Promising cannabinoid-based therapies for Parkinson's disease: Motor symptoms to neuroprotection

Molecular Neurodegeneration

Volumn 10, Issue 1, 2015, Pages

  More, Sandeep Vasant ^a   Choi, Dong Kug ^a  

^a Konkuk University   (South Korea)

Author keywords

Basal ganglia; Cannabinoids; CB1 receptors; CB2 receptors; Endocannabinoid signaling system; Neuroprotection; Parkinson's disease

Indexed keywords

CANNABINOID; ENDOCANNABINOID; NEUROPROTECTIVE AGENT; DOPAMINE;

BRADYKINESIA; CATALEPSY; CELL INTERACTION; CELLULAR DISTRIBUTION; CLINICAL FEATURE; CLINICAL TRIAL (TOPIC); DRUG METABOLISM; DRUG SYNTHESIS; DYSKINESIA; EXCITOTOXICITY; HUMAN; MOTOR DYSFUNCTION; MOTOR PERFORMANCE; MUSCLE RIGIDITY; NERVE CELL PLASTICITY; NERVOUS SYSTEM DEVELOPMENT; NERVOUS SYSTEM INFLAMMATION; NEUROANATOMY; NEUROPROTECTION; NONHUMAN; PARKINSON DISEASE; REVIEW; SIGNAL TRANSDUCTION; TREATMENT OUTCOME; TREATMENT RESPONSE; ANIMAL; BASAL GANGLION; METABOLISM; MOTOR ACTIVITY; PHYSIOLOGY;

ANIMALS; BASAL GANGLIA; CANNABINOIDS; DOPAMINE; HUMANS; MOTOR ACTIVITY; NEUROPROTECTIVE AGENTS; PARKINSON DISEASE;

EID: 84928044987     PISSN: None     EISSN: 17501326     Source Type: Journal    
DOI: 10.1186/s13024-015-0012-0     Document Type: Review

References (352)

1. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311:1670-83.
2. Skibinski G, Finkbeiner S. Drug discovery in Parkinson's disease-Update and developments in the use of cellular models. Int J High Throughput Screen. 2011;2011:15-25.
3. Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 2007; 16 Spec No. 2:R183-194.
4. Thomas B. Parkinson's disease: from molecular pathways in disease to therapeutic approaches. Antioxid Redox Signal. 2009;11:2077-82.
5. Schapira AH, Olanow CW, Greenamyre JT, Bezard E. Slowing of neurodegeneration in Parkinson's disease and Huntington's disease: future therapeutic perspectives. Lancet. 2014;384:545-55.
6. Davie CA. A review of Parkinson's disease. Br Med Bull. 2008;86:109-27.
7. Utsumi H, Okuma Y, Kano O, Suzuki Y, Iijima M, Tomimitsu H, et al. Evaluation of the efficacy of pramipexole for treating levodopa-induced dyskinesia in patients with Parkinson's disease. Intern Med. 2013;52:325-32.
8. Fernandez-Ruiz J, Moreno-Martet M, Rodriguez-Cueto C, Palomo-Garo C, Gomez-Canas M, Valdeolivas S, et al. Prospects for cannabinoid therapies in basal ganglia disorders. Br J Pharmacol. 2011;163:1365-78.
9. Hashimotodani Y, Ohno-Shosaku T, Kano M. Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus. J Neurosci. 2007;27:1211-9.
10. Hegyi Z, Hollo K, Kis G, Mackie K, Antal M. Differential distribution of diacylglycerol lipase-alpha and N-acylphosphatidylethanolamine-specific phospholipase d immunoreactivity in the superficial spinal dorsal horn of rats. Glia. 2012;60:1316-29.
11. Ivanov I, Borchert P, Hinz B. A simple method for simultaneous determination of N-arachidonoylethanolamine, N-oleoylethanolamine, N-palmitoylethanolamine and 2-arachidonoylglycerol in human cells. Anal Bioanal Chem. 2014;407:1781-7.
12. Snider NT, Walker VJ, Hollenberg PF. Oxidation of the endogenous cannabinoid arachidonoyl ethanolamide by the cytochrome P450 monooxygenases: physiological and pharmacological implications. Pharmacol Rev. 2010;62:136-54.
13. Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB(1) and CB(2). Pharmacol Rev. 2010;62:588-631.
14. Buczynski MW, Parsons LH. Quantification of brain endocannabinoid levels: methods, interpretations and pitfalls. Br J Pharmacol. 2010;160:423-42.
15. Felder CC, Nielsen A, Briley EM, Palkovits M, Priller J, Axelrod J, et al. Isolation and measurement of the endogenous cannabinoid receptor agonist, anandamide, in brain and peripheral tissues of human and rat. FEBS Lett. 1996;393:231-5.
16. Bisogno T, Berrendero F, Ambrosino G, Cebeira M, Ramos JA, Fernandez-Ruiz JJ, et al. Brain regional distribution of endocannabinoids: implications for their biosynthesis and biological function. Biochem Biophys Res Commun. 1999;256:377-80.
17. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50:83-90.
18. Gonsiorek W, Lunn C, Fan X, Narula S, Lundell D, Hipkin RW. Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Mol Pharmacol. 2000;57:1045-50.
19. Sugiura T, Kondo S, Kishimoto S, Miyashita T, Nakane S, Kodaka T, et al. Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells. J Biol Chem. 2000;275:605-12.
20. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci. 1991;11:563-83.
21. Di Marzo V, Hill MP, Bisogno T, Crossman AR, Brotchie JM. Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of Parkinson's disease. FASEB J. 2000;14:1432-8.
22. Di Marzo V, Berrendero F, Bisogno T, Gonzalez S, Cavaliere P, Romero J, et al. Enhancement of anandamide formation in the limbic forebrain and reduction of endocannabinoid contents in the striatum of delta9-tetrahydrocannabinol-tolerant rats. J Neurochem. 2000;74:1627-35.
23. Giuffrida A, Parsons LH, Kerr TM, Rodriguez de Fonseca F, Navarro M, Piomelli D. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci. 1999;2:358-63.
24. Saito A, Ballinger MD, Pletnikov MV, Wong DF, Kamiya A. Endocannabinoid system: potential novel targets for treatment of schizophrenia. Neurobiol Dis. 2013;53:10-7.
25. Harkany T, Guzman M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K. The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci. 2007;28:83-92.
26. Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol. 2003;163:463-8.
27. Murataeva N, Straiker A, Mackie K. Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. Br J Pharmacol. 2014;171:1379-91.
28. Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature. 1994;372:686-91.
29. Maccarrone M, van der Stelt M, Rossi A, Veldink GA, Vliegenthart JF, Agro AF. Anandamide hydrolysis by human cells in culture and brain. J Biol Chem. 1998;273:32332-9.
30. Castillo PE, Younts TJ, Chavez AE, Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron. 2012;76:70-81.
31. Egertova M, Giang DK, Cravatt BF, Elphick MR. A new perspective on cannabinoid signalling: complementary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain. Proc Biol Sci. 1998;265:2081-5.
32. Gulyas AI, Cravatt BF, Bracey MH, Dinh TP, Piomelli D, Boscia F, et al. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci. 2004;20:441-58.
33. Alexander S. Endocannabinoid-Metabolising Enzymes. Br J Pharmacol. 2009;158:S220-1.
34. Di Marzo V, Bisogno T, Sugiura T, Melck D, De Petrocellis L. The novel endogenous cannabinoid 2-arachidonoylglycerol is inactivated by neuronal- and basophil-like cells: connections with anandamide. Biochem J. 1998;331(Pt 1):15-9.
35. Goparaju SK, Ueda N, Yamaguchi H, Yamamoto S. Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand. FEBS Lett. 1998;422:69-73.
36. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A. 2002;99:10819-24.
37. Tanimura A, Uchigashima M, Yamazaki M, Uesaka N, Mikuni T, Abe M, et al. Synapse type-independent degradation of the endocannabinoid 2-arachidonoylglycerol after retrograde synaptic suppression. Proc Natl Acad Sci U S A. 2012;109:12195-200.
38. Bektas M, Payne SG, Liu H, Goparaju S, Milstien S, Spiegel S. A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells. J Cell Biol. 2005;169:801-11.
39. Kozak KR, Marnett LJ. Oxidative metabolism of endocannabinoids. Prostaglandins Leukot Essent Fatty Acids. 2002;66:211-20.
40. Marzo VD. Cannabinoids. Georgetown, Texas, USA: Plenum Publishers; 2004.
41. Sagredo O, Garcia-Arencibia M, de Lago E, Finetti S, Decio A, Fernandez-Ruiz J. Cannabinoids and neuroprotection in basal ganglia disorders. Mol Neurobiol. 2007;36:82-91.
42. Price DA, Martinez AA, Seillier A, Koek W, Acosta Y, Fernandez E, et al. 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. 2009;29:2177-86.
43. Groenewegen HJ. The basal ganglia and motor control. Neural Plast. 2003;10:107-20.
44. Fernandez-Ruiz J, Sagredo O, Pazos MR, Garcia C, Pertwee R, Mechoulam R, et al. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? Br J Clin Pharmacol. 2013;75:323-33.
45. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346:561-4.
46. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61-5.
47. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54:161-202.
48. Mackie K, Lai Y, Westenbroek R, Mitchell R. Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J Neurosci. 1995;15:6552-61.
49. Twitchell W, Brown S, Mackie K. Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J Neurophysiol. 1997;78:43-50.
50. Turu G, Hunyady L. Signal transduction of the CB1 cannabinoid receptor. J Mol Endocrinol. 2010;44:75-85.
51. Derkinderen P, Toutant M, Burgaya F, Le Bert M, Siciliano JC, de Franciscis V, et al. Regulation of a neuronal form of focal adhesion kinase by anandamide. Science. 1996;273:1719-22.
52. Gomez Del Pulgar T, De Ceballos ML, Guzman M, Velasco G. Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem. 2002;277:36527-33.
53. Sanchez C, Galve-Roperh I, Rueda D, Guzman M. Involvement of sphingomyelin hydrolysis and the mitogen-activated protein kinase cascade in the Delta9-tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes. Mol Pharmacol. 1998;54:834-43.
54. Waksman Y, Olson JM, Carlisle SJ, Cabral GA. The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells. J Pharmacol Exp Ther. 1999;288:1357-66.
55. Bosier B, Muccioli GG, Hermans E, Lambert DM. Functionally selective cannabinoid receptor signalling: therapeutic implications and opportunities. Biochem Pharmacol. 2010;80:1-12.
56. Benard G, Massa F, Puente N, Lourenco J, Bellocchio L, Soria-Gomez E, et al. Mitochondrial CB(1) receptors regulate neuronal energy metabolism. Nat Neurosci. 2012;15:558-64.
57. Romero J, Lastres-Becker I, de Miguel R, Berrendero F, Ramos JA, Fernandez-Ruiz J. The endogenous cannabinoid system and the basal ganglia. biochemical, pharmacological, and therapeutic aspects. Pharmacol Ther. 2002;95:137-52.
58. Martin AB, Fernandez-Espejo E, Ferrer B, Gorriti MA, Bilbao A, Navarro M, et al. Expression and function of CB1 receptor in the rat striatum: localization and effects on D1 and D2 dopamine receptor-mediated motor behaviors. Neuropsychopharmacology. 2008;33:1667-79.
59. Calabresi P, Picconi B, Tozzi A, Ghiglieri V, Di Filippo M. Direct and indirect pathways of basal ganglia: a critical reappraisal. Nat Neurosci. 2014;17:1022-30.
60. Munoz-Arenas G, Paz-Bermudez F, Baez-Cordero A, Caballero-Floran R, Gonzalez-Hernandez B, Floran B, et al. Cannabinoid CB1 receptors activation and coactivation with D2 receptors modulate GABAergic neurotransmission in the globus pallidus and increase motor asymmetry. Synapse. 2014;69:103-14.
61. Sierra S, Luquin N, Rico AJ, Gomez-Bautista V, Roda E, Dopeso-Reyes IG et al. Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism. Brain Struct Funct. 2014. Epub ahead of print.
62. Mailleux P, Vanderhaeghen JJ. Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience. 1992;48:655-68.
63. Herkenham M, Lynn AB, de Costa BR, Richfield EK. Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res. 1991;547:267-74.
64. Chaves-Kirsten GP, Mazucanti CH, Real CC, Souza BM, Britto LR, Torrao AS. Temporal changes of CB1 cannabinoid receptor in the basal ganglia as a possible structure-specific plasticity process in 6-OHDA lesioned rats. PLoS One. 2013;8:e76874.
65. Kofalvi A, Rodrigues RJ, Ledent C, Mackie K, Vizi ES, Cunha RA, et al. Involvement of cannabinoid receptors in the regulation of neurotransmitter release in the rodent striatum: a combined immunochemical and pharmacological analysis. J Neurosci. 2005;25:2874-84.
66. Hohmann AG, Herkenham M. Localization of cannabinoid CB(1) receptor mRNA in neuronal subpopulations of rat striatum: a double-label in situ hybridization study. Synapse. 2000;37:71-80.
67. Chiu CQ, Puente N, Grandes P, Castillo PE. Dopaminergic modulation of endocannabinoid-mediated plasticity at GABAergic synapses in the prefrontal cortex. J Neurosci. 2010;30:7236-48.
68. Coria SM, Roura-Martinez D, Ucha M, Assis MA, Miguens M, Garcia-Lecumberri C, et al. Strain differences in the expression of endocannabinoid genes and in cannabinoid receptor binding in the brain of Lewis and Fischer 344 rats. Prog Neuropsychopharmacol Biol Psychiatry. 2014;53:15-22.
69. Van Waes V, Beverley JA, Siman H, Tseng KY, Steiner H. CB1 Cannabinoid Receptor Expression in the Striatum: Association with Corticostriatal Circuits and Developmental Regulation. Front Pharmacol. 2012;3:21.
70. Ferre S, Goldberg SR, Lluis C, Franco R. Looking for the role of cannabinoid receptor heteromers in striatal function. Neuropharmacology. 2009;56 Suppl 1:226-34.
71. Hill MN, McLaughlin RJ, Pan B, Fitzgerald ML, Roberts CJ, Lee TT, et al. Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response. J Neurosci. 2011;31:10506-15.
72. Allen KL, Waldvogel HJ, Glass M, Faull RL. Cannabinoid (CB(1)), GABA(A) and GABA(B) receptor subunit changes in the globus pallidus in Huntington's disease. J Chem Neuroanat. 2009;37:266-81.
73. Dowie MJ, Bradshaw HB, Howard ML, Nicholson LF, Faull RL, Hannan AJ, et al. Altered CB1 receptor and endocannabinoid levels precede motor symptom onset in a transgenic mouse model of Huntington's disease. Neuroscience. 2009;163:456-65.
74. Walsh S, Mnich K, Mackie K, Gorman AM, Finn DP, Dowd E. Loss of cannabinoid CB1 receptor expression in the 6-hydroxydopamine-induced nigrostriatal terminal lesion model of Parkinson's disease in the rat. Brain Res Bull. 2010;81:543-8.
75. Spiga S, Lintas A, Migliore M, Diana M. Altered architecture and functional consequences of the mesolimbic dopamine system in cannabis dependence. Addict Biol. 2010;15:266-76.
76. Matyas F, Urban GM, Watanabe M, Mackie K, Zimmer A, Freund TF, et al. Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area. Neuropharmacology. 2008;54:95-107.
77. Dasilva M, Grieve KL, Cudeiro J, Rivadulla C. Anandamide activation of CB1 receptors increases spontaneous bursting and oscillatory activity in the thalamus. Neuroscience. 2014;265:72-82.
78. Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science. 1999;283:401-4.
79. Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci U S A. 1999;96:5780-5.
80. Polissidis A, Galanopoulos A, Naxakis G, Papahatjis D, Papadopoulou-Daifoti Z, Antoniou K. The cannabinoid CB1 receptor biphasically modulates motor activity and regulates dopamine and glutamate release region dependently. Int J Neuropsychopharmacol. 2013;16:393-403.
81. Pazos MR, Nunez E, Benito C, Tolon RM, Romero J. Functional neuroanatomy of the endocannabinoid system. Pharmacol Biochem Behav. 2005;81:239-47.
82. Stella N. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia. 2010;58:1017-30.
83. Metna-Laurent M, Marsicano G. Rising stars: Modulation of brain functions by astroglial type-1 cannabinoid receptors. Glia. 2014;63:353-64.
84. Rodriguez JJ, Mackie K, Pickel VM. Ultrastructural localization of the CB1 cannabinoid receptor in mu-opioid receptor patches of the rat Caudate putamen nucleus. J Neurosci. 2001;21:823-33.
85. Katona I, Sperlagh B, Sik A, Kafalvi A, Vizi ES, Mackie K, et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci. 1999;19:4544-58.
86. Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience. 1998;83:393-411.
87. Guzman M. Cannabinoids: potential anticancer agents. Nat Rev Cancer. 2003;3:745-55.
88. Navarrete M, Araque A. Endocannabinoids mediate neuron-astrocyte communication. Neuron. 2008;57:883-93.
89. Carrier EJ, Kearn CS, Barkmeier AJ, Breese NM, Yang W, Nithipatikom K, et al. Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol Pharmacol. 2004;65:999-1007.
90. More SV, Kumar H, Kim IS, Song SY, Choi DK. Cellular and molecular mediators of neuroinflammation in the pathogenesis of Parkinson's disease. Mediators Inflamm. 2013;2013:952375.
91. Beltramo M, Bernardini N, Bertorelli R, Campanella M, Nicolussi E, Fredduzzi S, et al. CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci. 2006;23:1530-8.
92. Hsieh GC, Pai M, Chandran P, Hooker BA, Zhu CZ, Salyers AK, et al. Central and peripheral sites of action for CB(2) receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats. Br J Pharmacol. 2011;162:428-40.
93. Ross RA, Coutts AA, McFarlane SM, Anavi-Goffer S, Irving AJ, Pertwee RG, et al. Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications for antinociception. Neuropharmacology. 2001;40:221-32.
94. Sokal DM, Elmes SJ, Kendall DA, Chapman V. Intraplantar injection of anandamide inhibits mechanically-evoked responses of spinal neurones via activation of CB2 receptors in anaesthetised rats. Neuropharmacology. 2003;45:404-11.
95. Skaper SD, Buriani A, Dal Toso R, Petrelli L, Romanello S, Facci L, et al. The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. Proc Natl Acad Sci U S A. 1996;93:3984-9.
96. Rodriguez-Cueto C, Benito C, Fernandez-Ruiz J, Romero J, Hernandez-Galvez M, Gomez-Ruiz M. Changes in CB(1) and CB(2) receptors in the post-mortem cerebellum of humans affected by spinocerebellar ataxias. Br J Pharmacol. 2014;171:1472-89.
97. Graham ES, Angel CE, Schwarcz LE, Dunbar PR, Glass M. Detailed characterisation of CB2 receptor protein expression in peripheral blood immune cells from healthy human volunteers using flow cytometry. Int J Immunopathol Pharmacol. 2010;23:25-34.
98. Stella N. Endocannabinoid signaling in microglial cells. Neuropharmacology. 2009;56 Suppl 1:244-53.
99. Merighi S, Gessi S, Varani K, Simioni C, Fazzi D, Mirandola P, et al. Cannabinoid CB(2) receptors modulate ERK-1/2 kinase signalling and NO release in microglial cells stimulated with bacterial lipopolysaccharide. Br J Pharmacol. 2012;165:1773-88.
100. Facchinetti F, Del Giudice E, Furegato S, Passarotto M, Leon A. Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. Glia. 2003;41:161-8.
101. Ashton JC, Friberg D, Darlington CL, Smith PF. Expression of the cannabinoid CB2 receptor in the rat cerebellum: an immunohistochemical study. Neurosci Lett. 2006;396:113-6.
102. Brusco A, Tagliaferro P, Saez T, Onaivi ES. Postsynaptic localization of CB2 cannabinoid receptors in the rat hippocampus. Synapse. 2008;62:944-9.
103. Klegeris A, Bissonnette CJ, McGeer PL. Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br J Pharmacol. 2003;139:775-86.
104. Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, et al. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci. 2003;23:1398-405.
105. Benito C, Nunez E, Tolon RM, Carrier EJ, Rabano A, Hillard CJ, et al. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains. J Neurosci. 2003;23:11136-41.
106. Nunez E, Benito C, Pazos MR, Barbachano A, Fajardo O, Gonzalez S, et al. Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse. 2004;53:208-13.
107. Onaivi ES. Commentary: Functional Neuronal CB2 Cannabinoid Receptors in the CNS. Curr Neuropharmacol. 2011;9:205-8.
108. Morgan NH, Stanford IM, Woodhall GL. Functional CB2 type cannabinoid receptors at CNS synapses. Neuropharmacology. 2009;57:356-68.
109. Brusco A, Tagliaferro PA, Saez T, Onaivi ES. Ultrastructural localization of neuronal brain CB2 cannabinoid receptors. Ann N Y Acad Sci. 2008;1139:450-7.
110. den Boon FS, Chameau P, Schaafsma-Zhao Q, van Aken W, Bari M, Oddi S, et al. Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors. Proc Natl Acad Sci U S A. 2012;109:3534-9.
111. Lanciego JL, Barroso-Chinea P, Rico AJ, Conte-Perales L, Callen L, Roda E, et al. Expression of the mRNA coding the cannabinoid receptor 2 in the pallidal complex of Macaca fascicularis. J Psychopharmacol. 2011;25:97-104.
112. Suarez J, Llorente R, Romero-Zerbo SY, Mateos B, Bermudez-Silva FJ, de Fonseca FR, et al. Early maternal deprivation induces gender-dependent changes on the expression of hippocampal CB(1) and CB(2) cannabinoid receptors of neonatal rats. Hippocampus. 2009;19:623-32.
113. Ternianov A, Perez-Ortiz JM, Solesio ME, Garcia-Gutierrez MS, Ortega-Alvaro A, Navarrete F, et al. Overexpression of CB2 cannabinoid receptors results in neuroprotection against behavioral and neurochemical alterations induced by intracaudate administration of 6-hydroxydopamine. Neurobiol Aging. 2012;33:421. e421-416.
114. Palazuelos J, Aguado T, Egia A, Mechoulam R, Guzman M, Galve-Roperh I. Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. FASEB J. 2006;20:2405-7.
115. Sagredo O, Gonzalez S, Aroyo I, Pazos MR, Benito C, Lastres-Becker I, et al. Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington's disease. Glia. 2009;57:1154-67.
116. Dhopeshwarkar A, Mackie K. CB2 Cannabinoid receptors as a therapeutic target-what does the future hold? Mol Pharmacol. 2014;86:430-7.
117. Mezey E, Toth ZE, Cortright DN, Arzubi MK, Krause JE, Elde R, et al. 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. 2000;97:3655-60.
118. Cristino L, de Petrocellis L, Pryce G, Baker D, Guglielmotti V, Di Marzo V. Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience. 2006;139:1405-15.
119. Cavanaugh DJ, Chesler AT, Jackson AC, Sigal YM, Yamanaka H, Grant R, et al. Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells. J Neurosci. 2011;31:5067-77.
120. Micale V, Cristino L, Tamburella A, Petrosino S, Leggio GM, Drago F, et al. Anxiolytic effects in mice of a dual blocker of fatty acid amide hydrolase and transient receptor potential vanilloid type-1 channels. Neuropsychopharmacology. 2009;34:593-606.
121. Di Marzo V, Lastres-Becker I, Bisogno T, De Petrocellis L, Milone A, Davis JB, et al. Hypolocomotor effects in rats of capsaicin and two long chain capsaicin homologues. Eur J Pharmacol. 2001;420:123-31.
122. de Lago E, de Miguel R, Lastres-Becker I, Ramos JA, Fernandez-Ruiz J. 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. 2004;1007:152-9.
123. Brown AJ. Novel cannabinoid receptors. Br J Pharmacol. 2007;152:567-75.
124. Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NO, Leonova J, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152:1092-101.
125. Sharir H, Abood ME. Pharmacological characterization of GPR55, a putative cannabinoid receptor. Pharmacol Ther. 2010;126:301-13.
126. Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng HH, et al. Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain. Brain Res Mol Brain Res. 1999;64:193-8.
127. Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T. Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun. 2007;362:928-34.
128. Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci U S A. 2008;105:2699-704.
129. Lastres-Becker I, Cebeira M, de Ceballos ML, Zeng BY, Jenner P, Ramos JA, et al. 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. 2001;14:1827-32.
130. van der Stelt M, Fox SH, Hill M, Crossman AR, Petrosino S, Di Marzo V, et al. 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. 2005;19:1140-2.
131. Meschler JP, Howlett AC, Madras BK. Cannabinoid receptor agonist and antagonist effects on motor function in normal and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated non-human primates. Psychopharmacology (Berl). 2001;156:79-85.
132. Centonze D, Finazzi-Agro A, Bernardi G, Maccarrone M. The endocannabinoid system in targeting inflammatory neurodegenerative diseases. Trends Pharmacol Sci. 2007;28:180-7.
133. Van Laere K, Casteels C, Lunskens S, Goffin K, Grachev ID, Bormans G, et al. Regional changes in type 1 cannabinoid receptor availability in Parkinson's disease in vivo. Neurobiol Aging. 2012;33:620. e621-628.
134. Prescott WR, Gold LH, Martin BR. Evidence for separate neuronal mechanisms for the discriminative stimulus and catalepsy induced by delta 9-THC in the rat. Psychopharmacology (Berl). 1992;107:117-24.
135. Crawley JN, Corwin RL, Robinson JK, Felder CC, Devane WA, Axelrod J. Anandamide, an endogenous ligand of the cannabinoid receptor, induces hypomotility and hypothermia in vivo in rodents. Pharmacol Biochem Behav. 1993;46:967-72.
136. Anderson LA, Anderson JJ, Chase TN, Walters JR. The cannabinoid agonists WIN 55,212-2 and CP 55,940 attenuate rotational behavior induced by a dopamine D1 but not a D2 agonist in rats with unilateral lesions of the nigrostriatal pathway. Brain Res. 1995;691:106-14.
137. Romero J, Garcia L, Cebeira M, Zadrozny D, Fernandez-Ruiz JJ, Ramos JA. The endogenous cannabinoid receptor ligand, anandamide, inhibits the motor behavior: role of nigrostriatal dopaminergic neurons. Life Sci. 1995;56:2033-40.
138. Fernandez-Ruiz J. The endocannabinoid system as a target for the treatment of motor dysfunction. Br J Pharmacol. 2009;156:1029-40.
139. Perez-Rial S, Garcia-Gutierrez MS, Molina JA, Perez-Nievas BG, Ledent C, Leiva C, et al. Increased vulnerability to 6-hydroxydopamine lesion and reduced development of dyskinesias in mice lacking CB1 cannabinoid receptors. Neurobiol Aging. 2011;32:631-45.
140. Shabani M, Hosseinmardi N, Haghani M, Shaibani V, Janahmadi M. Maternal exposure to the CB1 cannabinoid agonist WIN 55212-2 produces robust changes in motor function and intrinsic electrophysiological properties of cerebellar Purkinje neurons in rat offspring. Neuroscience. 2011;172:139-52.
141. French ED, Dillon K, Wu X. Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. Neuroreport. 1997;8:649-52.
142. Melis M, Gessa GL, Diana M. Different mechanisms for dopaminergic excitation induced by opiates and cannabinoids in the rat midbrain. Prog Neuropsychopharmacol Biol Psychiatry. 2000;24:993-1006.
143. Morera-Herreras T, Ruiz-Ortega JA, Gomez-Urquijo S, Ugedo L. Involvement of subthalamic nucleus in the stimulatory effect of Delta(9)-tetrahydrocannabinol on dopaminergic neurons. Neuroscience. 2008;151:817-23.
144. Lane DA, Chan J, Lupica CR, Pickel VM. Cannabinoid-1 receptor gene deletion has a compartment-specific affect on the dendritic and axonal availability of mu-opioid receptors and on dopamine axons in the mouse nucleus accumbens. Synapse. 2010;64:886-97.
145. Tanda G, Pontieri FE, Di Chiara G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science. 1997;276:2048-50.
146. Solinas M, Justinova Z, Goldberg SR, Tanda G. Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J Neurochem. 2006;98:408-19.
147. Pisani V, Moschella V, Bari M, Fezza F, Galati S, Bernardi G, et al. Dynamic changes of anandamide in the cerebrospinal fluid of Parkinson's disease patients. Mov Disord. 2010;25:920-4.
148. Venderova K, Ruzicka E, Vorisek V, Visnovsky P. Survey on cannabis use in Parkinson's disease: subjective improvement of motor symptoms. Mov Disord. 2004;19:1102-6.
149. Sieradzan KA, Fox SH, Hill M, Dick JP, Crossman AR, Brotchie JM. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study. Neurology. 2001;57:2108-11.
150. Carroll CB, Bain PG, Teare L, Liu X, Joint C, Wroath C, et al. Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study. Neurology. 2004;63:1245-50.
151. Mesnage V, Houeto JL, Bonnet AM, Clavier I, Arnulf I, Cattelin F, et al. Neurokinin B, neurotensin, and cannabinoid receptor antagonists and Parkinson disease. Clin Neuropharmacol. 2004;27:108-10.
152. DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch Neurol. 2007;64:20-4.
153. Surmeier DJ, Ding J, Day M, Wang Z, Shen W. D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci. 2007;30:228-35.
154. Grillner S, Hellgren J, Menard A, Saitoh K, Wikstrom MA. Mechanisms for selection of basic motor programs-roles for the striatum and pallidum. Trends Neurosci. 2005;28:364-70.
155. Bezard E, Brotchie JM, Gross CE. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci. 2001;2:577-88.
156. Hasbi A, Fan T, Alijaniaram M, Nguyen T, Perreault ML, O'Dowd BF, et al. Calcium signaling cascade links dopamine D1-D2 receptor heteromer to striatal BDNF production and neuronal growth. Proc Natl Acad Sci U S A. 2009;106:21377-82.
157. Perreault ML, Hasbi A, O'Dowd BF, George SR. Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance. Neuropsychopharmacology. 2014;39:156-68.
158. Calabresi P, Picconi B, Tozzi A, Di Filippo M. Dopamine-mediated regulation of corticostriatal synaptic plasticity. Trends Neurosci. 2007;30:211-9.
159. Russo SJ, Mazei-Robison MS, Ables JL, Nestler EJ. Neurotrophic factors and structural plasticity in addiction. Neuropharmacology. 2009;56 Suppl 1:73-82.
160. Brotchie JM. CB1 cannabinoid receptor signalling in Parkinson's disease. Curr Opin Pharmacol. 2003;3:54-61.
161. van der Stelt M, Di Marzo V. The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders. Eur J Pharmacol. 2003;480:133-50.
162. Aceves JJ, Rueda-Orozco PE, Hernandez-Martinez R, Galarraga E, Bargas J. Bidirectional plasticity in striatonigral synapses: a switch to balance direct and indirect basal ganglia pathways. Learn Mem. 2011;18:764-73.
163. Benarroch E. Endocannabinoids in basal ganglia circuits: implications for Parkinson disease. Neurology. 2007;69:306-9.
164. Huot P, Brotchie JM. 5-HT(1A) receptor stimulation and L-DOPA-induced dyskinesia in Parkinson's disease: bridging the gap between serotonergic and glutamatergic mechanisms. Exp Neurol. 2011;231:195-8.
165. Adermark L, Talani G, Lovinger DM. Endocannabinoid-dependent plasticity at GABAergic and glutamatergic synapses in the striatum is regulated by synaptic activity. Eur J Neurosci. 2009;29:32-41.
166. Mathur BN, Lovinger DM. Endocannabinoid-dopamine interactions in striatal synaptic plasticity. Front Pharmacol. 2012;3:66.
167. Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science. 2002;296:678-82.
168. Meschler JP, Howlett AC. Signal transduction interactions between CB1 cannabinoid and dopamine receptors in the rat and monkey striatum. Neuropharmacology. 2001;40:918-26.
169. Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 1997;77:299-318.
170. Marcellino D, Carriba P, Filip M, Borgkvist A, Frankowska M, Bellido I, et al. Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis. Neuropharmacology. 2008;54:815-23.
171. Jarrahian A, Watts VJ, Barker EL. D2 dopamine receptors modulate Galpha-subunit coupling of the CB1 cannabinoid receptor. J Pharmacol Exp Ther. 2004;308:880-6.
172. Pickel VM, Chan J, Kearn CS, Mackie K. Targeting dopamine D2 and cannabinoid-1 (CB1) receptors in rat nucleus accumbens. J Comp Neurol. 2006;495:299-313.
173. Kearn CS, Blake-Palmer K, Daniel E, Mackie K, Glass M. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk? Mol Pharmacol. 2005;67:1697-704.
174. Kreitzer AC, Malenka RC. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. Nature. 2007;445:643-7.
175. Callen L, Moreno E, Barroso-Chinea P, Moreno-Delgado D, Cortes A, Mallol J, et al. Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. J Biol Chem. 2012;287:20851-65.
176. Freestone PS, Guatteo E, Piscitelli F, di Marzo V, Lipski J, Mercuri NB. Glutamate spillover drives endocannabinoid production and inhibits GABAergic transmission in the Substantia Nigra pars compacta. Neuropharmacology. 2014;79:467-75.
177. Marinelli S, Di Marzo V, Florenzano F, Fezza F, Viscomi MT, van der Stelt M, et al. N-arachidonoyl-dopamine tunes synaptic transmission onto dopaminergic neurons by activating both cannabinoid and vanilloid receptors. Neuropsychopharmacology. 2007;32:298-308.
178. Bari M, Bonifacino T, Milanese M, Spagnuolo P, Zappettini S, Battista N, et al. The endocannabinoid system in rat gliosomes and its role in the modulation of glutamate release. Cell Mol Life Sci. 2011;68:833-45.
179. Grueter BA, Brasnjo G, Malenka RC. Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens. Nat Neurosci. 2010;13:1519-25.
180. Morgante F, Espay AJ, Gunraj C, Lang AE, Chen R. Motor cortex plasticity in Parkinson's disease and levodopa-induced dyskinesias. Brain. 2006;129:1059-69.
181. Picconi B, Centonze D, Hakansson K, Bernardi G, Greengard P, Fisone G, et al. Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat Neurosci. 2003;6:501-6.
182. Gerdeman GL, Ronesi J, Lovinger DM. Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci. 2002;5:446-51.
183. Kreitzer AC, Malenka RC. Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum. J Neurosci. 2005;25:10537-45.
184. Ronesi J, Gerdeman GL, Lovinger DM. Disruption of endocannabinoid release and striatal long-term depression by postsynaptic blockade of endocannabinoid membrane transport. J Neurosci. 2004;24:1673-9.
185. Nazzaro C, Greco B, Cerovic M, Baxter P, Rubino T, Trusel M, et al. SK channel modulation rescues striatal plasticity and control over habit in cannabinoid tolerance. Nat Neurosci. 2012;15:284-93.
186. Pisani V, Madeo G, Tassone A, Sciamanna G, Maccarrone M, Stanzione P, et al. Homeostatic changes of the endocannabinoid system in Parkinson's disease. Mov Disord. 2011;26:216-22.
187. Di Filippo M, Picconi B, Tozzi A, Ghiglieri V, Rossi A, Calabresi P. The endocannabinoid system in Parkinson's disease. Curr Pharm Des. 2008;14:2337-47.
188. Fusco FR, Martorana A, Giampa C, De March Z, Farini D, D'Angelo V, et al. Immunolocalization of CB1 receptor in rat striatal neurons: a confocal microscopy study. Synapse. 2004;53:159-67.
189. Picconi B, Bagetta V, Ghiglieri V, Paille V, Di Filippo M, Pendolino V, et al. Inhibition of phosphodiesterases rescues striatal long-term depression and reduces levodopa-induced dyskinesia. Brain. 2011;134:375-87.
190. Calabresi P, Gubellini P, Centonze D, Sancesario G, Morello M, Giorgi M, et al. A critical role of the nitric oxide/cGMP pathway in corticostriatal long-term depression. J Neurosci. 1999;19:2489-99.
191. Consroe P. Brain cannabinoid systems as targets for the therapy of neurological disorders. Neurobiol Dis. 1998;5:534-51.
192. Muller-Vahl KR, Kolbe H, Schneider U, Emrich HM. Cannabis in movement disorders. Forsch Komplementarmed. 1999;6 Suppl 3:23-7.
193. Papa SM. The cannabinoid system in Parkinson's disease: multiple targets to motor effects. Exp Neurol. 2008;211:334-8.
194. Heumann R, Moratalla R, Herrero MT, Chakrabarty K, Drucker-Colin R, Garcia-Montes JR, et al. Dyskinesia in Parkinson's disease: mechanisms and current non-pharmacological interventions. J Neurochem. 2014;130:472-89.
195. Price DA, Owens WA, Gould GG, Frazer A, Roberts JL, Daws LC, et al. CB1-independent inhibition of dopamine transporter activity by cannabinoids in mouse dorsal striatum. J Neurochem. 2007;101:389-96.
196. Gonzalez-Aparicio R, Moratalla R. Oleoylethanolamide reduces L-DOPA-induced dyskinesia via TRPV1 receptor in a mouse model of Parkinson s disease. Neurobiol Dis. 2014;62:416-25.
197. Maneuf YP, Crossman AR, Brotchie JM. The cannabinoid receptor agonist WIN 55,212-2 reduces D2, but not D1, dopamine receptor-mediated alleviation of akinesia in the reserpine-treated rat model of Parkinson's disease. Exp Neurol. 1997;148:265-70.
198. Huang P, Liu-Chen LY, Unterwald EM, Cowan A. Hyperlocomotion and paw tremors are two highly quantifiable signs of SR141716-precipitated withdrawal from delta9-tetrahydrocannabinol in C57BL/6 mice. Neurosci Lett. 2009;465:66-70.
199. Fernandez-Espejo E, Caraballo I, de Fonseca FR, El Banoua F, Ferrer B, Flores JA, et al. Cannabinoid CB1 antagonists possess antiparkinsonian efficacy only in rats with very severe nigral lesion in experimental parkinsonism. Neurobiol Dis. 2005;18:591-601.
200. Gonzalez S, Scorticati C, Garcia-Arensibia M, de Miguel R, Ramos JA, Vernandez-Ruiz J. Effects of rimnabant, a selective cannabinoid CB1 receptor antagonist, in a rat model of Parkinson's disease.0Brain Res. 2006;1073-1074:209-19.
201. Garcia-Arencibia M, Ferraro L, Tanganelli S, Fernandez-Ruiz J. Enhanced striatal glutamqte release after the administration of rimonabant to 6-hydroxyd pamine-lesioned rats. Neurosciett. 2008;438:10-3.
202. Nutt JG. Clinical pharmacology of levodopa-induced dyskinesia. An~ Neurol. 2000;47:S160-4. discussion S164-166.
203. Obeso JA, Olanow CW, Nutt JG. Levodopa motor complications in Parkinson's disease. Trends Neurosci. 2000;23:S2-7.
204. Ferrer B, Asbrock N, Kathuria S Piomelli D, Giuffrida A. Effects of levodopa on endocannabinoid levels in rat basal ganglia: implications for the treatment of levodopa-induced dyskinesias. Eur J Neurosci. 2003;18:1607-14.
205. Fox SH, Henry B, Hill M, Crossman A, Brotchie J. Stimulation of cannabinoid receptors reduces levodopa-induced dyskinesia in the MPTP-lesioned nonhuman primate model of Parkinson's disease. Mov Disord. 2002;17:1180-7.
206. Cao X, Liang L, Hadcock JR, Iredale PA, Griffith DA, Menniti FS, et al. 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. 2007;323:318-26.
207. Giorgi M, D'Angelo V, Esposito Z, Nuccetelli V, Sorge R, Martorana A, et al. Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias in hemiparkinsonian rats: new aspects in the pathogenetic mechanisms. Eur J Neurosci. 2008;28:941-50.
208. Rylander D, Parent M, O'Sullivan SS, Dovero S, Lees AJ, Bezard E, et al. Maladaptive plasticity of serotonin axon terminals in levodopa-induced dyskinesia. Ann Neurol. 2010;68:619-28.
209. Carta M, Carlsson T, Kirik D, Bjorklund A. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain. 2007;130:1819-33.
210. Lerner TN, Kreitzer AC. RGS4 is required for dopaminergic control of striatal LTD and susceptibility to parkinsonian motor deficits. Neuron. 2012;73:347-59.
211. Marinelli S, Di Marzo V, Berretta N, Matias I, Maccarrone M, Bernardi G, et al. Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors. J Neurosci. 2003;23:3136-44.
212. Lourenco J, Cannich A, Carta M, Coussen F, Mulle C, Marsicano G. Synaptic activation of kainate receptors gates presynaptic CB(1) signaling at GABAergic synapses. Nat Neurosci. 2010;13:197-204.
213. Gubellini P, Picconi B, Bari M, Battista N, Calabresi P, Centonze D, et al. Experimental parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission. J Neurosci. 2002;22:6900-7.
214. Paquette MA, Anderson AM, Lewis JR, Meshul CK, Johnson SW, Paul Berger S. MK-801 inhibits L-DOPA-induced abnormal involuntary movements only at doses that worsen parkinsonism. Neuropharmacology. 2010;58:1002-8.
215. Wolf E, Seppi K, Katzenschlager R, Hochschorner G, Ransmayr G, Schwingenschuh P, et al. Long-term antidyskinetic efficacy of amantadine in Parkinson's disease. Mov Disord. 2010;25:1357-63.
216. Ahmed I, Bose SK, Pavese N, Ramlackhansingh A, Turkheimer F, Hotton G, et al. Glutamate NMDA receptor dysregulation in Parkinson's disease with dyskinesias. Brain. 2011;134:979-86.
217. Pertwee RG, Wickens AP. Enhancement by chlordiazepoxide of catalepsy induced in rats by intravenous or intrapallidal injections of enantiomeric cannabinoids. Neuropharmacology. 1991;30:237-44.
218. Ferre S, Lluis C, Justinova Z, Quiroz C, Orru M, Navarro G, et al. Adenosine-cannabinoid receptor interactions. Implications for striatal function. Br J Pharmacol. 2010;160:443-53.
219. El-Banoua F, Caraballo I, Flores JA, Galan-Rodriguez B, Fernandez-Espejo E. Effects on turning of microinjections into basal ganglia of D(1) and D(2) dopamine receptors agonists and the cannabinoid CB(1) antagonist SR141716A in a rat Parkinson's model. Neurobiol Dis. 2004;16:377-85.
220. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400:452-7.
221. Smart D, Gunthorpe MJ, Jerman JC, Nasir S, Gray J, Muir AI, et al. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol. 2000;129:227-30.
222. Ho KW, Ward NJ, Calkins DJ. TRPV1: a stress response protein in the central nervous system. Am J Neurodegener Dis. 2012;1:1-14.
223. Morgese MG, Cassano T, Cuomo V, Giuffrida A. Anti-dyskinetic effects of cannabinoids in a rat model of Parkinson's disease: role of CB(1) and TRPV1 receptors. Exp Neurol. 2007;208:110-9.
224. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816-24.
225. Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fernandez-Ruiz J. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson's disease. Neurobiol Dis. 2005;19:96-107.
226. Ross RA. Anandamide and vanilloid TRPV1 receptors. Br J Pharmacol. 2003;140:790-801.
227. Lee J, Di Marzo V, Brotchie JM. A role for vanilloid receptor 1 (TRPV1) and endocannabinnoid signalling in the regulation of spontaneous and L-DOPA induced locomotion in normal and reserpine-treated rats. Neuropharmacology. 2006;51:557-65.
228. Kim SR, Lee DY, Chung ES, Oh UT, Kim SU, Jin BK. Transient receptor potential vanilloid subtype 1 mediates cell death of mesencephalic dopaminergic neurons in vivo and in vitro. J Neurosci. 2005;25:662-71.
229. Garcia Mdel C, Adler-Graschinsky E, Celuch SM. Enhancement of the hypotensive effects of intrathecally injected endocannabinoids by the entourage compound palmitoylethanolamide. Eur J Pharmacol. 2009;610:75-80.
230. Di Marzo V, Bisogno T, De Petrocellis L. Anandamide: some like it hot. Trends Pharmacol Sci. 2001;22:346-9.
231. Patwardhan AM, Jeske NA, Price TJ, Gamper N, Akopian AN, Hargreaves KM. The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin. Proc Natl Acad Sci U S A. 2006;103:11393-8.
232. Begg M, Pacher P, Batkai S, Osei-Hyiaman D, Offertaler L, Mo FM, et al. Evidence for novel cannabinoid receptors. Pharmacol Ther. 2005;106:133-45.
233. Guzman M. Effects on cell viability. Handb Exp Pharmacol. 2005;168:627-42.
234. Javier Fernández-Ruiz SG, Julián R, José Antonio R. Cannabinoids in neurodegeneration and neuroprotection. In: Mechoulam R, editor. Cannabinoids as Therapeutics. Birkhäuser Basel: Springer Science & Business Media; 2005. p. 79-109.
235. Mechoulam R, Shohami E. Endocannabinoids and traumatic brain injury. Mol Neurobiol. 2007;36:68-74.
236. Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci. 2012;367:3353-63.
237. Galve-Roperh I, Aguado T, Palazuelos J, Guzman M. The endocannabinoid system and neurogenesis in health and disease. Neuroscientist. 2007;13:109-14.
238. Hillard CJ. Role of cannabinoids and endocannabinoids in cerebral ischemia. Curr Pharm Des. 2008;14:2347-61.
239. Fernandez-Ruiz J, Romero J, Velasco G, Tolon RM, Ramos JA, Guzman M. Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol Sci. 2007;28:39-45.
240. de Lago E, Fernandez-Ruiz J. Cannabinoids and neuroprotection in motor-related disorders. CNS Neurol Disord Drug Targets. 2007;6:377-87.
241. Garcia-Arencibia M, Garcia C, Fernandez-Ruiz J. Cannabinoids and Parkinson's disease. CNS Neurol Disord Drug Targets. 2009;8:432-9.
242. England TJ, Hind WH, Rasid NA, O'Sullivan SE. Cannabinoids in experimental stroke: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2015;35:348-58.
243. Capettini LS, Savergnini SQ, da Silva RF, Stergiopulos N, Santos RA, Mach F, et al. Update on the role of cannabinoid receptors after ischemic stroke. Mediators Inflamm. 2012;2012:824093.
244. Rangel-Lopez E, Colin-Gonzalez AL, Paz-Loyola AL, Pinzon E, Torres I, Serratos IN, et al. Cannabinoid receptor agonists reduce the short-term mitochondrial dysfunction and oxidative stress linked to excitotoxicity in the rat brain. Neuroscience. 2015;285:97-106.
245. Zogopoulos P, Vasileiou I, Patsouris E, Theocharis S. The neuroprotective role of endocannabinoids against chemical-induced injury and other adverse effects. J Appl Toxicol. 2013;33:246-64.
246. Vendel E, de Lange EC. Functions of the CB1 and CB 2 receptors in neuroprotection at the level of the blood-brain barrier. Neuromolecular Med. 2014;16:620-42.
247. Ashton JC, Rahman RM, Nair SM, Sutherland BA, Glass M, Appleton I. Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain. Neurosci Lett. 2007;412:114-7.
248. Palazuelos J, Aguado T, Pazos MR, Julien B, Carrasco C, Resel E, et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity. Brain. 2009;132:3152-64.
249. Nunez E, Benito C, Tolon RM, Hillard CJ, Griffin WS, Romero J. Glial expression of cannabinoid CB(2) receptors and fatty acid amide hydrolase are beta amyloid-linked events in Down's syndrome. Neuroscience. 2008;151:104-10.
250. Benito C, Romero JP, Tolon RM, Clemente D, Docagne F, Hillard CJ, et al. Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci. 2007;27:2396-402.
251. Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, et al. COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol. 2006;6:12.
252. Esposito G, Iuvone T, Savani C, Scuderi C, De Filippis D, Papa M, et al. Opposing control of cannabinoid receptor stimulation on amyloid-beta-induced reactive gliosis: in vitro and in vivo evidence. J Pharmacol Exp Ther. 2007;322:1144-52.
253. Kong W, Li H, Tuma RF, Ganea D. Selective CB2 receptor activation ameliorates EAE by reducing Th17 differentiation and immune cell accumulation in the CNS. Cell Immunol. 2014;287:1-17.
254. Zhang M, Martin BR, Adler MW, Razdan RK, Jallo JI, Tuma RF. Cannabinoid CB(2) receptor activation decreases cerebral infarction in a mouse focal ischemia/reperfusion model. J Cereb Blood Flow Metab. 2007;27:1387-96.
255. Martin-Moreno AM, Brera B, Spuch C, Carro E, Garcia-Garcia L, Delgado M, et al. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflammation. 2012;9:8.
256. Kim K, Moore DH, Makriyannis A, Abood ME. AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis. Eur J Pharmacol. 2006;542:100-5.
257. Viscomi MT, Oddi S, Latini L, Pasquariello N, Florenzano F, Bernardi G, et al. Selective CB2 receptor agonism protects central neurons from remote axotomy-induced apoptosis through the PI3K/Akt pathway. J Neurosci. 2009;29:4564-70.
258. Fernandez-Ruiz J, Garcia C, Sagredo O, Gomez-Ruiz M, de Lago E. The endocannabinoid system as a target for the treatment of neuronal damage. Expert Opin Ther Targets. 2010;14:387-404.
259. Kamat PK, Kalani A, Kyles P, Tyagi SC, Tyagi N. Autophagy of Mitochondria: A Promising Therapeutic Target for Neurodegenerative Disease. Cell Biochem Biophys. 2014;70:707-19.
260. Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J. 2012;441:523-40.
261. Hernandes MS, Cafe-Mendes CC, Britto LR. NADPH oxidase and the degeneration of dopaminergic neurons in parkinsonian mice. Oxid Med Cell Longev. 2013;2013:157857.
262. Hebert-Chatelain E, Reguero L, Puente N, Lutz B, Chaouloff F, Rossignol R, et al. Cannabinoid control of brain bioenergetics: Exploring the subcellular localization of the CB1 receptor. Molecular Metabolism. 2014;3:495-504.
263. Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci. 2011;88:730-6.
264. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A. 1998;95:8268-73.
265. Comelli F, Bettoni I, Colleoni M, Giagnoni G, Costa B. Beneficial effects of a Cannabis sativa extract treatment on diabetes-induced neuropathy and oxidative stress. Phytother Res. 2009;23:1678-84.
266. Cassol-Jr OJ, Comim CM, Silva BR, Hermani FV, Constantino LS, Felisberto F, et al. Treatment with cannabidiol reverses oxidative stress parameters, cognitive impairment and mortality in rats submitted to sepsis by cecal ligation and puncture. Brain Res. 2010;1348:128-38.
267. Velez-Pardo C, Jimenez-Del-Rio M, Lores-Arnaiz S, Bustamante J. Protective effects of the synthetic cannabinoids CP55,940 and JWH-015 on rat brain mitochondria upon paraquat exposure. Neurochem Res. 2010;35:1323-32.
268. Pan H, Mukhopadhyay P, Rajesh M, Patel V, Mukhopadhyay B, Gao B, et al. Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death. J Pharmacol Exp Ther. 2009;328:708-14.
269. Garcia-Arencibia M, Gonzalez S, de Lago E, Ramos JA, Mechoulam R, Fernandez-Ruiz J. 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. 2007;1134:162-70.
270. Campillo NE, Paez JA. Cannabinoid system in neurodegeneration: new perspectives in Alzheimer's disease. Mini Rev Med Chem. 2009;9:539-59.
271. Juknat A, Pietr M, Kozela E, Rimmerman N, Levy R, Gao F, et al. Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 microglial cells. PLoS One. 2013;8:e61462.
272. Juknat A, Pietr M, Kozela E, Rimmerman N, Levy R, Coppola G, et al. Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Delta9-tetrahydrocannabinol in BV-2 microglial cells. Br J Pharmacol. 2012;165:2512-28.
273. Garcia C, Palomo-Garo C, Garcia-Arencibia M, Ramos J, Pertwee R, Fernandez-Ruiz J. Symptom-relieving and neuroprotective effects of the phytocannabinoid Delta(9)-THCV in animal models of Parkinson's disease. Br J Pharmacol. 2011;163:1495-506.
274. Esposito G, Scuderi C, Savani C, Steardo Jr L, De Filippis D, Cottone P, et al. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol. 2007;151:1272-9.
275. Na SJ, DiLella AG, Lis EV, Jones K, Levine DM, Stone DJ, et al. Molecular profiling of a 6-hydroxydopamine model of Parkinson's disease. Neurochem Res. 2010;35:761-72.
276. Marchalant Y, Brothers HM, Norman GJ, Karelina K, DeVries AC, Wenk GL. Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis. Neurobiol Dis. 2009;34:300-7.
277. Martin-Moreno AM, Reigada D, Ramirez BG, Mechoulam R, Innamorato N, Cuadrado A, et al. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease. Mol Pharmacol. 2011;79:964-73.
278. Esposito G, De Filippis D, Maiuri MC, De Stefano D, Carnuccio R, Iuvone T. 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. 2006;399:91-5.
279. O'Sullivan SE, Kendall DA. Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease. Immunobiology. 2010;215:611-6.
280. Esposito G, Scuderi C, Valenza M, Togna GI, Latina V, De Filippis D, et al. Cannabidiol reduces Abeta-induced neuroinflammation and promotes hippocampal neurogenesis through PPARgamma involvement. PLoS One. 2011;6:e28668.
281. Hill AJ, Williams CM, Whalley BJ, Stephens GJ. Phytocannabinoids as novel therapeutic agents in CNS disorders. Pharmacol Ther. 2012;133:79-97.
282. Ullrich O, Merker K, Timm J, Tauber S. Immune control by endocannabinoids - new mechanisms of neuroprotection? J Neuroimmunol. 2007;184:127-35.
283. Helton TD, Otsuka T, Lee MC, Mu Y, Ehlers MD. Pruning and loss of excitatory synapses by the parkin ubiquitin ligase. Proc Natl Acad Sci U S A. 2008;105:19492-7.
284. Lang AE, Lozano AM. Parkinson's disease. First of two parts. N Engl J Med. 1998;339:1044-53.
285. Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther. 1999;81:163-221.
286. Juttler E, Potrovita I, Tarabin V, Prinz S, Dong-Si T, Fink G, et al. The cannabinoid dexanabinol is an inhibitor of the nuclear factor-kappa B (NF-kappa B). Neuropharmacology. 2004;47:580-92.
287. Sanchez-Blazquez P, Rodriguez-Munoz M, Vicente-Sanchez A, Garzon J. Cannabinoid receptors couple to NMDA receptors to reduce the production of NO and the mobilization of zinc induced by glutamate. Antioxid Redox Signal. 2013;19:1766-82.
288. Janero DR, Vadivel SK, Makriyannis A. Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders: drug-discovery strategies. Int Rev Psychiatry. 2009;21:122-33.
289. Naidoo V, Nikas SP, Karanian DA, Hwang J, Zhao J, Wood JT, et al. A new generation fatty acid amide hydrolase inhibitor protects against kainate-induced excitotoxicity. J Mol Neurosci. 2011;43:493-502.
290. Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003;302:84-8.
291. Zhao P, Leonoudakis D, Abood ME, Beattie EC. Cannabinoid receptor activation reduces TNFalpha-induced surface localization of AMPAR-type glutamate receptors and excitotoxicity. Neuropharmacology. 2010;58:551-8.
292. Pintor A, Tebano MT, Martire A, Grieco R, Galluzzo M, Scattoni ML, et al. The cannabinoid receptor agonist WIN 55,212-2 attenuates the effects induced by quinolinic acid in the rat striatum. Neuropharmacology. 2006;51:1004-12.
293. Grundy RI, Rabuffetti M, Beltramo M. Cannabinoids and neuroprotection. Mol Neurobiol. 2001;24:29-51.
294. van der Stelt M, Veldhuis WB, van Haaften GW, Fezza F, Bisogno T, Bar PR, et al. Exogenous anandamide protects rat brain against acute neuronal injury in vivo. J Neurosci. 2001;21:8765-71.
295. Abood ME, Rizvi G, Sallapudi N, McAllister SD. Activation of the CB1 cannabinoid receptor protects cultured mouse spinal neurons against excitotoxicity. Neurosci Lett. 2001;309:197-201.
296. Shen M, Thayer SA. Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol Pharmacol. 1998;54:459-62.
297. Nagayama T, Sinor AD, Simon RP, Chen J, Graham SH, Jin K, et al. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci. 1999;19:2987-95.
298. van der Stelt M, Veldhuis WB, Maccarrone M, Bar PR, Nicolay K, Veldink GA, et al. Acute neuronal injury, excitotoxicity, and the endocannabinoid system. Mol Neurobiol. 2002;26:317-46.
299. Chiarlone A, Bellocchio L, Blazquez C, Resel E, Soria-Gomez E, Cannich A, et al. A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proc Natl Acad Sci U S A. 2014;111:8257-62.
300. Stauffer B, Wallis KT, Wilson SP, Egertova M, Elphick MR, Lewis DL, et al. CRIP1a switches cannabinoid receptor agonist/antagonist-mediated protection from glutamate excitotoxicity. Neurosci Lett. 2011;503:224-8.
301. Nadler V, Mechoulam R, Sokolovsky M. Blockade of 45Ca2+ influx through the N-methyl-D-aspartate receptor ion channel by the non-psychoactive cannabinoid HU-211. Brain Res. 1993;622:79-85.
302. Nadler V, Biegon A, Beit-Yannai E, Adamchik J, Shohami E. 45Ca accumulation in rat brain after closed head injury; attenuation by the novel neuroprotective agent HU-211. Brain Res. 1995;685:1-11.
303. Eshhar N, Striem S, Kohen R, Tirosh O, Biegon A. Neuroprotective and antioxidant activities of HU-211, a novel NMDA receptor antagonist. Eur J Pharmacol. 1995;283:19-29.
304. Hampson AJ, Bornheim LM, Scanziani M, Yost CS, Gray AT, Hansen BM, et al. Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission. J Neurochem. 1998;70:671-6.
305. Sanudo-Pena MC, Patrick SL, Khen S, Patrick RL, Tsou K, Walker JM. Cannabinoid effects in basal ganglia in a rat model of Parkinson's disease. Neurosci Lett. 1998;248:171-4.
306. Blandini F, Nappi G, Tassorelli C, Martignoni E. Functional changes of the basal ganglia circuitry in Parkinson's disease. Prog Neurobiol. 2000;62:63-88.
307. Frankel JP, Hughes A, Lees AJ, Stern GM. Marijuana for parkinsonian tremor. J Neurol Neurosurg Psychiatry. 1990;53:436.
308. Fagan SG, Campbell VA. The influence of cannabinoids on generic traits of neurodegeneration. Br J Pharmacol. 2014;171:1347-60.
309. More SV, Koppula S, Kim IS, Kumar H, Kim BW, Choi DK. The role of bioactive compounds on the promotion of neurite outgrowth. Molecules. 2012;17:6728-53.
310. Maccarrone M, Guzman M, Mackie K, Doherty P, Harkany T. Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat Rev Neurosci. 2014;15:786-801.
311. Jin K, Xie L, Kim SH, Parmentier-Batteur S, Sun Y, Mao XO, et al. Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice. Mol Pharmacol. 2004;66:204-8.
312. Aguado T, Romero E, Monory K, Palazuelos J, Sendtner M, Marsicano G, et al. The CB1 cannabinoid receptor mediates excitotoxicity-induced neural progenitor proliferation and neurogenesis. J Biol Chem. 2007;282:23892-8.
313. Molina-Holgado F, Rubio-Araiz A, Garcia-Ovejero D, Williams RJ, Moore JD, Arevalo-Martin A, et al. CB2 cannabinoid receptors promote mouse neural stem cell proliferation. Eur J Neurosci. 2007;25:629-34.
314. Garcia-Ovejero D, Arevalo-Martin A, Navarro-Galve B, Pinteaux E, Molina-Holgado E, Molina-Holgado F. Neuroimmmune interactions of cannabinoids in neurogenesis: focus on interleukin-1beta (IL-1beta) signalling. Biochem Soc Trans. 2013;41:1577-82.
315. Skaper SD, Di Marzo V. Endocannabinoids in nervous system health and disease: the big picture in a nutshell. Philos Trans R Soc Lond B Biol Sci. 2012;367:3193-200.
316. Marxreiter F, Regensburger M, Winkler J. Adult neurogenesis in Parkinson's disease. Cell Mol Life Sci. 2013;70:459-73.
317. Le Grand JN, Gonzalez-Cano L, Pavlou MA, Schwamborn JC. Neural stem cells in Parkinson's disease: a role for neurogenesis defects in onset and progression. Cell Mol Life Sci. 2015;72:773-97.
318. Peng J, Andersen JK. Mutant alpha-synuclein and aging reduce neurogenesis in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. Aging Cell. 2011;10:255-62.
319. Desplats P, Spencer B, Crews L, Pathel P, Morvinski-Friedmann D, Kosberg K, et al. alpha-Synuclein induces alterations in adult neurogenesis in Parkinson disease models via p53-mediated repression of Notch1. J Biol Chem. 2012;287:31691-702.
320. Marxreiter F, Ettle B, May VE, Esmer H, Patrick C, Kragh CL, et al. Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice. Neurobiol Dis. 2013;59:38-51.
321. Khaspekov LG, Brenz Verca MS, Frumkina LE, Hermann H, Marsicano G, Lutz B. Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity. Eur J Neurosci. 2004;19:1691-8.
322. Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol. 2005;192:348-56.
323. Ventriglia M, Zanardini R, Bonomini C, Zanetti O, Volpe D, Pasqualetti P, et al. Serum brain-derived neurotrophic factor levels in different neurological diseases. Biomed Res Int. 2013;2013:901082.
324. Scalzo P, Kummer A, Bretas TL, Cardoso F, Teixeira AL. Serum levels of brain-derived neurotrophic factor correlate with motor impairment in Parkinson's disease. J Neurol. 2010;257:540-5.
325. Maison P, Walker DJ, Walsh FS, Williams G, Doherty P. BDNF regulates neuronal sensitivity to endocannabinoids. Neurosci Lett. 2009;467:90-4.
326. Kim SH, Won SJ, Mao XO, Ledent C, Jin K, Greenberg DA. Role for neuronal nitric-oxide synthase in cannabinoid-induced neurogenesis. J Pharmacol Exp Ther. 2006;319:150-4.
327. Goncalves MB, Suetterlin P, Yip P, Molina-Holgado F, Walker DJ, Oudin MJ, et al. A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner. Mol Cell Neurosci. 2008;38:526-36.
328. Gowran A, Noonan J, Campbell VA. The multiplicity of action of cannabinoids: implications for treating neurodegeneration. CNS Neurosci Ther. 2011;17:637-44.
329. Palazuelos J, Ortega Z, Diaz-Alonso J, Guzman M, Galve-Roperh I. CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. J Biol Chem. 2012;287:1198-209.
330. Compagnucci C, Di Siena S, Bustamante MB, Di Giacomo D, Di Tommaso M, Maccarrone M, et al. Type-1 (CB1) cannabinoid receptor promotes neuronal differentiation and maturation of neural stem cells. PLoS One. 2013;8:e54271.
331. Avraham HK, Jiang S, Fu Y, Rockenstein E, Makriyannis A, Zvonok A, et al. The cannabinoid CB(2) receptor agonist AM1241 enhances neurogenesis in GFAP/Gp120 transgenic mice displaying deficits in neurogenesis. Br J Pharmacol. 2014;171:468-79.
332. Little JP, Villanueva EB, Klegeris A. Therapeutic potential of cannabinoids in the treatment of neuroinflammation associated with Parkinson's disease. Mini Rev Med Chem. 2011;11:582-90.
333. Giuffrida A, McMahon LR. In vivo pharmacology of endocannabinoids and their metabolic inhibitors: therapeutic implications in Parkinson's disease and abuse liability. Prostaglandins Other Lipid Mediat. 2010;91:90-103.
334. Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82:1556-63.
335. Lotan I, Treves TA, Roditi Y, Djaldetti R. Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study. Clin Neuropharmacol. 2014;37:41-4.
336. Song L, Yang X, Ma Y, Wu N, Liu Z. The CB1 cannabinoid receptor agonist reduces L-DOPA-induced motor fluctuation and ERK1/2 phosphorylation in 6-OHDA-lesioned rats. Drug Des Devel Ther. 2014;8:2173-9.
337. Sayd A, Anton M, Alen F, Caso J, Pavon J, Leza J et al. Systemic Administration Of Oleoylethanolamide Protects From Neuroinflammation And Anhedonia Induced By Lps In Rats. Int J Neuropsychopharmacol. 2014. 1457-1461. Epub ahead of print.
338. Chung ES, Bok E, Chung YC, Baik HH, Jin BK. Cannabinoids prevent lipopolysaccharide-induced neurodegeneration in the rat substantia nigra in vivo through inhibition of microglial activation and NADPH oxidase. Brain Res. 2012;1451:110-6.
339. Carroll CB, Zeissler ML, Hanemann CO, Zajicek JP. Delta(9)-tetrahydrocannabinol (Delta(9)-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson's disease. Neuropathol Appl Neurobiol. 2012;38:535-47.
340. Moldzio R, Pacher T, Krewenka C, Kranner B, Novak J, Duvigneau JC, et al. Effects of cannabinoids Delta(9)-tetrahydrocannabinol, Delta(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomedicine. 2012;19:819-24.
341. Martinez A, Macheda T, Morgese MG, Trabace L, Giuffrida A. The cannabinoid agonist WIN55212-2 decreases L-DOPA-induced PKA activation and dyskinetic behavior in 6-OHDA-treated rats. Neurosci Res. 2012;72:236-42.
342. Jeon P, Yang S, Jeong H, Kim H. Cannabinoid receptor agonist protects cultured dopaminergic neurons from the death by the proteasomal dysfunction. Anat Cell Biol. 2011;44:135-42.
343. Chung YC, Bok E, Huh SH, Park JY, Yoon SH, Kim SR, et al. Cannabinoid receptor type 1 protects nigrostriatal dopaminergic neurons against MPTP neurotoxicity by inhibiting microglial activation. J Immunol. 2011;187:6508-17.
344. Walsh S, Gorman AM, Finn DP, Dowd E. The effects of cannabinoid drugs on abnormal involuntary movements in dyskinetic and non-dyskinetic 6-hydroxydopamine lesioned rats. Brain Res. 2010;1363:40-8.
345. Kelsey JE, Harris O, Cassin J. The CB(1) antagonist rimonabant is adjunctively therapeutic as well as monotherapeutic in an animal model of Parkinson's disease. Behav Brain Res. 2009;203:304-7.
346. Blazquez C, Chiarlone A, Bellocchio L, Resel E, Pruunsild P, Garcia-Rincon D et al. The CB cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway. Cell Death Differ. 2015. Epub ahead of print.
347. Sagredo O, Ramos JA, Decio A, Mechoulam R, Fernandez-Ruiz J. Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid in vivo by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors. Eur J Neurosci. 2007;26:843-51.
348. Aso E, Juves S, Maldonado R, Ferrer I. CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AbetaPP/PS1 mice. J Alzheimers Dis. 2013;35:847-58.
349. Casarejos MJ, Perucho J, Gomez A, Munoz MP, Fernandez-Estevez M, Sagredo O, et al. Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy. J Alzheimers Dis. 2013;35:525-39.
350. Wu J, Bie B, Yang H, Xu JJ, Brown DL, Naguib M. Activation of the CB2 receptor system reverses amyloid-induced memory deficiency. Neurobiol Aging. 2013;34:791-804.
351. Valdeolivas S, Navarrete C, Cantarero I, Bellido ML, Munoz E, Sagredo O. Neuroprotective Properties of Cannabigerol in Huntington's Disease: Studies in R6/2 Mice and 3-Nitropropionate-lesioned Mice. Neurotherapeutics. 2015;12:185-99.
352. Scotter EL, Goodfellow CE, Graham ES, Dragunow M, Glass M. Neuroprotective potential of CB1 receptor agonists in an in vitro model of Huntington's disease. Br J Pharmacol. 2010;160:747-61.