Skip to main content

Cannabidiol and Cannabinoid Compounds as Potential Strategies for Treating Parkinson’s Disease and l-DOPA-Induced Dyskinesia

Abstract

Parkinson’s disease (PD) and l-DOPA-induced dyskinesia (LID) are motor disorders with significant impact on the patient’s quality of life. Unfortunately, pharmacological treatments that improve these disorders without causing severe side effects are not yet available. Delay in initiating l-DOPA is no longer recommended as LID development is a function of disease duration rather than cumulative l-DOPA exposure. Manipulation of the endocannabinoid system could be a promising therapy to control PD and LID symptoms. In this way, phytocannabinoids and synthetic cannabinoids, such as cannabidiol (CBD), the principal non-psychotomimetic constituent of the Cannabis sativa plant, have received considerable attention in the last decade. In this review, we present clinical and preclinical evidence suggesting CBD and other cannabinoids have therapeutic effects in PD and LID. Here, we discuss CBD pharmacology, as well as its neuroprotective effects and those of other cannabinoids. Finally, we discuss the modulation of several pro- or anti-inflammatory factors as possible mechanisms responsible for the therapeutic/neuroprotective potential of Cannabis-derived/cannabinoid synthetic compounds in motor disorders.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

Abbreviations

2-AG:

2-Arachidonoylglicerol

6-OHDA:

6-Hydroxydopamine

AEA:

Anandamide

AIMs:

Abnormal involuntary movements

AMT:

Anandamide membrane transporter

cAMP:

Cyclic adenosine monophosphate

CBD:

Cannabidiol

COX-2:

Cyclooxygenase-2

CPZ:

Capsazepine

CREB:

cAMP response element-binding protein

ERK:

Extracellular signal-regulated kinase

FAAH:

Fatty acid amide hydrolase

IL-1β:

Interleukin-1β

LID:

l-DOPA-induced dyskinesia

MAGL:

Monoacylglycerol lipase

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NF-κB:

Nuclear factor κB

PD:

Parkinson’s disease

PKA:

Protein kinase A

PPAR:

Peroxisome proliferator-activated receptor

SN:

Substantia nigra

SNpc:

Substantia nigra pars compacta

SNpr:

Substantia nigra pars reticulata

THC:

Tetrahydrocannabinol

THCV:

Tetrahydrocannabivarin

TNF-α:

Tumor necrosis factor-α

TRPV:

Transient receptor potential vanilloid receptor

References

  • Adams R, Madison H (1940) Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. J Am Chem Soc 62:196–200

    CAS  Article  Google Scholar 

  • Ahmed I, Bose SK, Pavese N, Ramlackhansingh A, Turkheimer F, Hotton G, Hammers A, Brooks DJ (2011) Glutamate NMDA receptor dysregulation in Parkinson’s disease with dyskinesias. Brain J Neurol 134:979–986

    Article  Google Scholar 

  • Ahrens J, Demir R, Leuwer M, de la Roche J, Krampfl K, Foadi N, Karst M, Haeseler G (2009) The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-beta glycine receptor function. Pharmacology 83:217–222

    CAS  PubMed  Article  Google Scholar 

  • Allam MF, Campbell MJ, Hofman A, Del Castillo AS, Fernandez-Crehuet Navajas R (2004) Smoking and Parkinson’s disease: systematic review of prospective studies. Mov Disord 19:614–621

    PubMed  Article  Google Scholar 

  • Ameri A (1999) The effects of cannabinoids on the brain. Prog Neurobiol 58:315–348

    CAS  PubMed  Article  Google Scholar 

  • Ascherio A, Chen H, Schwarzschild MA, Zhang SM, Colditz GA, Speizer FE (2003) Caffeine, postmenopausal estrogen, and risk of Parkinson’s disease. Neurology 60:790–795

    CAS  Article  PubMed  Google Scholar 

  • Ascherio A, Weisskopf MG, O'Reilly EJ, McCullough ML, Calle EE, Rodriguez C, Thun MJ (2004) Coffee consumption, gender, and Parkinson’s disease mortality in the cancer prevention study II cohort: the modifying effects of estrogen. Am J Epidemiol 160:977–984

    PubMed  Article  Google Scholar 

  • Ashton JC (2007) Cannabinoids for the treatment of inflammation. Curr Opin Investig Drugs 8:373–384

    CAS  PubMed  Google Scholar 

  • Atakan Z (2012) Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharmacol 2:241–254

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Aymerich MS, Aso E, Abellanas MA, Tolon RM, Ramos JA, Ferrer I, Romero J, Fernandez-Ruiz J (2018) Cannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system. Biochem Pharmacol

  • Baldwin AS Jr (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683

    CAS  PubMed  Article  Google Scholar 

  • Barish GD (2006) Peroxisome proliferator-activated receptors and liver X receptors in atherosclerosis and immunity. J Nutr 136:690–694

    CAS  PubMed  Article  Google Scholar 

  • Barnum CJ, Eskow KL, Dupre K, Blandino P Jr, Deak T, Bishop C (2008) Exogenous corticosterone reduces L-DOPA-induced dyskinesia in the hemi-parkinsonian rat: role for interleukin-1beta. Neuroscience 156:30–41

    CAS  PubMed  Article  Google Scholar 

  • Baune BT, Wiede F, Braun A, Golledge J, Arolt V, Koerner H (2008) Cognitive dysfunction in mice deficient for TNF- and its receptors. Am J Med Genet B Neuropsychiatr Genet 147B:1056–1064

    CAS  PubMed  Article  Google Scholar 

  • Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC (2002) Control of synaptic strength by glial TNFalpha. Science 295:2282–2285

    CAS  PubMed  Article  Google Scholar 

  • Benarroch E (2007) Endocannabinoids in basal ganglia circuits: implications for Parkinson disease. Neurology 69:306–309

    PubMed  Article  Google Scholar 

  • Bezard E, Gross CE, Qin L, Gurevich VV, Benovic JL, Gurevich EV (2005) L-DOPA reverses the MPTP-induced elevation of the arrestin2 and GRK6 expression and enhanced ERK activation in monkey brain. Neurobiol Dis 18:323–335

    CAS  PubMed  Article  Google Scholar 

  • Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134:845–852

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Blandini F (2003) Adenosine receptors and L-DOPA-induced dyskinesia in Parkinson’s disease: potential targets for a new therapeutic approach. Exp Neurol 184:556–560

    CAS  PubMed  Article  Google Scholar 

  • Blanpied TA, Clarke RJ, Johnson JW (2005) Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J Neurosci 25:3312–3322

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Bloom AS, Hillard CJ (1985) Cannabinoids, neurotransmitter receptors and brain membranes. In: Harvey DJ (ed) Marihuana ‘84. IRL Press, Oxford, pp 217–231

    Google Scholar 

  • Bornheim LM, Everhart ET, Li J, Correia MA (1993) Characterization of cannabidiol-mediated cytochrome P450 inactivation. Biochem Pharmacol 45:1323–1331

    CAS  PubMed  Article  Google Scholar 

  • Bornheim LM, Kim KY, Li J, Perotti BY, Benet LZ (1995) Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain. Drug Metab Dispos 23:825–831

    CAS  PubMed  Google Scholar 

  • Bortolanza M, Cavalcanti-Kiwiatkoski R, Padovan-Neto FE, da-Silva CA, Mitkovski M, Raisman-Vozari R, Del-Bel E (2015a) Glial activation is associated with l-DOPA induced dyskinesia and blocked by a nitric oxide synthase inhibitor in a rat model of Parkinson’s disease. Neurobiol Dis 73:377–387

    CAS  PubMed  Article  Google Scholar 

  • Bortolanza M, Padovan-Neto FE, Cavalcanti-Kiwiatkoski R, Dos Santos-Pereira M, Mitkovski M, Raisman-Vozari R, Del-Bel E (2015b) Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson’s disease induced by L-DOPA? Philos Trans R Soc Lond Ser B Biol Sci 370

  • Bortolanza M, Nascimento GC, Socias SB, Ploper D, Chehin RN, Raisman-Vozari R, Del-Bel E (2018) Tetracycline repurposing in neurodegeneration: focus on Parkinson’s disease. J Neural Transm (Vienna) 125:1403–1415

    CAS  Article  Google Scholar 

  • Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM, Hirsch EC (2002) Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson’s disease. J Neurochem 82:615–624

    CAS  PubMed  Article  Google Scholar 

  • Brotchie JM (2003) CB1 cannabinoid receptor signalling in Parkinson’s disease. Curr Opin Pharmacol 3:54–61

    CAS  PubMed  Article  Google Scholar 

  • Buhmann C, Mainka T, Ebersbach G, Gandor F (2019) Evidence for the use of cannabinoids in Parkinson’s disease. J Neural Transm

  • Cadas H, di Tomaso E, Piomelli D (1997) Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J Neurosci 17:1226–1242

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Calabresi P, Ghiglieri V, Mazzocchetti P, Corbelli I, Picconi B (2015) Levodopa-induced plasticity: a double-edged sword in Parkinson’s disease? Philos Trans R Soc Lond Ser B Biol Sci 370

    Article  CAS  Google Scholar 

  • Campos AC, Fogaca MV, Sonego AB, Guimaraes FS (2016) Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res 112:119–127

    CAS  PubMed  Article  Google Scholar 

  • Cao X, Liang L, Hadcock JR, Iredale PA, Griffith DA, Menniti FS, Factor S, Greenamyre JT, Papa SM (2007) Blockade of cannabinoid type 1 receptors augments the antiparkinsonian action of levodopa without affecting dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys. J Pharmacol Exp Ther 323:318–326

    CAS  PubMed  Article  Google Scholar 

  • Carrier EJ, Auchampach JA, Hillard CJ (2006) Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A 103:7895–7900

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Carroll CB, Bain PG, Teare L, Liu X, Joint C, Wroath C, Parkin SG, Fox P, Wright D, Hobart J, Zajicek JP (2004) Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study. Neurology 63:1245–1250

    CAS  PubMed  Article  Google Scholar 

  • Carroll CB, Zeissler ML, Hanemann CO, Zajicek JP (2012) Delta(9)-tetrahydrocannabinol (delta(9)-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson’s disease. Neuropathol Appl Neurobiol 38:535–547

    CAS  PubMed  Article  Google Scholar 

  • Carta M, Tronci E (2014) Serotonin system implication in l-DOPA-induced dyskinesia: from animal models to clinical investigations. Front Neurol 5:78

    PubMed  PubMed Central  Article  Google Scholar 

  • Carta AR, Frau L, Pisanu A, Wardas J, Spiga S, Carboni E (2011a) Rosiglitazone decreases peroxisome proliferator receptor-gamma levels in microglia and inhibits TNF-alpha production: new evidences on neuroprotection in a progressive Parkinson’s disease model. Neuroscience 194:250–261

    CAS  PubMed  Article  Google Scholar 

  • Carta AR, Pisanu A, Carboni E (2011b) Do PPAR-gamma agonists have a future in Parkinson’s disease therapy? Parkinsons Dis 2011:689181

    PubMed  PubMed Central  Google Scholar 

  • Carta AR, Mulas G, Bortolanza M, Duarte T, Pillai E, Fisone G, Vozari RR, Del-Bel E (2017) L-DOPA-induced dyskinesia and neuroinflammation: do microglia and astrocytes play a role? Eur J Neurosci 45:73–91

    PubMed  Article  Google Scholar 

  • Castillo A, Tolon MR, Fernandez-Ruiz J, Romero J, Martinez-Orgado J (2010) The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol Dis 37:434–440

    CAS  PubMed  Article  Google Scholar 

  • Catlow B, Sanchez-Ramos J (2015) Cannabinoids for the treatment of movement disorders. Curr Treat Options Neurol 17:370

    PubMed  Article  Google Scholar 

  • Celorrio M, Fernandez-Suarez D, Rojo-Bustamante E, Echeverry-Alzate V, Ramirez MJ, Hillard CJ, Lopez-Moreno JA, Maldonado R, Oyarzabal J, Franco R, Aymerich MS (2016) Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson’s disease. Brain Behav Immun 57:94–105

    CAS  PubMed  Article  Google Scholar 

  • Cenci MA, Konradi C (2010) Maladaptive striatal plasticity in L-DOPA-induced dyskinesia. Prog Brain Res 183:209–233

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Cenci MA, Ohlin KE, Rylander D (2009) Plastic effects of L-DOPA treatment in the basal ganglia and their relevance to the development of dyskinesia. Parkinsonism Relat Disord 15(Suppl 3):S59–S63

    PubMed  Article  Google Scholar 

  • Cerovic M, Bagetta V, Pendolino V, Ghiglieri V, Fasano S, Morella I, Hardingham N, Heuer A, Papale A, Marchisella F, Giampa C, Calabresi P, Picconi B, Brambilla R (2015) Derangement of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and extracellular signal-regulated kinase (ERK) dependent striatal plasticity in L-DOPA-induced dyskinesia. Biol Psychiatry 77:106–115

    CAS  PubMed  Article  Google Scholar 

  • Chagas MH, Eckeli AL, Zuardi AW, Pena-Pereira MA, Sobreira-Neto MA, Sobreira ET, Camilo MR, Bergamaschi MM, Schenck CH, Hallak JE, Tumas V, Crippa JA (2014a) Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson’s disease patients: a case series. J Clin Pharm Ther 39:564–566

    CAS  PubMed  Article  Google Scholar 

  • Chagas MH, Zuardi AW, Tumas V, Pena-Pereira MA, Sobreira ET, Bergamaschi MM, dos Santos AC, Teixeira AL, Hallak JE, Crippa JA (2014b) Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol 28:1088–1098

    PubMed  Article  CAS  Google Scholar 

  • Chiang IT, Liu YC, Wang WH, Hsu FT, Chen HW, Lin WJ, Chang WY, Hwang JJ (2012) Sorafenib inhibits TPA-induced MMP-9 and VEGF expression via suppression of ERK/NF-kappaB pathway in hepatocellular carcinoma cells. In vivo 26:671–681

    CAS  PubMed  Google Scholar 

  • Chung YC, Bok E, Huh SH, Park JY, Yoon SH, Kim SR, Kim YS, Maeng S, Park SH, Jin BK (2011) Cannabinoid receptor type 1 protects nigrostriatal dopaminergic neurons against MPTP neurotoxicity by inhibiting microglial activation. J Immunol 187:6508–6517

    CAS  PubMed  Article  Google Scholar 

  • Citraro R, Russo E, Scicchitano F, van Rijn CM, Cosco D, Avagliano C, Russo R, D’Agostino G, Petrosino S, Guida F, Gatta L, van Luijtelaar G, Maione S, Di Marzo V, Calignano A, De Sarro G (2013) Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-alpha receptor activation in a genetic model of absence epilepsy. Neuropharmacology 69:115–126

    CAS  PubMed  Article  Google Scholar 

  • Colosimo C, Craus A (2003) Noradrenergic drugs for levodopa-induced dyskinesia. Clin Neuropharmacol 26:299–305

    CAS  PubMed  Article  Google Scholar 

  • Consroe P, Sandyk R, Snider SR (1986) Open label evaluation of cannabidiol in dystonic movement disorders. Int J Neurosci 30:277–282

    CAS  PubMed  Article  Google Scholar 

  • Cools R, Lewis SJ, Clark L, Barker RA, Robbins TW (2007) L-DOPA disrupts activity in the nucleus accumbens during reversal learning in Parkinson’s disease. Neuropsychopharmacology 32:180–189

    CAS  PubMed  Article  Google Scholar 

  • Costa B, Colleoni M, Conti S, Parolaro D, Franke C, Trovato AE, Giagnoni G (2004) Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedeberg's Arch Pharmacol 369:294–299

    CAS  Article  Google Scholar 

  • Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87

    CAS  PubMed  Article  Google Scholar 

  • Crippa JAS, Hallak JEC, Zuardi AW, Guimaraes FS, Tumas V, Dos Santos RG (2019) Is cannabidiol the ideal drug to treat non-motor Parkinson’s disease symptoms? Eur Arch Psychiatry Clin Neurosci 269:121–133

    PubMed  Article  Google Scholar 

  • Cristino L, de Petrocellis L, Pryce G, Baker D, Guglielmotti V, Di Marzo V (2006) Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience 139:1405–1415

    CAS  PubMed  Article  Google Scholar 

  • Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 25:9275–9284

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • de Lago E, de Miguel R, Lastres-Becker I, Ramos JA, Fernandez-Ruiz J (2004) Involvement of vanilloid-like receptors in the effects of anandamide on motor behavior and nigrostriatal dopaminergic activity: in vivo and in vitro evidence. Brain Res 1007:152–159

    PubMed  Article  CAS  Google Scholar 

  • De Petrocellis L, Ligresti A, Moriello AS, Allara M, Bisogno T, Petrosino S, Stott CG, Di Marzo V (2011) Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 163:1479–1494

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Del-Bel E, Padovan-Neto FE, Bortolanza M, Tumas V, Aguiar AS Jr, Raisman-Vozari R, Prediger RD (2015) Nitric oxide, a new player in L-DOPA-induced dyskinesia. Front Biosci 7:168–192

    Article  Google Scholar 

  • Del-Bel E, Bortolanza M, Dos-Santos-Pereira M, Bariotto K, Raisman-Vozari R (2016) L-DOPA-induced dyskinesia in Parkinson’s disease: are neuroinflammation and astrocytes key elements? Synapse 70:479–500

    CAS  PubMed  Article  Google Scholar 

  • Desarnaud F, Cadas H, Piomelli D (1995) Anandamide amidohydrolase activity in rat brain microsomes. Identification and partial characterization. J Biol Chem 270:6030–6035

    CAS  PubMed  Article  Google Scholar 

  • Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613

    CAS  PubMed  Google Scholar 

  • Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949

    CAS  PubMed  Article  Google Scholar 

  • Di Filippo M, Pini LA, Pelliccioli GP, Calabresi P, Sarchielli P (2008) Abnormalities in the cerebrospinal fluid levels of endocannabinoids in multiple sclerosis. J Neurol Neurosurg Psychiatry 79:1224–1229

    PubMed  Article  Google Scholar 

  • Di Marzo V, De Petrocellis L (2012) Why do cannabinoid receptors have more than one endogenous ligand? Philos Trans R Soc Lond Ser B Biol Sci 367:3216–3228

    Article  CAS  Google Scholar 

  • Di Marzo V, Bisogno T, De Petrocellis L (2001) Anandamide: some like it hot. Trends Pharmacol Sci 22:346–349

    PubMed  Article  Google Scholar 

  • Domercq M, Vazquez-Villoldo N, Matute C (2013) Neurotransmitter signaling in the pathophysiology of microglia. Front Cell Neurosci 7:49

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dos-Santos-Pereira M, da-Silva CA, Guimaraes FS, Del-Bel E (2016) Co-administration of cannabidiol and capsazepine reduces L-DOPA-induced dyskinesia in mice: possible mechanism of action. Neurobiol Dis 94:179–195

    CAS  PubMed  Article  Google Scholar 

  • Du H, Chen X, Zhang J, Chen C (2011) Inhibition of COX-2 expression by endocannabinoid 2-arachidonoylglycerol is mediated via PPAR-gamma. Br J Pharmacol 163:1533–1549

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Elbaz A, Tranchant C (2007) Epidemiologic studies of environmental exposures in Parkinson’s disease. J Neurol Sci 262:37–44

    PubMed  Article  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

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  • Esposito G, De Filippis D, Maiuri MC, De Stefano D, Carnuccio R, Iuvone T (2006) Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement. Neurosci Lett 399:91–95

    CAS  PubMed  Article  Google Scholar 

  • Fakhfouri G, Ahmadiani A, Rahimian R, Grolla AA, Moradi F, Haeri A (2012) WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-gamma pathway. Neuropharmacology 63:653–666

    CAS  PubMed  Article  Google Scholar 

  • Farber K, Kettenmann H (2005) Physiology of microglial cells. Brain Res Brain Res Rev 48:133–143

    PubMed  Article  CAS  Google Scholar 

  • Feigin A, Ghilardi MF, Carbon M, Edwards C, Fukuda M, Dhawan V, Margouleff C, Ghez C, Eidelberg D (2003) Effects of levodopa on motor sequence learning in Parkinson’s disease. Neurology 60:1744–1749

    CAS  PubMed  Article  Google Scholar 

  • Fernandez-Espejo E, Caraballo I, de Fonseca FR, El Banoua F, Ferrer B, Flores JA, Galan-Rodriguez B (2005) Cannabinoid CB1 antagonists possess antiparkinsonian efficacy only in rats with very severe nigral lesion in experimental parkinsonism. Neurobiol Dis 18:591–601

    CAS  PubMed  Article  Google Scholar 

  • zcccxcx

  • Fernandez-Ruiz J, Sagredo O, Pazos MR, Garcia C, Pertwee R, Mechoulam R, Martinez-Orgado J (2013) Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? Br J Clin Pharmacol 75:323–333

    CAS  PubMed  Article  Google Scholar 

  • Fernandez-Ruiz J, Romero J, Ramos JA (2015) Endocannabinoids and neurodegenerative disorders: Parkinson’s disease, Huntington’s chorea, Alzheimer’s disease, and others. Handb Exp Pharmacol 231:233–259

    CAS  PubMed  Article  Google Scholar 

  • Fernandez-Suarez D, Celorrio M, Riezu-Boj JI, Ugarte A, Pacheco R, Gonzalez H, Oyarzabal J, Hillard CJ, Franco R, Aymerich MS (2014) Monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model. Neurobiol Aging 35:2603–2616

    CAS  PubMed  Article  Google Scholar 

  • Finseth TA, Hedeman JL, Brown RP 2nd, Johnson KI, Binder MS, Kluger BM (2015) Self-reported efficacy of cannabis and other complementary medicine modalities by Parkinson’s disease patients in Colorado. Evid Based Complement Alternat Med 2015:874849

    PubMed  PubMed Central  Article  Google Scholar 

  • Fischedick JT, Hazekamp A, Erkelens T, Choi YH, Verpoorte R (2010) Metabolic fingerprinting of Cannabis sativa L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes. Phytochemistry 71:2058–2073

    CAS  PubMed  Article  Google Scholar 

  • Fox SH, Henry B, Hill M, Crossman A, Brotchie J (2002) Stimulation of cannabinoid receptors reduces levodopa-induced dyskinesia in the MPTP-lesioned nonhuman primate model of Parkinson’s disease. Mov Disord 17:1180–1187

    PubMed  Article  Google Scholar 

  • Fusco FR, Martorana A, Giampa C, De March Z, Farini D, D'Angelo V, Sancesario G, Bernardi G (2004) Immunolocalization of CB1 receptor in rat striatal neurons: a confocal microscopy study. Synapse 53:159–167

    CAS  PubMed  Article  Google Scholar 

  • Galve-Roperh I, Chiurchiu V, Diaz-Alonso J, Bari M, Guzman M, Maccarrone M (2013) Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog Lipid Res 52:633–650

    CAS  PubMed  Article  Google Scholar 

  • Gao HM, Liu B, Zhang W, Hong JS (2003) Novel anti-inflammatory therapy for Parkinson’s disease. Trends Pharmacol Sci 24:395–401

    CAS  PubMed  Article  Google Scholar 

  • Garcia C, Palomo-Garo C, Garcia-Arencibia M, Ramos J, Pertwee R, Fernandez-Ruiz J (2011) Symptom-relieving and neuroprotective effects of the phytocannabinoid Delta(9)-THCV in animal models of Parkinson’s disease. Br J Pharmacol 163:1495–1506

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • 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

    CAS  PubMed  Article  Google Scholar 

  • Gasparini C, Feldmann M (2012) NF-kappaB as a target for modulating inflammatory responses. Curr Pharm Des 18:5735–5745

    CAS  PubMed  Article  Google Scholar 

  • Gerdeman G, Lovinger DM (2001) CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J Neurophysiol 85:468–471

    CAS  PubMed  Article  Google Scholar 

  • Gerdeman GL, Ronesi J, Lovinger DM (2002) Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci 5:446–451

    CAS  PubMed  Article  Google Scholar 

  • Gilbert GL, Kim HJ, Waataja JJ, Thayer SA (2007) Delta9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity. Brain Res 1128:61–69

    CAS  PubMed  Article  Google Scholar 

  • Gilgun-Sherki Y, Melamed E, Mechoulam R, Offen D (2003) The CB1 cannabinoid receptor agonist, HU-210, reduces levodopa-induced rotations in 6-hydroxydopamine-lesioned rats. Pharmacol Toxicol 93:66–70

    CAS  PubMed  Article  Google Scholar 

  • Giuffrida A, Parsons LH, Kerr TM, Rodriguez de Fonseca F, Navarro M, Piomelli D (1999) Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci 2:358–363

    CAS  PubMed  Article  Google Scholar 

  • Glass M, Dragunow M, Faull RL (2000) The pattern of neurodegeneration in Huntington’s disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease. Neuroscience 97:505–519

    CAS  PubMed  Article  Google Scholar 

  • Gomez-Galvez Y, Palomo-Garo C, Fernandez-Ruiz J, Garcia C (2016) Potential of the cannabinoid CB(2) receptor as a pharmacological target against inflammation in Parkinson’s disease. Prog Neuro-Psychopharmacol Biol Psychiatry 64:200–208

    CAS  Article  Google Scholar 

  • Gonzalez S, Scorticati C, Garcia-Arencibia M, de Miguel R, Ramos JA, Fernandez-Ruiz J (2006) Effects of rimonabant, a selective cannabinoid CB1 receptor antagonist, in a rat model of Parkinson’s disease. Brain Res 1073-1074:209–219

    CAS  PubMed  Article  Google Scholar 

  • Gonzalez-Aparicio R, Moratalla R (2014) Oleoylethanolamide reduces L-DOPA-induced dyskinesia via TRPV1 receptor in a mouse model of Parkinson’s disease. Neurobiol Dis 62:416–425

    CAS  PubMed  Article  Google Scholar 

  • Gubellini P, Picconi B, Bari M, Battista N, Calabresi P, Centonze D, Bernardi G, Finazzi-Agro A, Maccarrone M (2002) Experimental parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission. J Neurosci 22:6900–6907

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Gutierrez-Valdez AL, Garcia-Ruiz R, Anaya-Martinez V, Torres-Esquivel C, Espinosa-Villanueva J, Reynoso-Erazo L, Tron-Alvarez R, Aley-Medina P, Sanchez-Betancourt J, Montiel-Flores E, Avila-Costa MR (2013) The combination of oral L-DOPA/rimonabant for effective dyskinesia treatment and cytological preservation in a rat model of Parkinson's disease and L-DOPA-induced dyskinesia. Behav Pharmacol 24:640–652

    CAS  PubMed  Article  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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Heiman M, Heilbut A, Francardo V, Kulicke R, Fenster RJ, Kolaczyk ED, Mesirov JP, Surmeier DJ, Cenci MA, Greengard P (2014) Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia. Proc Natl Acad Sci U S A 111:4578–4583

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Herkenham M, Lynn AB, de Costa BR, Richfield EK (1991a) Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res 547:267–274

    CAS  PubMed  Article  Google Scholar 

  • Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991b) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Hermann H, Marsicano G, Lutz B (2002) Coexpression of the cannabinoid receptor type 1 with dopamine and serotonin receptors in distinct neuronal subpopulations of the adult mouse forebrain. Neuroscience 109:451–460

    CAS  PubMed  Article  Google Scholar 

  • Herrero MT, Estrada C, Maatouk L, Vyas S (2015) Inflammation in Parkinson’s disease: role of glucocorticoids. Front Neuroanat 9:32

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Hiscott J, Kwon H, Genin P (2001) Hostile takeovers: viral appropriation of the NF-kappaB pathway. J Clin Invest 107:143–151

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Hohmann AG, Herkenham M (2000) Localization of cannabinoid CB(1) receptor mRNA in neuronal subpopulations of rat striatum: a double-label in situ hybridization study. Synapse 37:71–80

    CAS  PubMed  Article  Google Scholar 

  • Howlett AC, Fleming RM (1984) Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol 26:532–538

    CAS  PubMed  Google Scholar 

  • Howlett AC, Blume LC, Dalton GD (2010) CB(1) cannabinoid receptors and their associated proteins. Curr Med Chem 17:1382–1393

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Huot P, Johnston TH, Koprich JB, Fox SH, Brotchie JM (2013) The pharmacology of L-DOPA-induced dyskinesia in Parkinson’s disease. Pharmacol Rev 65:171–222

    CAS  PubMed  Article  Google Scholar 

  • Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA (2004) Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem 89:134–141

    CAS  PubMed  Article  Google Scholar 

  • Janefjord E, Maag JL, Harvey BS, Smid SD (2014) Cannabinoid effects on beta amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro. Cell Mol Neurobiol 34:31–42

    CAS  PubMed  Article  Google Scholar 

  • Jenner P (2008) Molecular mechanisms of L-DOPA-induced dyskinesia. Nat Rev Neurosci 9:665–677

    CAS  PubMed  Article  Google Scholar 

  • Johnston TH, Huot P, Fox SH, Wakefield JD, Sykes KA, Bartolini WP, Milne GT, Pearson JP, Brotchie JM (2011) Fatty acid amide hydrolase (FAAH) inhibition reduces L-3,4-dihydroxyphenylalanine-induced hyperactivity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned non-human primate model of Parkinson’s disease. J Pharmacol Exp Ther 336:423–430

    CAS  PubMed  Article  Google Scholar 

  • Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, Stephens GJ (2010) Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther 332:569–577

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Kaneko M, Stryker MP (2017) Homeostatic plasticity mechanisms in mouse V1. Philos Trans R Soc Lond Ser B Biol Sci 372

    Article  CAS  Google Scholar 

  • Khan SS, Lee FJ (2014) Delineation of domains within the cannabinoid CB1 and dopamine D2 receptors that mediate the formation of the heterodimer complex. J Mol Neurosci 53:10–21

    CAS  PubMed  Article  Google Scholar 

  • Kirschmann EK, Mauna JC, Willis CM, Foster RL, Chipman AM, Thiels E (2014) Appetitive cue-evoked ERK signaling in the nucleus accumbens requires NMDA and D1 dopamine receptor activation and regulates CREB phosphorylation. Learn Mem 21:606–615

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Kozela E, Pietr M, Juknat A, Rimmerman N, Levy R, Vogel Z (2010) Cannabinoids delta(9)-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-kappaB and interferon-beta/STAT proinflammatory pathways in BV-2 microglial cells. J Biol Chem 285:1616–1626

    CAS  PubMed  Article  Google Scholar 

  • Kunert-Keil C, Bisping F, Kruger J, Brinkmeier H (2006) Tissue-specific expression of TRP channel genes in the mouse and its variation in three different mouse strains. BMC Genomics 7:159

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM (2015) Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 172:4790–4805

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Lastres-Becker I, Cebeira M, de Ceballos ML, Zeng BY, Jenner P, Ramos JA, Fernandez-Ruiz JJ (2001) Increased cannabinoid CB1 receptor binding and activation of GTP-binding proteins in the basal ganglia of patients with Parkinson’s syndrome and of MPTP-treated marmosets. Eur J Neurosci 14:1827–1832

    CAS  PubMed  Article  Google Scholar 

  • Lastres-Becker I, de Miguel R, De Petrocellis L, Makriyannis A, Di Marzo V, Fernandez-Ruiz J (2003) Compounds acting at the endocannabinoid and/or endovanilloid systems reduce hyperkinesia in a rat model of Huntington’s disease. J Neurochem 84:1097–1109

    CAS  PubMed  Article  Google Scholar 

  • Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fernandez-Ruiz J (2005) Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol Dis 19:96–107

    CAS  PubMed  Article  Google Scholar 

  • Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Lees AJ, Hardy J, Revesz T (2009) Parkinson’s disease. Lancet 373:2055–2066

    CAS  PubMed  Article  Google Scholar 

  • Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkotter J, Hellmich M, Koethe D (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2:e94

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Li K, Feng JY, Li YY, Yuece B, Lin XH, Yu LY, Li YN, Feng YJ, Storr M (2013) Anti-inflammatory role of cannabidiol and O-1602 in cerulein-induced acute pancreatitis in mice. Pancreas 42:123–129

    CAS  PubMed  Article  Google Scholar 

  • Liu J, Li H, Burstein SH, Zurier RB, Chen JD (2003) Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid. Mol Pharmacol 63:983–992

    CAS  PubMed  Article  Google Scholar 

  • Lopez-Sendon Moreno JL, Garcia Caldentey J, Trigo Cubillo P, Ruiz Romero C, Garcia Ribas G, Alonso Arias MA, Garcia de Yebenes MJ, Tolon RM, Galve-Roperh I, Sagredo O, Valdeolivas S, Resel E, Ortega-Gutierrez S, Garcia-Bermejo ML, Fernandez Ruiz J, Guzman M, Garcia de Yebenes Prous J (2016) A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington’s disease. J Neurol 263:1390–1400

    CAS  PubMed  Article  Google Scholar 

  • Lotan I, Treves TA, Roditi Y, Djaldetti R (2014) Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study. Clin Neuropharmacol 37:41–44

    PubMed  Article  Google Scholar 

  • Lovinger DM (2010) Neurotransmitter roles in synaptic modulation, plasticity and learning in the dorsal striatum. Neuropharmacology 58:951–961

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Luginger E, Wenning GK, Bosch S, Poewe W (2000) Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson’s disease. Mov Disord 15:873–878

    CAS  PubMed  Article  Google Scholar 

  • Lundblad M, Andersson M, Winkler C, Kirik D, Wierup N, Cenci MA (2002) Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson’s disease. Eur J Neurosci 15:120–132

    CAS  PubMed  Article  Google Scholar 

  • Lynn AB, Herkenham M (1994) Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor-mediated immune modulation by cannabinoids. J Pharmacol Exp Ther 268:1612–1623

    CAS  PubMed  Google Scholar 

  • Maccarrone M, Gubellini P, Bari M, Picconi B, Battista N, Centonze D, Bernardi G, Finazzi-Agro A, Calabresi P (2003) Levodopa treatment reverses endocannabinoid system abnormalities in experimental parkinsonism. J Neurochem 85:1018–1025

    CAS  PubMed  Article  Google Scholar 

  • Macchio GJ, Ito V, Sahgal V (1993) Amantadine-induced coma. Arch Phys Med Rehabil 74:1119–1120

    CAS  PubMed  Article  Google Scholar 

  • Machado MMF, Bassani TB, Coppola-Segovia V, Moura ELR, Zanata SM, Andreatini R, Vital M (2019) PPAR-gamma agonist pioglitazone reduces microglial proliferation and NF-kappaB activation in the substantia nigra in the 6-hydroxydopamine model of Parkinson's disease. Pharmacol Rep 71:556–564

    CAS  PubMed  Article  Google Scholar 

  • Mackie K (2006) Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength. Int J Obes 30(Suppl 1):S19–S23

    CAS  Article  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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Marcellino D, Carriba P, Filip M, Borgkvist A, Frankowska M, Bellido I, Tanganelli S, Muller CE, Fisone G, Lluis C, Agnati LF, Franco R, Fuxe K (2008) Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis. Neuropharmacology 54:815–823

    CAS  PubMed  Article  Google Scholar 

  • Marin I, Kipnis J (2013) Learning and memory ... and the immune system. Learn Mem 20:601–606

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11:4213–4225

    CAS  PubMed  Article  Google Scholar 

  • Martinez A, Macheda T, Morgese MG, Trabace L, Giuffrida A (2012) The cannabinoid agonist WIN55212-2 decreases L-DOPA-induced PKA activation and dyskinetic behavior in 6-OHDA-treated rats. Neurosci Res 72:236–242

    CAS  PubMed  Article  Google Scholar 

  • Martinez AA, Morgese MG, Pisanu A, Macheda T, Paquette MA, Seillier A, Cassano T, Carta AR, Giuffrida A (2015) Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats. Neurobiol Dis 74:295–304

    CAS  PubMed  Article  Google Scholar 

  • Martin-Moreno AM, Reigada D, Ramirez BG, Mechoulam R, Innamorato N, Cuadrado A, de Ceballos ML (2011) Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease. Mol Pharmacol 79:964–973

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564

    CAS  PubMed  Article  Google Scholar 

  • McCoy MK, Tansey MG (2008) TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 5:45

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • McGeer PL, McGeer EG (2004) Inflammation and neurodegeneration in Parkinson’s disease. Parkinsonism Relat Disord 10(Suppl 1):S3–S7

    PubMed  Article  Google Scholar 

  • McHugh D, Page J, Dunn E, Bradshaw HB (2012) Delta(9) -tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. Br J Pharmacol 165:2414–2424

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • McPartland JM, Duncan M, Di Marzo V, Pertwee RG (2015) Are cannabidiol and delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol 172:737–753

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Mechoulam R, Hanus L (2000) A historical overview of chemical research on cannabinoids. Chem Phys Lipids 108:1–13

    CAS  PubMed  Article  Google Scholar 

  • Mechoulam R, Shvo Y (1963) Hashish. I. The structure of cannabidiol. Tetrahedron 19:2073–2078

    CAS  PubMed  Article  Google Scholar 

  • Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90

    CAS  PubMed  Article  Google Scholar 

  • Mesnage V, Houeto JL, Bonnet AM, Clavier I, Arnulf I, Cattelin F, Le Fur G, Damier P, Welter ML, Agid Y (2004) Neurokinin B, neurotensin, and cannabinoid receptor antagonists and Parkinson disease. Clin Neuropharmacol 27:108–110

    CAS  PubMed  Article  Google Scholar 

  • Metman LV, Del Dotto P, LePoole K, Konitsiotis S, Fang J, Chase TN (1999) Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol 56:1383–1386

    CAS  PubMed  Article  Google Scholar 

  • Mezey E, Toth ZE, Cortright DN, Arzubi MK, Krause JE, Elde R, Guo A, Blumberg PM, Szallasi A (2000) Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc Natl Acad Sci U S A 97:3655–3660

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Michel PP, Hirsch EC, Hunot S (2016) Understanding dopaminergic cell death pathways in Parkinson disease. Neuron 90:675–691

    CAS  PubMed  Article  Google Scholar 

  • Moldrich G, Wenger T (2000) Localization of the CB1 cannabinoid receptor in the rat brain. An immunohistochemical study. Peptides 21:1735–1742

    CAS  PubMed  Article  Google Scholar 

  • Moldzio R, Pacher T, Krewenka C, Kranner B, Novak J, Duvigneau JC, Rausch WD (2012) Effects of cannabinoids delta(9)-tetrahydrocannabinol, delta(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomedicine 19:819–824

    CAS  PubMed  Article  Google Scholar 

  • Morgese MG, Cassano T, Cuomo V, Giuffrida A (2007) Anti-dyskinetic effects of cannabinoids in a rat model of Parkinson’s disease: role of CB(1) and TRPV1 receptors. Exp Neurol 208:110–119

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Morin N, Di Paolo T (2014) Pharmacological treatments inhibiting levodopa-induced dyskinesias in MPTP-lesioned monkeys: brain glutamate biochemical correlates. Front Neurol 5:144

    PubMed  PubMed Central  Article  Google Scholar 

  • Mounsey RB, Mustafa S, Robinson L, Ross RA, Riedel G, Pertwee RG, Teismann P (2015) Increasing levels of the endocannabinoid 2-AG is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Exp Neurol 273:36–44

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Mulas G, Espa E, Fenu S, Spiga S, Cossu G, Pillai E, Carboni E, Simbula G, Jadzic D, Angius F, Spolitu S, Batetta B, Lecca D, Giuffrida A, Carta AR (2016) Differential induction of dyskinesia and neuroinflammation by pulsatile versus continuous l-DOPA delivery in the 6-OHDA model of Parkinson’s disease. Exp Neurol 286:83–92

    CAS  PubMed  Article  Google Scholar 

  • Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65

    CAS  PubMed  Article  Google Scholar 

  • Murillo-Rodriguez E, Palomero-Rivero M, Millan-Aldaco D, Mechoulam R, Drucker-Colin R (2011) Effects on sleep and dopamine levels of microdialysis perfusion of cannabidiol into the lateral hypothalamus of rats. Life Sci 88:504–511

    CAS  PubMed  Article  Google Scholar 

  • Musella A, De Chiara V, Rossi S, Prosperetti C, Bernardi G, Maccarrone M, Centonze D (2009) TRPV1 channels facilitate glutamate transmission in the striatum. Mol Cell Neurosci 40:89–97

    CAS  PubMed  Article  Google Scholar 

  • Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M, Schulte C, Keller MF, Arepalli S, Letson C, Edsall C, Stefansson H, Liu X, Pliner H, Lee JH, Cheng R, International Parkinson’s Disease Genomics C, Parkinson’s Study Group Parkinson’s Research: The Organized GI, andMe, GenePd, NeuroGenetics Research C, Hussman Institute of Human G, Ashkenazi Jewish Dataset I, Cohorts for H, Aging Research in Genetic E, North American Brain Expression C, United Kingdom Brain Expression C, Greek Parkinson’s Disease C, Alzheimer Genetic Analysis G, Ikram MA, Ioannidis JP, Hadjigeorgiou GM, Bis JC, Martinez M, Perlmutter JS, Goate A, Marder K, Fiske B, Sutherland M, Xiromerisiou G, Myers RH, Clark LN, Stefansson K, Hardy JA, Heutink P, Chen H, Wood NW, Houlden H, Payami H, Brice A, Scott WK, Gasser T, Bertram L, Eriksson N, Foroud T, Singleton AB (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet 46:989–993

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Nam JH, Park ES, Won SY, Lee YA, Kim KI, Jeong JY, Baek JY, Cho EJ, Jin M, Chung YC, Lee BD, Kim SH, Kim EG, Byun K, Lee B, Woo DH, Lee CJ, Kim SR, Bok E, Kim YS, Ahn TB, Ko HW, Brahmachari S, Pletinkova O, Troconso JC, Dawson VL, Dawson TM, Jin BK (2015) TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson’s disease via CNTF. Brain J Neurol 138:3610–3622

    Article  Google Scholar 

  • Niesink RJ, van Laar MW (2013) Does cannabidiol protect against adverse psychological effects of THC? Front Psychiatry 4:130

    PubMed  PubMed Central  Article  Google Scholar 

  • Nutt JG (1990) Levodopa-induced dyskinesia: review, observations, and speculations. Neurology 40:340–345

    CAS  PubMed  Article  Google Scholar 

  • O’Sullivan SE (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 152:576–582

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • O’Sullivan SE, Sun Y, Bennett AJ, Randall MD, Kendall DA (2009) Time-dependent vascular actions of cannabidiol in the rat aorta. Eur J Pharmacol 612:61–68

    PubMed  Article  CAS  Google Scholar 

  • Obeso JA, Stamelou M, Goetz CG, Poewe W, Lang AE, Weintraub D, Burn D, Halliday GM, Bezard E, Przedborski S, Lehericy S, Brooks DJ, Rothwell JC, Hallett M, DeLong MR, Marras C, Tanner CM, Ross GW, Langston JW, Klein C, Bonifati V, Jankovic J, Lozano AM, Deuschl G, Bergman H, Tolosa E, Rodriguez-Violante M, Fahn S, Postuma RB, Berg D, Marek K, Standaert DG, Surmeier DJ, Olanow CW, Kordower JH, Calabresi P, Schapira AHV, Stoessl AJ (2017) Past, present, and future of Parkinson’s disease: a special essay on the 200th anniversary of the shaking palsy. Mov Disord 32:1264–1310

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Ojha S, Javed H, Azimullah S, Haque ME (2016) Beta-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

    CAS  PubMed  Article  Google Scholar 

  • Olmos G, Llado J (2014) Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity. Mediat Inflamm 2014:861231

    Article  CAS  Google Scholar 

  • Onaivi ES, Ishiguro H, Gong JP, Patel S, Perchuk A, Meozzi PA, Myers L, Mora Z, Tagliaferro P, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Iwasaki S, Arinami T, Teasenfitz L, Uhl GR (2006) Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann N Y Acad Sci 1074:514–536

    CAS  PubMed  Article  Google Scholar 

  • Ossola B, Schendzielorz N, Chen SH, Bird GS, Tuominen RK, Mannisto PT, Hong JS (2011) Amantadine protects dopamine neurons by a dual action: reducing activation of microglia and inducing expression of GDNF in astroglia [corrected]. Neuropharmacology 61:574–582

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, Reynet C (2006) Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab 3:167–175

    CAS  PubMed  Article  Google Scholar 

  • Pandolfo P, Silveirinha V, dos Santos-Rodrigues A, Venance L, Ledent C, Takahashi RN, Cunha RA, Kofalvi A (2011) Cannabinoids inhibit the synaptic uptake of adenosine and dopamine in the rat and mouse striatum. Eur J Pharmacol 655:38–45

    CAS  PubMed  Article  Google Scholar 

  • Panikashvili D, Mechoulam R, Beni SM, Alexandrovich A, Shohami E (2005) CB1 cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibition. J Cereb Blood Flow Metab 25:477–484

    CAS  PubMed  Article  Google Scholar 

  • Papa SM, Chase TN (1996) Levodopa-induced dyskinesias improved by a glutamate antagonist in Parkinsonian monkeys. Ann Neurol 39:574–578

    CAS  PubMed  Article  Google Scholar 

  • Parkinson J (2002) An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci 14:223–236 discussion 222

    PubMed  Article  Google Scholar 

  • Pavon N, Martin AB, Mendialdua A, Moratalla R (2006) ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice. Biol Psychiatry 59:64–74

    CAS  PubMed  Article  Google Scholar 

  • Payandemehr B, Ebrahimi A, Gholizadeh R, Rahimian R, Varastehmoradi B, Gooshe M, Aghaei HN, Mousavizadeh K, Dehpour AR (2015) Involvement of PPAR receptors in the anticonvulsant effects of a cannabinoid agonist, WIN 55,212-2. Prog Neuro-Psychopharmacol Biol Psychiatry 57:140–145

    CAS  Article  Google Scholar 

  • Perez XA, Bordia T, Quik M (2018) The striatal cholinergic system in L-dopa-induced dyskinesias. J Neural Transm 125:1251–1262

    CAS  PubMed  Article  Google Scholar 

  • Perez-Rial S, Garcia-Gutierrez MS, Molina JA, Perez-Nievas BG, Ledent C, Leiva C, Leza JC, Manzanares J (2011) Increased vulnerability to 6-hydroxydopamine lesion and reduced development of dyskinesias in mice lacking CB1 cannabinoid receptors. Neurobiol Aging 32:631–645

    CAS  PubMed  Article  Google Scholar 

  • Pertwee RG (2005) Pharmacological actions of cannabinoids. Handb Exp Pharmacol:1–51

  • Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199–215

    CAS  PubMed  Article  Google Scholar 

  • Pertwee RG (2015) Endocannabinoids and their pharmacological actions. Handb Exp Pharmacol 231:1–37

    CAS  PubMed  Article  Google Scholar 

  • Pertwee RG, Ross RA (2002) Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fat Acids 66:101–121

    CAS  Article  Google Scholar 

  • Pinto M, Nissanka N, Peralta S, Brambilla R, Diaz F, Moraes CT (2016) Pioglitazone ameliorates the phenotype of a novel Parkinson’s disease mouse model by reducing neuroinflammation. Mol Neurodegener 11:25

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884

    CAS  PubMed  Article  Google Scholar 

  • Pisani V, Moschella V, Bari M, Fezza F, Galati S, Bernardi G, Stanzione P, Pisani A, Maccarrone M (2010) Dynamic changes of anandamide in the cerebrospinal fluid of Parkinson’s disease patients. Mov Disord 25:920–924

    PubMed  Article  Google Scholar 

  • Pisani V, Madeo G, Tassone A, Sciamanna G, Maccarrone M, Stanzione P, Pisani A (2011) Homeostatic changes of the endocannabinoid system in Parkinson’s disease. Mov Disord 26:216–222

    PubMed  Article  Google Scholar 

  • Pisanu A, Lecca D, Mulas G, Wardas J, Simbula G, Spiga S, Carta AR (2014) Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-gamma agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson’s disease. Neurobiol Dis 71:280–291

    CAS  PubMed  Article  Google Scholar 

  • Pisanu A, Boi L, Mulas G, Spiga S, Fenu S, Carta AR (2018) Neuroinflammation in L-DOPA-induced dyskinesia: beyond the immune function. J Neural Transm

  • Polissidis A, Chouliara O, Galanopoulos A, Naxakis G, Papahatjis D, Papadopoulou-Daifoti Z, Antoniou K (2014) Cannabinoids negatively modulate striatal glutamate and dopamine release and behavioural output of acute D-amphetamine. Behav Brain Res 270:261–269

    CAS  PubMed  Article  Google Scholar 

  • Prescott IA, Dostrovsky JO, Moro E, Hodaie M, Lozano AM, Hutchison WD (2009) Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson’s disease patients. Brain J Neurol 132:309–318

    CAS  Article  Google Scholar 

  • Price DA, Martinez AA, Seillier A, Koek W, Acosta Y, Fernandez E, Strong R, Lutz B, Marsicano G, Roberts JL, Giuffrida A (2009) WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Eur J Neurosci 29:2177–2186

    PubMed  PubMed Central  Article  Google Scholar 

  • Qin N, Neeper MP, Liu Y, Hutchinson TL, Lubin ML, Flores CM (2008) TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci 28:6231–6238

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Ramirez BG, Blazquez C, Gomez del Pulgar T, Guzman M, de Ceballos ML (2005) Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 25:1904–1913

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Reale M, Iarlori C, Thomas A, Gambi D, Perfetti B, Di Nicola M, Onofrj M (2009) Peripheral cytokines profile in Parkinson’s disease. Brain Behav Immun 23:55–63

    CAS  PubMed  Article  Google Scholar 

  • Reber L, Vermeulen L, Haegeman G, Frossard N (2009) Ser276 phosphorylation of NF-kB p65 by MSK1 controls SCF expression in inflammation. PLoS One 4:e4393

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Reglodi D, Renaud J, Tamas A, Tizabi Y, Socias SB, Del-Bel E, Raisman-Vozari R (2017) Novel tactics for neuroprotection in Parkinson’s disease: role of antibiotics, polyphenols and neuropeptides. Prog Neurobiol 155:120–148

    CAS  PubMed  Article  Google Scholar 

  • Rimmerman N, Juknat A, Kozela E, Levy R, Bradshaw HB, Vogel Z (2011) The non-psychoactive plant cannabinoid, cannabidiol affects cholesterol metabolism-related genes in microglial cells. Cell Mol Neurobiol 31:921–930

    CAS  PubMed  Article  Google Scholar 

  • Rockwell CE, Kaminski NE (2004) A cyclooxygenase metabolite of anandamide causes inhibition of interleukin-2 secretion in murine splenocytes. J Pharmacol Exp Ther 311:683–690

    CAS  PubMed  Article  Google Scholar 

  • Rojo-Bustamante E, Abellanas MA, Clavero P, Thiolat ML, Li Q, Luquin MR, Bezard E, Aymerich MS (2018) The expression of cannabinoid type 1 receptor and 2-arachidonoyl glycerol synthesizing/degrading enzymes is altered in basal ganglia during the active phase of levodopa-induced dyskinesia. Neurobiol Dis 118:64–75

    CAS  PubMed  Article  Google Scholar 

  • Ross RA (2003) Anandamide and vanilloid TRPV1 receptors. Br J Pharmacol 140:790–801

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Russo EB (2018) Cannabis therapeutics and the future of neurology. Front Integr Neurosci 12:51

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037–1043

    CAS  PubMed  Article  Google Scholar 

  • Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ (2007) The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 152:1092–1101

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Rylander D, Recchia A, Mela F, Dekundy A, Danysz W, Cenci MA (2009) Pharmacological modulation of glutamate transmission in a rat model of L-DOPA-induced dyskinesia: effects on motor behavior and striatal nuclear signaling. J Pharmacol Exp Ther 330:227–235

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Sagredo O, Garcia-Arencibia M, de Lago E, Finetti S, Decio A, Fernandez-Ruiz J (2007) Cannabinoids and neuroprotection in basal ganglia disorders. Mol Neurobiol 36:82–91

    CAS  PubMed  Article  Google Scholar 

  • Santello M, Volterra A (2012) TNFalpha in synaptic function: switching gears. Trends Neurosci 35:638–647

    CAS  PubMed  Article  Google Scholar 

  • Santello M, Bezzi P, Volterra A (2011) TNFalpha controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69:988–1001

    CAS  PubMed  Article  Google Scholar 

  • Santini E, Alcacer C, Cacciatore S, Heiman M, Herve D, Greengard P, Girault JA, Valjent E, Fisone G (2009) L-DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice. J Neurochem 108:621–633

    CAS  PubMed  Article  Google Scholar 

  • Santini E, Sgambato-Faure V, Li Q, Savasta M, Dovero S, Fisone G, Bezard E (2010) Distinct changes in cAMP and extracellular signal-regulated protein kinase signalling in L-DOPA-induced dyskinesia. PLoS One 5:e12322

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Santos NA, Martins NM, Sisti FM, Fernandes LS, Ferreira RS, Queiroz RH, Santos AC (2015) The neuroprotection of cannabidiol against MPP(+)-induced toxicity in PC12 cells involves trkA receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson’s disease. Toxicol In Vitro 30:231–240

    CAS  PubMed  Article  Google Scholar 

  • Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22:565–572

    CAS  PubMed  Article  Google Scholar 

  • Sgambato-Faure V, Cenci MA (2012) Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson’s disease. Prog Neurobiol 96:69–86

    CAS  PubMed  Article  Google Scholar 

  • Shannon KM, Goetz CG, Carroll VS, Tanner CM, Klawans HL (1987) Amantadine and motor fluctuations in chronic Parkinson’s disease. Clin Neuropharmacol 10:522–526

    CAS  PubMed  Article  Google Scholar 

  • Shih IF, Starhof C, Lassen CF, Hansen J, Liew Z, Ritz B (2017) Occupational and recreational physical activity and Parkinson’s disease in Denmark. Scand J Work Environ Health 43:210–216

    PubMed  Article  Google Scholar 

  • Sieradzan KA, Fox SH, Hill M, Dick JP, Crossman AR, Brotchie JM (2001) Cannabinoids reduce levodopa-induced dyskinesia in Parkinson’s disease: a pilot study. Neurology 57:2108–2111

    CAS  PubMed  Article  Google Scholar 

  • Sierra S, Luquin N, Rico AJ, Gomez-Bautista V, Roda E, Dopeso-Reyes IG, Vazquez A, Martinez-Pinilla E, Labandeira-Garcia JL, Franco R, Lanciego JL (2015) Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism. Brain Struct Funct 220:2721–2738

    CAS  PubMed  Article  Google Scholar 

  • Solis O, Garcia-Sanz P, Herranz AS, Asensio MJ, Moratalla R (2016) L-DOPA reverses the increased free amino acids tissue levels induced by dopamine depletion and rises GABA and tyrosine in the striatum. Neurotox Res 30:67–75

    CAS  PubMed  Article  Google Scholar 

  • Sugiura T, Kishimoto S, Oka S, Gokoh M (2006) Biochemistry, pharmacology and physiology of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Prog Lipid Res 45:405–446

    CAS  PubMed  Article  Google Scholar 

  • Szallasi A, Di Marzo V (2000) New perspectives on enigmatic vanilloid receptors. Trends Neurosci 23:491–497

    CAS  PubMed  Article  Google Scholar 

  • Tanabe T, Tohnai N (2002) Cyclooxygenase isozymes and their gene structures and expression. Prostaglandins Other Lipid Mediat 68-69:95–114

    CAS  PubMed  Article  Google Scholar 

  • Tansey MG, McCoy MK, Frank-Cannon TC (2007) Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 208:1–25

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Teema AM, Zaitone SA, Moustafa YM (2016) Ibuprofen or piroxicam protects nigral neurons and delays the development of l-dopa induced dyskinesia in rats with experimental Parkinsonism: influence on angiogenesis. Neuropharmacology 107:432–450

    CAS  PubMed  Article  Google Scholar 

  • Thacker EL, Chen H, Patel AV, McCullough ML, Calle EE, Thun MJ, Schwarzschild MA, Ascherio A (2008) Recreational physical activity and risk of Parkinson’s disease. Mov Disord 23:69–74

    PubMed  PubMed Central  Article  Google Scholar 

  • Thomas A, Iacono D, Luciano AL, Armellino K, Di Iorio A, Onofrj M (2004) Duration of amantadine benefit on dyskinesia of severe Parkinson’s disease. J Neurol Neurosurg Psychiatry 75:141–143

  • 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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Tzavara ET, Li DL, Moutsimilli L, Bisogno T, Di Marzo V, Phebus LA, Nomikos GG, Giros B (2006) Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications. Biol Psychiatry 59:508–515

    CAS  PubMed  Article  Google Scholar 

  • van der Stelt M, Di Marzo V (2003) The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders. Eur J Pharmacol 480:133–150

    PubMed  Article  CAS  Google Scholar 

  • van der Stelt M, Fox SH, Hill M, Crossman AR, Petrosino S, Di Marzo V, Brotchie JM (2005) A role for endocannabinoids in the generation of parkinsonism and levodopa-induced dyskinesia in MPTP-lesioned non-human primate models of Parkinson's disease. FASEB J 19:1140–1142

    PubMed  Article  CAS  Google Scholar 

  • Van Laere K, Casteels C, Lunskens S, Goffin K, Grachev ID, Bormans G, Vandenberghe W (2012) Regional changes in type 1 cannabinoid receptor availability in Parkinson’s disease in vivo. Neurobiol Aging 33:620 e621–620 e628

    Google Scholar 

  • Venderova K, Ruzicka E, Vorisek V, Visnovsky P (2004) Survey on cannabis use in Parkinson’s disease: subjective improvement of motor symptoms. Mov Disord 19:1102–1106

    PubMed  Article  Google Scholar 

  • Vesce S, Rossi D, Brambilla L, Volterra A (2007) Glutamate release from astrocytes in physiological conditions and in neurodegenerative disorders characterized by neuroinflammation. Int Rev Neurobiol 82:57–71

    CAS  PubMed  Article  Google Scholar 

  • Villapol S (2018) Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflammation. Cell Mol Neurobiol 38:121–132

    CAS  PubMed  Article  Google Scholar 

  • Viveros-Paredes JM, Gonzalez-Castaneda RE, Escalante-Castaneda A, Tejeda-Martinez AR, Castaneda-Achutigui F, Flores-Soto ME (2019) Effect of inhibition of fatty acid amide hydrolase on MPTP-induced dopaminergic neuronal damage. Neurologia 34:143–152

    CAS  PubMed  Article  Google Scholar 

  • Wandinger KP, Hagenah JM, Kluter H, Rothermundt M, Peters M, Vieregge P (1999) Effects of amantadine treatment on in vitro production of interleukin-2 in de-novo patients with idiopathic Parkinson’s disease. J Neuroimmunol 98:214–220

    CAS  PubMed  Article  Google Scholar 

  • Wang Y, Zhang QJ, Wang HS, Wang T, Liu J (2014) Genome-wide microarray analysis identifies a potential role for striatal retrograde endocannabinoid signaling in the pathogenesis of experimental L-DOPA-induced dyskinesia. Synapse 68:332–343

    CAS  PubMed  Article  Google Scholar 

  • Wang Y, Zhang GJ, Sun YN, Yao L, Wang HS, Du CX, Zhang L, Liu J (2018) Identification of metabolite biomarkers for L-DOPA-induced dyskinesia in a rat model of Parkinson’s disease by metabolomic technology. Behav Brain Res 347:175–183

    PubMed  Article  Google Scholar 

  • Watzl B, Scuderi P, Watson RR (1991) Marijuana components stimulate human peripheral blood mononuclear cell secretion of interferon-gamma and suppress interleukin-1 alpha in vitro. Int J Immunopharmacol 13:1091–1097

    CAS  PubMed  Article  Google Scholar 

  • Wiecki TV, Frank MJ (2010) Neurocomputational models of motor and cognitive deficits in Parkinson's disease. Prog Brain Res 183:275–297

    CAS  PubMed  Article  Google Scholar 

  • Wolf E, Seppi K, Katzenschlager R, Hochschorner G, Ransmayr G, Schwingenschuh P, Ott E, Kloiber I, Haubenberger D, Auff E, Poewe W (2010) Long-term antidyskinetic efficacy of amantadine in Parkinson's disease. Mov Disord 25:1357–1363

    PubMed  Article  Google Scholar 

  • Wyss-Coray T, Mucke L (2002) Inflammation in neurodegenerative disease--a double-edged sword. Neuron 35:419–432

    CAS  PubMed  Article  Google Scholar 

  • Zeissler ML, Eastwood J, McCorry K, Hanemann CO, Zajicek JP, Carroll CB (2016) Delta-9-tetrahydrocannabinol protects against MPP+ toxicity in SH-SY5Y cells by restoring proteins involved in mitochondrial biogenesis. Oncotarget 7:46603–46614

    PubMed  PubMed Central  Article  Google Scholar 

  • Zhang J, Chen C (2008) Endocannabinoid 2-arachidonoylglycerol protects neurons by limiting COX-2 elevation. J Biol Chem 283:22601–22611

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG (1982) Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology 76:245–250

    CAS  PubMed  Article  Google Scholar 

  • Zuardi AW, Crippa JA, Hallak JE, Pinto JP, Chagas MH, Rodrigues GG, Dursun SM, Tumas V (2009) Cannabidiol for the treatment of psychosis in Parkinson’s disease. J Psychopharmacol 23:979–983

    CAS  PubMed  Article  Google Scholar 

Download references

Funding

This work was supported by Fundação de Apoio ao Ensino, Pesquisa e Assistência da Universidade de São Paulo (FAEPA USP/RP 98/16); Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2014/25029-4; 2017/14207-7; 12/17626-7); Conselho nacional de Desenvolvimento Científico e Tecnológico (CNPq 201187/2016-7); and Coordenação de Aperfeiçoamento de pessoal de Nível Superior (CAPES PROEX-USP PROEX0051047).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Elaine Del Bel.

Ethics declarations

Conflict of Interests

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Highlights

• Investigation of cannabidiol as a possible treatment for motor dysfunctions.

• Compilation of evidence on how cannabinoids can treat PD and LID.

• Preclinical and clinical works show an altered cannabinoid signaling in PD and LID.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Junior, N.C.F., dos- Santos-Pereira, M., Guimarães, F.S. et al. Cannabidiol and Cannabinoid Compounds as Potential Strategies for Treating Parkinson’s Disease and l-DOPA-Induced Dyskinesia. Neurotox Res 37, 12–29 (2020). https://doi.org/10.1007/s12640-019-00109-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-019-00109-8

Keywords

  • Cannabinoid system
  • Endocannabinoids
  • Cannabinoid receptor (CB)
  • Transient receptor potential vanilloid receptor (TRPV)
  • Peroxisome proliferator-activated receptor (PPAR)
  • Neuroinflammation