA (1974) Role of superoxide radical in mitochondrial dehydrogenase reactions. Biochem Biophys Res Commun 60:1044–1050

    Article  CAS  PubMed  Google Scholar 

  40. Prabhakar NR, Kumar GK (2004) Oxidative stress in the systemic and cellular responses to intermittent hypoxia. Biol Chem 385:217–221

    Article  CAS  PubMed  Google Scholar 

  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 282:7939–7949

    Article  CAS  PubMed  Google Scholar 

  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–L306

    CAS  PubMed  Google Scholar 

  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 364:131–137

    Article  CAS  PubMed  Google Scholar 

  44. Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29:2053–2063

    Article  CAS  PubMed  Google Scholar 

  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)):77–88

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from Colciencias (#1115-343-19119), “Proyecto Enfermedades Neurodegenerativas- University of Antioquia” (#8780), Programa de Sostenibilidad 2008/2009 to CV-P and MJ-Del-Rio, and by grants from University of Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and Agencia Nacional de Promoción de Científica y Tecnológica (ANPCYT), Argentina.

Author information

Authors and Affiliations

  1. School of Medicine, Biomedical Research Institute, Neuroscience Research Group, University of Antioquia, Calle 62 # 52-59, SIU-Lab 411/412, Medellin, Colombia

    Carlos Velez-Pardo & Marlene Jimenez-Del-Rio

  2. Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry, University of Buenos Aires, Junın 956, 1113, Buenos Aires, Argentina

    Silvia Lores-Arnaiz & Juanita Bustamante

Authors
  1. Carlos Velez-Pardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marlene Jimenez-Del-Rio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia Lores-Arnaiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juanita Bustamante
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlos Velez-Pardo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Velez-Pardo, C., Jimenez-Del-Rio, M., Lores-Arnaiz, S. et al. Protective Effects of the Synthetic Cannabinoids CP55,940 and JWH-015 on Rat Brain Mitochondria upon Paraquat Exposure. Neurochem Res 35, 1323–1332 (2010). https://doi.org/10.1007/s11064-010-0188-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-010-0188-1

Keywords

Search

Navigation