Skip to main content

Advertisement

SpringerLink
Log in

Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids

  • INVITED REVIEW
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.

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

Similar content being viewed by others

REFERENCES

  • Al-Izki S, Pryce G, O’Neill JK, Butter C, Giovannoni G, Amor S, Baker D (2012) Practical guide to the induction of relapsing progressive experimental autoimmune encephalomyelitis in the Biozzi ABH mouse. Mult Scler Rel Dis 1:29–38

    Article  Google Scholar 

  • Al-Izki S, Pryce G, Hankey DJ, Lidster K, von Kutzleben SM, Browne L, Clutterbuck L, Posada C, Edith Chan AW, Amor S, Perkins V, Gerritsen WH, Ummenthum K, Peferoen-Baert R, van der Valk P, Montoya A, Joel SP, Garthwaite J, Giovannoni G, Selwood DL, Baker D (2014) Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain 137:92–108

    Article  PubMed  Google Scholar 

  • Baker D, Amor S (2012) Publication guidelines for refereeing and reporting on animal use in experimental autoimmune encephalomyelitis. J Neuroimmunol 242:78–83

    Article  CAS  PubMed  Google Scholar 

  • Baker D, Amor S (2014) Experimental autoimmune encephalomyelitis is a good model of multiple sclerosis if used wisely. Mult Scler Rel Dis 3:555–564

    Article  Google Scholar 

  • Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, Layward L (2000) Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404:84–87

    Article  CAS  PubMed  Google Scholar 

  • Baker D, Gerritsen W, Rundle J, Amor S (2011) Critical appraisal of animal models of multiple sclerosis. Mult Scler 17:647–657

    Article  PubMed  Google Scholar 

  • Baker D, Pryce G, Jackson SJ, Bolton C, Giovannoni G (2012) The biology that underpins the therapeutic potential of cannabis-based medicines for the control of spasticity in multiple sclerosis. Mult Scler Rel Dis 1:64–75

    Article  CAS  Google Scholar 

  • Bernal-Chico A, Canedo M, Manterola A, Victoria Sánchez-Gómez M, Pérez-Samartín A, Rodríguez-Puertas R, Matute C, Mato S (2015) Blockade of monoacylglycerol lipase inhibits oligodendrocyte excitotoxicity and prevents demyelination in vivo. Glia 63:163–176

    Article  PubMed  Google Scholar 

  • Bolton C, O’Neill JK, Allen SJ, Baker D (1997) Regulation of chronic relapsing experimental allergic encephalomyelitis by endogenous and exogenous glucocorticoids. Int Arch Allergy Immunol 114:74–80

    Article  CAS  PubMed  Google Scholar 

  • Burgdorf JR, Kilmer B, Pacula RL (2011) Heterogeneity in the composition of marijuana seized in California. Drug Alcohol Depend 117:59–61

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Carroll CB, Zeissler ML, Hanemann CO, Zajicek JP (2012) Δ9-tetrahydrocannabinol (Δ9-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson’s disease. Neuropathol Appl Neurobiol 38:535–547

    Article  CAS  PubMed  Google Scholar 

  • Chong MS, Wolff K, Wise K, Tanton C, Winstock A, Silber E (2006) Cannabis use in patients with multiple sclerosis. Mult Scler 12:646–651

    Article  CAS  PubMed  Google Scholar 

  • Clark AJ, Ware MA, Yazer E, Murray TJ, Lynch ME (2004) Patterns of cannabis use among patients with multiple sclerosis. Neurology 62:2098–2100

    Article  CAS  PubMed  Google Scholar 

  • Compston A, Coles A (2002) Multiple sclerosis. Lancet 359:1221–1231

    Article  PubMed  Google Scholar 

  • Compston A, Coles A (2008) Multiple sclerosis. Lancet 372:1502–1517

    Article  CAS  PubMed  Google Scholar 

  • Consroe P, Musty R, Rein J, Tillery W, Pertwee R (1997) The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur Neurol 38:44–48

    Article  CAS  PubMed  Google Scholar 

  • Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H, Gouaux B (2012) Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ 184:1143–1150

    Article  PubMed Central  PubMed  Google Scholar 

  • Correa F, Docagne F, Mestre L, Clemente D, Hernangómez M, Loría F, Guaza C (2009) A role for CB2 receptors in anandamide signalling pathways involved in the regulation of IL-12 and IL-23 in microglial cells. Biochem Pharmacol 77:86–100

    Article  CAS  PubMed  Google Scholar 

  • Croxford JL, Pryce G, Jackson SJ, Ledent C, Giovannoni G, Pertwee RG, Yamamura T, Baker D (2008) Cannabinoid-mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis. J Neuroimmunol 193:120–129

    Article  CAS  PubMed  Google Scholar 

  • Dalton WS, Martz R, Lemberger L, Rodda BE, Forney RB (1976) Influence of cannabidiol on delta-9-tetrahydrocannabinol effects. Clin Pharmacol Ther 19:300–309

    CAS  PubMed  Google Scholar 

  • de Lago E, Moreno-Martet M, Cabranes A, Ramos JA, Fernández-Ruiz J (2012) Cannabinoids ameliorate disease progression in a model of multiple sclerosis in mice, acting preferentially through CB1 receptor-mediated anti-inflammatory effects. Neuropharmacology 62:2299–2308

    Article  PubMed  Google Scholar 

  • Docagne F, Muñetón V, Clemente D, Ali C, Loría F, Correa F, Hernangómez M, Mestre L, Vivien D, Guaza C (2007) Excitotoxicity in a chronic model of multiple sclerosis: Neuroprotective effects of cannabinoidsthrough CB1 and CB2 receptor activation. Mol Cell Neurosci 34:551–561

    Article  CAS  PubMed  Google Scholar 

  • Eljaschewitsch E, Witting A, Mawrin C, Lee T, Schmidt PM, Wolf S, Hoertnagl H, Raine CS, Schneider-Stock R, Nitsch R, Ullrich O (2006) The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron 49:67–79

    Article  CAS  PubMed  Google Scholar 

  • El-Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai NJ, Roon P, Caldwell RB, Caldwell RW, Green K, Liou GI (2003) Neuroprotective effect of (−)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am J Pathol 163:1997–2008

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • ElSohly MA, Ross SA, Mehmedic Z, Arafat R, Yi B, Banahan BF (2000) Potency trends of delta9-Δ9-THC and other cannabinoids in confiscated marijuana from 1980–1997. J Forensic Sci 45:24–30

    CAS  PubMed  Google Scholar 

  • Espejo-Porras F, Fernández-Ruiz J, Pertwee RG, Mechoulam R, García C (2013) Motor effects of the non-psychotropic phytocannabinoidcannabidiol that are mediated by 5-HT1A receptors. Neuropharmacology 75:155–163

    Article  CAS  PubMed  Google Scholar 

  • European Monitoring Centre for Drugs and Drug Addiction (2008) A cannabis reader: global issues and local experiences, Monograph series 8, vol 1. European Monitoring Centre for Drugs and Drug Addiction, Lisbon

    Google Scholar 

  • Garthwaite G, Goodwin DA, Neale S, Riddall D, Garthwaite J (2002) Soluble guanylylcyclase activator YC-1 protects white matter axons from nitric oxide toxicity and metabolic stress, probably through Na(+) channel inhibition. Mol Pharmacol 61:97–104

    Article  CAS  PubMed  Google Scholar 

  • Giovannoni G, Baker D, Schmierer K (2015) The problems with repurposing: is there really an alternative to ‘Big Pharma’ for developing new drugs for MS? Mult Scler Rel Dis. doi:10.1016/j.msard.2014.11.005

  • Gnanapavan S, Grant D, Morant S, Furby J, Hayton T, Teunissen CE, Leoni V, Marta M, Brenner R, Palace J, Miller DH, Kapoor R, Giovannoni G (2013) Biomarker report from the phase II lamotrigine trial in secondary progressive MS - neurofilament as a surrogate of disease progression. PLoS One 8:e70019

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gunnarsson M, Malmeström C, Axelsson M, Sundström P, Dahle C, Vrethem M, Olsson T, Piehl F, Norgren N, Rosengren L, Svenningsson A, Lycke J (2011) Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol 69:83–89

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hasseldam H, Johansen FF (2010) Neuroprotection without immunomodulation is not sufficient to reduce first relapse severity in experimental autoimmune encephalomyelitis. Neuroimmunomodulation 17:252–264

    Article  CAS  PubMed  Google Scholar 

  • Hayakawa K, Mishima K, Nozako M, Hazekawa M, Irie K, Fujioka M, Orito K, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M (2007) Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism. J Neurochem 102:1488–1496

    Article  CAS  PubMed  Google Scholar 

  • Hernández-Torres G, Cipriano M, Hedén E, Björklund E, Canales A, Zian D, Feliú A, Mecha M, Guaza C, Fowler CJ, Ortega-Gutiérrez S, López-Rodríguez ML (2014) A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis. Angew Chem Int Ed Engl 53:13765–13770

    Article  PubMed  Google Scholar 

  • Hill AJ, Jones NA, Smith I, Hill CL, Williams CM, Stephens GJ, Whalley BJ (2014) Voltage-gated sodium (NaV) channel blockade by plant cannabinoids does not confer anticonvulsant effects per se. Neurosci Lett 566:269–274

    Article  CAS  PubMed  Google Scholar 

  • Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202

    Article  CAS  PubMed  Google Scholar 

  • Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, Russo E, Whalley BJ, Di Marzo V, Stephens GJ (2014) The non-psychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci 5:1131–1141

    Article  CAS  PubMed  Google Scholar 

  • Kapoor R, Furby J, Hayton T, Smith KJ, Altmann DR, Brenner R, Chataway J, Hughes RA, Miller DH (2010) Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol 9:681–688

    Article  CAS  PubMed  Google Scholar 

  • Katona S, Kaminski E, Sanders H, Zajicek J (2005) Cannabinoid influence on cytokine profile in multiple sclerosis. Clin Exp Immunol 140:580–585

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Killestein J, Hoogervorst EL, Reif M, Blauw B, Smits M, Uitdehaag BM, Nagelkerken L, Polman CH (2003) Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis. J Neuroimmunol 137:140–143

    Article  CAS  PubMed  Google Scholar 

  • Kozela E, Lev N, Kaushansky N, Eilam R, Rimmerman N, Levy R, Ben-Nun A, Juknat A, Vogel Z (2011) Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. Br J Pharmacol 16:1507–1519

    Article  Google Scholar 

  • Langford RM, Mares J, Novotna A, Vachova M, Novakova I, Notcutt W, Ratcliffe S (2013) A double-blind, randomized, placebo-controlled, parallel-group study of Δ9-THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. J Neurol 260:984–997

    Article  CAS  PubMed  Google Scholar 

  • Leray E, Yaouanq J, Le Page E, Coustans M, Laplaud D, Oger J, Edan G (2010) Evidence for a two-stage disability progression in multiple sclerosis. Brain 133:1900–1913

    Article  PubMed Central  PubMed  Google Scholar 

  • Lyman WD, Sonett JR, Brosnan CF, Elkin R, Bornstein MB (1989) Delta 9-tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J Neuroimmunol 23:73–81

    Article  CAS  PubMed  Google Scholar 

  • Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M (2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A 97:9561–9566

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Maresz K, Pryce G, Ponomarev ED, Marsicano G, Croxford JL, Shriver LP, Ledent C, Cheng X, Carrier EJ, Mann MK, Giovannoni G, Pertwee RG, Yamamura T, Buckley NE, Hillard CJ, Lutz B, Baker D, Dittel BN (2007) Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat Med 13:492–497

    Article  CAS  PubMed  Google Scholar 

  • Marta M, Giovannoni G (2012) Disease modifying drugs in multiple sclerosis: mechanisms of action and new drugs in the horizon.CNSNeurolDisord Drug. Targets 11:610–623

    CAS  Google Scholar 

  • Masullo L, Papas MA, Cotugna N, Baker S, Mahoney L, Trabulsi J (2015) Complementary and alternative medicine use and nutrient intake among individuals with multiple sclerosis in the United States. J Community Health. Jul 1.2014 [Epub ahead of print]

  • Mecha M, Torrao AS, Mestre L, Carrillo-Salinas FJ, Mechoulam R, Guaza C (2012) Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress. Cell Death Dis 3:e331

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mecha M, Feliú A, Iñigo PM, Mestre L, Carrillo-Salinas FJ, Guaza C (2013) Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiol Dis 59:141–150

    Article  CAS  PubMed  Google Scholar 

  • Mechoulam R, Parker LA, Gallily R (2002) Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol 42(11 Suppl):11S–19S

    Article  CAS  PubMed  Google Scholar 

  • Morsali D, Bechtold D, Lee W, Chauhdry S, Palchaudhuri U, Hassoon P, Snell DM, Malpass K, Piers T, Pocock J, Roach A, Smith KJ (2013) Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain 136:1067–1082

    Article  PubMed  Google Scholar 

  • Musella A, Sepman H, Mandolesi G, Gentile A, Fresegna D, Haji N, Conrad A, Lutz B, Maccarrone M, Centonze D (2014) Pre- and postsynaptic type-1 cannabinoid receptors control the alterations of glutamate transmission in experimental autoimmune encephalomyelitis. Neuropharmacology 79:567–572

    Article  CAS  PubMed  Google Scholar 

  • Nguyen BM, Kim D, Bricker S, Bongard F, Neville A, Putnam B, Smith J, Plurad D (2014) Effect of marijuana use on outcomes in traumatic brain injury. Am Surg 80:979–983

    PubMed  Google Scholar 

  • Novotna A, Mares J, Ratcliffe S, Novakova I, Vachova M, Zapletalova O, Gasperini C, Pozzilli C, Cefaro L, Comi G, Rossi P, Ambler Z, Stelmasiak Z, Erdmann A, Montalban X, Klimek A, Davies P, Sativex Spasticity Study Group (2011) A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex(®)), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol 18:1122–1131

    Article  CAS  PubMed  Google Scholar 

  • Oliviero A, Arevalo-Martin A, Rotondi M, García-Ovejero D, Mordillo-Mateos L, Lozano-Sicilia A, Panyavin I, Chiovato L, Aguilar J, Foffani G, Di Lazzaro V, Molina-Holgado E (2012) CB1 receptor antagonism/inverse agonism increases motor system excitability in humans. Eur Neuropsychopharmacol 22:27–35

    Article  CAS  PubMed  Google Scholar 

  • Pauwels PJ, Leysen JE, Laduron PM (1986) [3H]Batrachotoxinin A 20-alpha-benzoate binding to sodium channels in rat brain: characterization and pharmacological significance. Eur J Pharmacol 124:291–298

    Article  CAS  PubMed  Google Scholar 

  • Pryce G, Baker D (2007) Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors. Br J Pharmacol 150:519–525

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pryce G, Ahmed Z, Hankey DJ, Jackson SJ, Croxford JL, Pocock JM, Ledent C, Petzold A, Thompson AJ, Giovannoni G, Cuzner ML, Baker D (2003) Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 126:2191–2202

    Article  PubMed  Google Scholar 

  • Pryce G, Visintin C, Ramagopalan SV, Al-Izki S, De Faveri LE, Nuamah RA, Mein CA, Montpetit A, Hardcastle AJ, Kooij G, de Vries HE, Amor S, Thomas SA, Ledent C, Marsicano G, Lutz B, Thompson AJ, Selwood DL, Giovannoni G, Baker D (2014) Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists. FASEB J 28:117–130

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro R, Yu F, Wen J, Vana A, Zhang Y (2013) herapeutic potential of a novel cannabinoid agent CB52 in the mouse model of experimental autoimmune encephalomyelitis. Neuroscience 254:427–442

    Article  CAS  PubMed  Google Scholar 

  • Rossi S, Furlan R, De Chiara V, Muzio L, Musella A, Motta C, Studer V, Cavasinni F, Bernardi G, Martino G, Cravatt BF, Lutz B, Maccarrone M, Centonze D (2011a) Cannabinoid CB1 receptors regulate neuronal TNF-α effects in experimental autoimmune encephalomyelitis. Brain Behav Immun 25:1242–1248

    Article  CAS  PubMed  Google Scholar 

  • Rossi S, Buttari F, Studer V, Motta C, Gravina P, Castelli M, Mantovani V, De Chiara V, Musella A, Fiore S, Masini S, Bernardi G, Maccarrone M, Bernardini S, Centonze D (2011b) The (AAT)n repeat of the cannabinoid CB1 receptor gene influences disease progression inrelapsing multiple sclerosis. Mult Scler 17:281–288

    Article  CAS  PubMed  Google Scholar 

  • Rossi S, Bozzali M, Bari M, Mori F, Studer V, Motta C, Buttari F, Cercignani M, Gravina P, Mastrangelo N, Castelli M, Mancino R, Nucci C, Sottile F, Bernardini S, Maccarrone M, Centonze D (2013) Association between a genetic variant of type-1 cannabinoid receptor and inflammatory neurodegeneration in multiple sclerosis. PLoS One 8(12):e82848

    Article  PubMed Central  PubMed  Google Scholar 

  • Russo E, Guy GW (2006) A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 66:234–246

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Sexton M, Cudaback E, Abdullah RA, Finnell J, Mischley LK, Rozga M, Lichtman AH, Stella N (2014) Cannabis use by individuals with multiple sclerosis: effects on specific immune parameters. Inflammopharmacology 2014(22):295–303

    Article  Google Scholar 

  • Sisay S, Pryce G, Jackson SJ, Tanner C, Ross RA, Michael GJ, Selwood DL, Giovannoni G, Baker D (2013) Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis. PLoS One 8(10):e76907

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150:613–623

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vann RE, Gamage TF, Warner JA, Marshall EM, Taylor NL, Martin BR, Wiley JL (2008) Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Delta(9)-tetrahydrocannabinol. Drug Alcohol Depend 94:191–198

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Varvel SA, Wiley JL, Yang R, Bridgen DT, Long K, Lichtman AH, Martin BR (2006) Interactions between Δ9-THC and cannabidiol in mouse models of cannabinoid activity. Psychopharmacology 186:226–234

    Article  CAS  PubMed  Google Scholar 

  • Wade DT, Robson P, House H, Makela P, Aram J (2003) A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil 17:21–219

    Article  PubMed  Google Scholar 

  • Waxman SG (2002) Sodium channels as molecular targets in multiple sclerosis. J Rehabil Res Dev 39:233–242

    PubMed  Google Scholar 

  • Webb M, Luo L, Ma JY, Tham CS (2008) Genetic deletion of Fatty Acid Amide Hydrolase results in improved long-term outcome in chronic autoimmune encephalitis. Neurosci Lett 439:106–110

    Article  CAS  PubMed  Google Scholar 

  • Wilkinson JD, Whalley BJ, Baker D, Pryce G, Constanti A, Gibbons S, Williamson EM (2003) Medicinal cannabis: is delta9-tetrahydrocannabinol necessary for all its effects? J Pharm Pharmacol 55:1687–1694

    Article  CAS  PubMed  Google Scholar 

  • Yadav V, Bever C Jr, Bowen J, Bowling A, Weinstock-Guttman B, Cameron M, Bourdette D, Gronseth GS, Narayanaswami P (2014) Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology 82:1083–1092

    Article  PubMed Central  PubMed  Google Scholar 

  • Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, Thompson A, UK MS Research Group (2003) Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 362:1517–1526

    Article  CAS  PubMed  Google Scholar 

  • Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, Nunn AJ, Teare LJ, Fox PJ, Thompson AJ (2005) Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up.J NeurolNeurosurg. Psychiatry 76:1664–1669

    CAS  Google Scholar 

  • Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG, MUSEC Research Group (2012) Multiple sclerosis and extract of cannabis: results of the MUSEC trial.J NeurolNeurosurg. Psychiatry 83:1125–1132

    Google Scholar 

  • Zajicek J, Ball S, Wright D, Vickery J, Nunn A, Miller D, Gomez Cano M, McManus D, Mallik S, Hobart J, CUPID investigator group (2013) Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol 12:857–865

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the support of the National MS Society (USA) and the MS Society (UK). We thank Prof. John Zajicek and Susan Ball, Plymouth, UK for providing access to data from the CUPID trial.

Conflicts of Interest

None.

Author information

Authors and Affiliations

  1. Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK

    Gareth Pryce, Gavin Giovannoni & David Baker

  2. Wolfson Institute of Biomedical Research, University College London, London, UK

    Dieter R. Riddall & David L. Selwood

Authors
  1. Gareth Pryce
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dieter R. Riddall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David L. Selwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gavin Giovannoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Baker.

Additional information

Materials and Methods

Induction of autoimmune experimental encephalomyelitis protocols consistent with the ARRIVE guidelines have been published previously (Al-Izki et al. 2012; Baker and Amor 2012). Animal studies were approved following local ethical and United Kingdom Government, Home Office review in accordance with the United Kingdom Animals (Scientific Procedures) Act 1986. Full working protocols of the methods and doses and use of cannabinoids in animals have been reported previously (Pryce et al. 2003; Croxford et al. 2008; Al-Izki et al. 2012). Briefly, 6–8 week adult Biozzi ABH mice (Al-Izki et al. 2012) were injected with spinal cord homogenate in Freunds adjuvant on day 0 and 7 to induce experimental autoimmune encephalomyelitis with onset around day 15–19 post-inoculation (p.i.) and again during remission from paralytic attack on day 28 p.i. to induce a relapse 7–8 days later (Al-Izki et al. 2012). Animals were scored daily: 0 = normal; 1 = limp tail; 2 = impaired righting reflex; 3 = hindlimb paresis; 4 = hindlimb paralysis; 5 = moribund. Scores were assessed using Mann Whitney U statistics (Al-Izki et al. 2012). The motor co-ordination was assessed on an accelerating (0–40 rpm/5 min) rotorod and analysed using Students t test following normality and equal variance tests (Al-Izki et al.2012). Synthetic Δ9-THC and CBD were purchased from Δ9-THC Pharm GmbH. Frankfurt, Germany and were diluted in alcohol:cremophor:phosphate buffered saline (1:1:18). Various doses injected in 0.1 ml intraperitioneally (i.p). as described previously (Pryce et al. 2003; Croxford et al. 2008). These were administered shortly before anticipated relapse (Al-Izki et al. 2012, 2014).

Veratrine induced flux of [ 14 C]guanidine in synaptosomes has been reported previously (Pauwels et al. 1986; Garthwaite et al. 2002). Briefly veratrine (100 μg/ml final concentration), and rat cerebral cortex synaptosomes (4 mg/ml, wet weight) were incubated in the absence or presence of compound at 37 °C for 5 min in polypropylene test tubes. Uptake was initiated by the addition of pre-warmed [14C]-guanidine (final concentration 1 μCi/ml) and stopped 2 min later by the addition of 10 ml of ice-cold wash medium as described previously (Pauwels et al. 1986). Incubates were immediately filtered under vacuum through GF/C filters by using a Brandel harvester. The incubation tubes were rinsed with 5 ml of ice-cold wash buffer, which was then used to wash the filter. Filters were transferred to minivials (Beckman Coulter, Fullerton, CA) with the use of a Brandel deposit/dispense system and subsequently counted by liquid scintillation spectroscopy with Picofluor40 liquid scintillator (Garthwaite et al. 2002). Cannabidiol; YC-1 (5-[1-phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol (Cayman, Chem Ann Arbor, Michigan, USA); Nabilone (Cambridge Labs; Newcastle, UK); Lamotrigine (6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine. Tocris, Bristol, UK) and Sipatrigine (BW619C89. 2-(4-Methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)-4-pyrimidinamine. Tocris Ltd) were diluted with medium from 10 mM stock solutions.

Batrachotoxin-B (BTX-B) Binding. This was performed as described previously (Garthwaite et al. 2002). Binding was initiated by the addition of synaptosomes (final concentration 10 mg/ml, wet weight) to a mixture of test compound and 10 nM [3H]Batrachotoxin-B in the absence or presence of scorpion venom (25 μg/ml final concentration). Samples were mixed and incubated for 90 min at 25 °C. Ice-cold wash medium (5 ml) was added and then the samples subjected to vacuum filtration through GF/C filters by using a Brandel harvester. Incubation tubes were rinsed with 5 ml of ice-cold wash buffer, which was then used to wash the filter. Radioactivity in the filter was counted as described above.

Randomised, double-blind, placebo-controlled trial of Δ9-THC in people with progressive MS has been reported previously (Zajicek et al. 2013), with an International Standard Randomised Controlled Trial number 62942668. Human studies were approved by the South and West Devon Research Ethics Committee and done in accordance with Good Clinical Practice guidelines. Eligible patients provided written informed consent before participation as International Standard Randomised Controlled Trial (ISRCTN 62942668). Briefly, 18–65 year old humans with primary or secondary progressive MS (Expanded disability status scale (EDSS) Score4.0–6.5), not on current disease modifying therapy (DMT), were enrolled into the study. These were randomised to oral dronabinol (Δ9-THC) starting at 3.5 mg twice a day escalated to a maximum of 28 mg/day depending on tolerability (n = 329) or vegetable oil placebo in gelatin capsules (n = 164). These were supplied by Insys Therapeutics (Phoenix, AZ, USA). Analysis of the total population (n = 493) or subgroup analysis on time to progression in those participants with a baseline EDSS score of 5 · 5 or lower (n = 110) was performed using a log-rank test to compare probability of progression between treatment groups (Zajicek et al. 2013).

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 18 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pryce, G., Riddall, D.R., Selwood, D.L. et al. Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids. J Neuroimmune Pharmacol 10, 281–292 (2015). https://doi.org/10.1007/s11481-014-9575-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-014-9575-8

Keywords

Search

Navigation