Endocannabinoids and Neurodegenerative Disorders: Parkinson’s Disease, Huntington’s Chorea, Alzheimer’s Disease, and Others

  • Javier Fernández-RuizEmail author
  • Julián Romero
  • José A. Ramos
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 231)


This review focuses on the role of the endocannabinoid signaling system in controlling neuronal survival, an extremely important issue to be considered when developing new therapies for neurodegenerative disorders. First, we will describe the cellular and molecular mechanisms, and the signaling pathways, underlying these neuroprotective properties, including the control of glutamate homeostasis, calcium influx, the toxicity of reactive oxygen species, glial activation and other inflammatory events; and the induction of autophagy. We will then concentrate on the preclinical studies and the few clinical trials that have been carried out targeting endocannabinoid signaling in three important chronic progressive neurodegenerative disorders (Parkinson’s disease, Huntington’s chorea, and Alzheimer’s disease), as well as in other less well-studied disorders. We will end by offering some ideas and proposals for future research that should be carried out to optimize endocannabinoid-based treatments for these disorders. Such studies will strengthen the possibility that these therapies will be investigated in the clinical scenario and licensed for their use in specific disorders.


Alzheimer’s disease Cannabinoids Endocannabinoids Huntington’s disease Neurodegeneration Neuroprotection Parkinson’s disease 







Serotonin 1A receptor type


Alzheimer’s disease




α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid


β-site amyloid precursor protein cleaving enzyme 1


Blood brain barrier






Cannabinoid receptor type 1


Cannabinoid receptor type 2






Central Nervous System




Diacylglycerol lipase




Fatty acid amide hydrolase


Huntington’s disease






Inducible nitric oxide synthase




Monoacylglycerol lipase




Nicotinamide adenine dinucleotide phosphate




Parkinson’s disease


Peroxisome proliferator-activated receptor


Reactive oxygen species


Spinocerebellar ataxia


Tumor necrosis factor-α


Transient receptor potential vanilloid type 1







This work was supported by grants from CIBERNED (CB06/05/0089), MINECO (SAF2012/39173), and CAM (S2011/BMD-2308).


  1. Abood ME, Rizvi G, Sallapudi N, McAllister SD (2001) Activation of the CB1 cannabinoid receptor protects cultured mouse spinal neurons against excitotoxicity. Neurosci Lett 309:197–201PubMedCrossRefGoogle Scholar
  2. Aso E, Palomer E, Juvés S et al (2012) CB1 agonist ACEA protects neurons and reduces the cognitive impairment of AβPP/PS1 mice. J Alzheimers Dis 30:439–459PubMedGoogle Scholar
  3. Aso E, Juvés S, Maldonado R, Ferrer I (2013) CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AβPP/PS1 mice. J Alzheimers Dis 35:847–858PubMedGoogle Scholar
  4. Athauda D, Foltynie T (2014) The ongoing pursuit of neuroprotective therapies in Parkinson’s disease. Nat Rev Neurol 11:25–40PubMedCrossRefGoogle Scholar
  5. Benito C, Nuñez E, Tolon RM et al (2003) Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J Neurosci 23:11136–11141PubMedGoogle Scholar
  6. Benito C, Tolon RM, Castillo AI et al (2012) β-Amyloid exacerbates inflammation in astrocytes lacking fatty acid amide hydrolase through a mechanism involving PPARα, PPARγ and TRPV1, but not CB1 or CB2 receptors. Br J Pharmacol 166:1474–1489PubMedCentralPubMedCrossRefGoogle Scholar
  7. Berk C, Paul G, Sabbagh M (2014) Investigational drugs in Alzheimer’s disease: current progress. Expert Opin Investig Drugs 23:837–846PubMedCrossRefGoogle Scholar
  8. Bisogno T, Hanus L, De Petrocellis L et al (2001) Molecular targets for cannabidiol and its synthetic analogues: effects on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134:845–852PubMedCentralPubMedCrossRefGoogle Scholar
  9. Blázquez C, Chiarlone A, Sagredo O et al (2011) Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease. Brain 134:119–136PubMedCrossRefGoogle Scholar
  10. Bouchard J, Truong J, Bouchard K et al (2012) Cannabinoid receptor 2 signaling in peripheral immune cells modulates disease onset and severity in mouse models of Huntington’s disease. J Neurosci 32:18259–18268PubMedCentralPubMedCrossRefGoogle Scholar
  11. Carrier EJ, Kearn CS, Barkmeier AJ et al (2004) Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol Pharmacol 65:999–1007PubMedCrossRefGoogle Scholar
  12. Carroll CB, Zeissler ML, Hanemann CO, Zajicek JP (2012) Δ9-tetrahydrocannabinol (Δ9-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson’s disease. Neuropathol Appl Neurobiol 38:535–547PubMedCrossRefGoogle Scholar
  13. Carta AR, Simuni T (2014) Thiazolidinediones under preclinical and early clinical development for the treatment of Parkinson’s disease. Expert Opin Investig Drugs 17:1–9Google Scholar
  14. Casarejos MJ, Perucho J, Gómez A et al (2013) Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy. J Alzheimers Dis 35:525–539PubMedGoogle Scholar
  15. Castillo A, Tolón MR, Fernández-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 CB2 and adenosine receptors. Neurobiol Dis 37:434–440PubMedCrossRefGoogle Scholar
  16. Chen Y, McCarron RM, Ohara Y et al (2000) Human brain capillary endothelium: 2-arachidonoglycerol (endocannabinoid) interacts with endothelin-1. Circ Res 87:323–327PubMedCrossRefGoogle Scholar
  17. Chen R, Zhang J, Wu Y et al (2012) Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Rep 2:1329–1339PubMedCentralPubMedCrossRefGoogle Scholar
  18. Chen R, Zhang J, Fan N et al (2013) Δ9-THC-Caused synaptic and memory impairments are mediated through COX-2 signaling. Cell 155:1154–1165PubMedCentralPubMedCrossRefGoogle Scholar
  19. Chiarlone A, Bellocchio L, Blázquez C et al (2014) A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proc Natl Acad Sci U S A 111:8257–8262PubMedCentralPubMedCrossRefGoogle Scholar
  20. Choi IY, Ju C, Anthony Jalin AM et al (2013) Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury. Am J Pathol 182:928–939PubMedCrossRefGoogle Scholar
  21. Chung YC, Bok E, Huh SH et al (2011) Cannabinoid receptor type 1 protects nigrostriatal dopaminergic neurons against MPTP neurotoxicity by inhibiting microglial activation. J Immunol 187:6508–6517PubMedCrossRefGoogle Scholar
  22. D’Addario C, Di Francesco A, Arosio B et al (2012) Epigenetic regulation of fatty acid amide hydrolase in Alzheimer disease. PLoS One 7:e39186PubMedCentralPubMedCrossRefGoogle Scholar
  23. Dirikoc S, Priola SA, Marella M, Zsürger N, Chabry J (2007) Non-psychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity. J Neurosci 27:9537–9544PubMedCrossRefGoogle Scholar
  24. Dowie MJ, Grimsey NL, Hoffman T, Faull RL, Glass M (2014) Cannabinoid receptor CB2 is expressed on vascular cells, but not astroglial cells in the post-mortem human Huntington’s disease brain. J Chem Neuroanat 59–60:62–71PubMedCrossRefGoogle Scholar
  25. Duarte JM, Ferreira SG, Carvalho RA, Cunha RA, Köfalvi A (2012) CB1 receptor activation inhibits neuronal and astrocytic intermediary metabolism in the rat hippocampus. Neurochem Int 60:1–8PubMedCrossRefGoogle Scholar
  26. El-Remessy AB, Khalil IE, Matragoon S et al (2003) Neuroprotective effect of (-)Δ9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am J Pathol 163:1997–2008PubMedCentralPubMedCrossRefGoogle Scholar
  27. Esposito G, De Filippis D, Maiuri MC et al (2006a) Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in β-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement. Neurosci Lett 399:91–95PubMedCrossRefGoogle Scholar
  28. Esposito G, De Filippis D, Carnuccio R, Izzo AA, Iuvone T (2006b) The marijuana component cannabidiol inhibits β-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells. J Mol Med 84:253–258PubMedCrossRefGoogle Scholar
  29. Esposito G, Scuderi C, Savani C et al (2007) Cannabidiol in vivo blunts β-amyloid induced neuroinflammation by suppressing IL-1β and iNOS expression. Br J Pharmacol 151:1272–1279PubMedCentralPubMedCrossRefGoogle Scholar
  30. Esposito G, Scuderi C, Valenza M et al (2011) Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One 6:e28668PubMedCentralPubMedCrossRefGoogle Scholar
  31. Eubanks LM, Rogers CJ, Beuscher AE et al (2006) A molecular link between the active component of marijuana and Alzheimer’s disease pathology. Mol Pharm 3:773–777PubMedCentralPubMedCrossRefGoogle Scholar
  32. Fagan SG, Campbell VA (2014) The influence of cannabinoids on generic traits of neurodegeneration. Br J Pharmacol 171:1347–1360PubMedCentralPubMedCrossRefGoogle Scholar
  33. Fakhfouri G, Ahmadiani A, Rahimian R et al (2012) WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway. Neuropharmacology 63:653–666PubMedCrossRefGoogle Scholar
  34. Fernández-Ruiz J (2009) The endocannabinoid system as a target for the treatment of motor dysfunction. Br J Pharmacol 156:1029–1040PubMedCentralPubMedCrossRefGoogle Scholar
  35. Fernández-Ruiz J, González S, Romero J, Ramos JA (2005) Cannabinoids in neurodegeneration and neuroprotection. In: Mechoulam R (ed) Cannabinoids as therapeutics (MDT). Birkhaüser Verlag, Basel, pp 79–109CrossRefGoogle Scholar
  36. Fernández-Ruiz J, Romero J, Velasco G et al (2007) Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol Sci 28:39–45PubMedCrossRefGoogle Scholar
  37. Fernández-Ruiz J, García C, Sagredo O, Gómez-Ruiz M, de Lago E (2010) The endocannabinoid system as a target for the treatment of neuronal damage. Expert Opin Ther Targets 14:387–404PubMedCrossRefGoogle Scholar
  38. Fernández-Ruiz J, Sagredo O, Pazos MR et al (2013) Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? Br J Clin Pharmacol 75:323–333PubMedCentralPubMedCrossRefGoogle Scholar
  39. Fernández-Ruiz J, de Lago E, Gómez-Ruiz M et al (2014) Neurodegenerative disorders other than multiple sclerosis. In: Pertwee RG (ed) Handbook of cannabis. Oxford University Press, Oxford, pp 505–525CrossRefGoogle Scholar
  40. Fidaleo M, Fanelli F, Ceru MP, Moreno S (2014) Neuroprotective properties of peroxisome proliferator-activated receptor-α (PPARα) and its lipid ligands. Curr Med Chem 21:2803–2821PubMedCrossRefGoogle Scholar
  41. Fowler CJ, Rojo ML, Rodriguez-Gaztelumendi A (2010) Modulation of the endocannabinoid system: neuroprotection or neurotoxicity? Exp Neurol 224:37–47PubMedCrossRefGoogle Scholar
  42. Fujii M, Sherchan P, Krafft PR et al (2014) Cannabinoid type 2 receptor stimulation attenuates brain edema by reducing cerebral leukocyte infiltration following subarachnoid hemorrhage in rats. J Neurol Sci 342:101–106PubMedCentralPubMedCrossRefGoogle Scholar
  43. García C, Palomo-Garo C, García-Arencibia M, Ramos J, Pertwee R, Fernández-Ruiz J (2011) Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ9-THCV in animal models of Parkinson’s disease. Br J Pharmacol 163:1495–1506PubMedCentralPubMedCrossRefGoogle Scholar
  44. García MC, Cinquina V, Palomo-Garo C, Rábano A, Fernández-Ruiz J (2015) Identification of CB2 receptors in human nigral neurons that degenerate in Parkinson’s disease. Neurosci Lett 587:1–4PubMedCrossRefGoogle Scholar
  45. García-Arencibia M, González S, de Lago E et al (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 1134:162–170PubMedCrossRefGoogle Scholar
  46. García-Arencibia M, García C, Fernández-Ruiz J (2009) Cannabinoids and Parkinson’s disease. CNS Neurol Disord Drug Targets 8:432–439PubMedCrossRefGoogle Scholar
  47. García-Caldentey J, Trillo P, Ruiz C et al (2015) A double-blind, cross-over, placebo-controlled, phase II trial with Sativex in Huntington’s disease. Submitted. See also
  48. Geldenhuys WJ, Van der Schyf CJ (2013) Rationally designed multi-targeted agents against neurodegenerative diseases. Curr Med Chem 20:1662–1672PubMedCrossRefGoogle Scholar
  49. Glass M, Dragunow M, Faull RLM (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 97:505–519PubMedCrossRefGoogle Scholar
  50. Gómez O, Arévalo-Martin A, García-Ovejero D et al (2010) The constitutive production of the endocannabinoid 2-arachidonoylglycerol participates in oligodendrocyte differentiation. Glia 58:1913–1927PubMedCrossRefGoogle Scholar
  51. Gómez O, Sanchez-Rodriguez A, Le M et al (2011) Cannabinoid receptor agonists modulate oligodendrocyte differentiation by activating PI3K/Akt and the mammalian target of rapamycin (mTOR) pathways. Br J Pharmacol 163:1520–1532PubMedCentralPubMedCrossRefGoogle Scholar
  52. Gowran A, Noonan J, Campbell VA (2011) The multiplicity of action of cannabinoids: implications for treating neurodegeneration. CNS Neurosci Ther 17:637–644PubMedCrossRefGoogle Scholar
  53. Gubellini P, Picconi B, Bari M et al (2002) Experimental parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission. J Neurosci 22:6900–6907PubMedGoogle Scholar
  54. Hampson AJ, Bornheim LM, Scanziani M et al (1998) Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission. J Neurochem 70:671–676PubMedCrossRefGoogle Scholar
  55. Iuvone T, Esposito G, Esposito R et al (2004) Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem 89:134–141PubMedCrossRefGoogle Scholar
  56. Iuvone T, Esposito G, De Filippis D, Scuderi C, Steardo L (2009) Cannabidiol: a promising drug for neurodegenerative disorders? CNS Neurosci Ther 15:65–75PubMedCrossRefGoogle Scholar
  57. Jia J, Ma L, Wu M et al (2014) Anandamide protects HT22 cells exposed to hydrogen peroxide by inhibiting CB1 receptor-mediated type 2 NADPH oxidase. Oxid Med Cell Longev 2014:893516PubMedCentralPubMedCrossRefGoogle Scholar
  58. Jiménez-Del-Rio M, Daza-Restrepo A, Velez-Pardo C (2008) The cannabinoid CP55,940 prolongs survival and improves locomotor activity in Drosophila melanogaster against paraquat: implications in Parkinson’s disease. Neurosci Res 61:404–411PubMedCrossRefGoogle Scholar
  59. Jung K, Astarita G, Yasar S et al (2012) An amyloid β42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer’s disease. Neurobiol Aging 33:1522–1532PubMedCentralPubMedCrossRefGoogle Scholar
  60. Kallendrusch S, Kremzow S, Nowicki M et al (2013) The G protein-coupled receptor 55 ligand l-α-lysophosphatidylinositol exerts microglia-dependent neuroprotection after excitotoxic lesion. Glia 61:1822–1831PubMedCrossRefGoogle Scholar
  61. Karl T, Cheng D, Garner B, Arnold JC (2012) The therapeutic potential of the endocannabinoid system for Alzheimer’s disease. Expert Opin Ther Targets 16:407–420PubMedCrossRefGoogle Scholar
  62. Klein TW, Newton CA (2007) Therapeutic potential of cannabinoid-based drugs. Adv Exp Med Biol 601:395–413PubMedCrossRefGoogle Scholar
  63. Kozela E, Pietr M, Juknat A et al (2010) Cannabinoids Δ9-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-kappaB and interferon-β/STAT proinflammatory pathways in BV-2 microglial cells. J Biol Chem 285:1616–1626PubMedCentralPubMedCrossRefGoogle Scholar
  64. Lanciego JL, Barroso-Chinea P, Rico AJ, Conte-Perales L, Callén L, Roda E, Gómez-Bautista V, López IP, Lluis C, Labandeira-García JL, Franco R (2011) Expression of the mRNA coding the cannabinoid receptor 2 in the pallidal complex of Macaca fascicularis. J Psychopharmacol 25:97–104PubMedCrossRefGoogle Scholar
  65. Lastres-Becker I, Cebeira M, de Ceballos M et al (2001) Increased cannabinoid CB1 receptor binding and activation of GTP-binding proteins in the basal ganglia of patients with Parkinson’s disease and MPTP-treated marmosets. Eur J Neurosci 14:1827–1832PubMedCrossRefGoogle Scholar
  66. Lastres-Becker I, Berrendero F, Lucas JJ et al (2002) Loss of mRNA levels, binding and activation of GTP-binding proteins for cannabinoid CB1 receptors in the basal ganglia of a transgenic model of Huntington’s disease. Brain Res 929:236–242PubMedCrossRefGoogle Scholar
  67. Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fernández-Ruiz J (2005) Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol Dis 19:96–107PubMedCrossRefGoogle Scholar
  68. Leweke FM, Piomelli D, Pahlisch F et al (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2:e94PubMedCentralPubMedCrossRefGoogle Scholar
  69. Manuel I, de San G, Román E, Giralt MT, Ferrer I, Rodríguez-Puertas R (2014) Type-1 cannabinoid receptor activity during Alzheimer’s disease progression. J Alzheimers Dis 42:761–766PubMedGoogle Scholar
  70. Marsicano G, Moosmann B, Hermann H, Lutz B, Behl C (2002) Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J Neurochem 80:448–456PubMedCrossRefGoogle Scholar
  71. Marsicano G, Goodenough S, Monory K et al (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88PubMedCrossRefGoogle Scholar
  72. Martín-Moreno AM, Brera B, Spuch C et al (2012) Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflammation 9:8PubMedCentralPubMedCrossRefGoogle Scholar
  73. Mechoulam R, Spatz M, Shohami E (2002) Endocannabinoids and neuroprotection. Sci STKE 2002(129):re5PubMedGoogle Scholar
  74. Molina-Holgado F, Pinteaux E, Moore JD et al (2003) Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. J Neurosci 23:6470–6474PubMedGoogle Scholar
  75. Nadler V, Mechoulam R, Sokolovsky M (1993) Blockade of 45Ca2+ influx through the N-methyl-D-aspartate receptor ion channel by the non-psychoactive cannabinoid HU-211. Brain Res 622:79–85PubMedCrossRefGoogle Scholar
  76. Nagayama T, Sinor AD, Simon RP et al (1999) Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci 19:2987–2995PubMedGoogle Scholar
  77. Nomura DK, Morrison BE, Blankman JL et al (2011) Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334:809–813PubMedCentralPubMedCrossRefGoogle Scholar
  78. Núñez E, Benito C, Tolón RM et al (2008) Glial expression of cannabinoid CB2 receptors and fatty acid amide hydrolase are β-amyloid-linked events in Down’s syndrome. Neuroscience 151:104–110PubMedCrossRefGoogle Scholar
  79. Oh YT, Lee JY, Lee J et al (2010) Oleamide suppresses lipopolysaccharide-induced expression of iNOS and COX-2 through inhibition of NFκB activation in BV2 murine microglial cells. Neurosci Lett 474:148–153PubMedCrossRefGoogle Scholar
  80. Ohno-Shosaku T, Kano M (2014) Endocannabinoid-mediated retrograde modulation of synaptic transmission. Curr Opin Neurobiol 29C:1–8CrossRefGoogle Scholar
  81. Pacher P, Mechoulam R (2011) Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res 50:193–211PubMedCentralPubMedCrossRefGoogle Scholar
  82. Palazuelos J, Aguado T, Pazos MR et al (2009) Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain 132:3152–3164PubMedCrossRefGoogle Scholar
  83. Panikashvili D, Simeonidou C, Ben-Shabat S et al (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413:527–531PubMedCrossRefGoogle Scholar
  84. Pazos MR, Mohammed N, Lafuente H et al (2013) Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT1A and CB2 receptors. Neuropharmacology 71:282–291PubMedCrossRefGoogle Scholar
  85. Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol 153:199–215PubMedCentralPubMedCrossRefGoogle Scholar
  86. Petrosino S, Ménard B, Zsürger N, Di Marzo V, Chabry J (2011) Alteration of the endocannabinoid system in mouse brain during prion disease. Neuroscience 177:292–297PubMedCrossRefGoogle Scholar
  87. Pintor A, Tebano MT, Martire A et al (2006) The cannabinoid receptor agonist WIN 55,212-2 attenuates the effects induced by quinolinic acid in the rat striatum. Neuropharmacology 51:1004–1012PubMedCrossRefGoogle Scholar
  88. Piro JR, Benjamin DI, Duerr JM et al (2012) A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer’s disease. Cell Rep 1:617–623PubMedCentralPubMedCrossRefGoogle Scholar
  89. Pisani A, Fezza F, Galati S et al (2005) High endogenous cannabinoid levels in the cerebrospinal fluid of untreated Parkinson’s disease patients. Ann Neurol 57:777–779PubMedCrossRefGoogle Scholar
  90. Price DA, Martinez AA, Seillier A et al (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 29:2177–2186PubMedCentralPubMedCrossRefGoogle Scholar
  91. Ramírez BG, Blázquez C, Gómez del Pulgar T, Guzmán M, de Ceballos ML (2005) Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 25:1904–1913PubMedCrossRefGoogle Scholar
  92. Rodríguez-Cueto C, Benito C, Fernández-Ruiz J et al (2014a) Changes in CB1 and CB2 receptors in the post-mortem cerebellum of humans affected by spinocerebellar ataxias. Br J Pharmacol 171:1472–1489PubMedCentralPubMedCrossRefGoogle Scholar
  93. Rodríguez-Cueto C, Benito C, Romero J et al (2014b) Endocannabinoid-hydrolysing enzymes in the post-mortem cerebellum of humans affected by hereditary autosomal dominant ataxias. Pathobiology 81:149–159PubMedCrossRefGoogle Scholar
  94. Rossi M, Perez-Lloret S, Doldan L et al (2014) Autosomal dominant cerebellar ataxias: a systematic review of clinical features. Eur J Neurol 21:607–615PubMedCrossRefGoogle Scholar
  95. Ruiz-Valdepeñas L, Martínez-Orgado JA, Benito C et al (2011) Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study. J Neuroinflammation 8:5PubMedCentralPubMedCrossRefGoogle Scholar
  96. Sagredo O, Ramos JA, Decio A, Mechoulam R, Fernández-Ruiz J (2007) 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 26:843–851PubMedCrossRefGoogle Scholar
  97. Sagredo O, González S, Aroyo I et al (2009) Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington’s disease. Glia 57:1154–1167PubMedCentralPubMedCrossRefGoogle Scholar
  98. Sagredo O, Pazos MR, Satta V et al (2011) Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease. J Neurosci Res 89:1509–1518PubMedCrossRefGoogle Scholar
  99. Sagredo O, Pazos MR, Valdeolivas S, Fernandez-Ruiz J (2012) Cannabinoids: novel medicines for the treatment of Huntington’s disease. Recent Pat CNS Drug Discov 7:41–48PubMedCrossRefGoogle Scholar
  100. Sampaio C, Borowsky B, Reilmann R (2014) Clinical trials in Huntington’s disease: interventions in early clinical development and newer methodological approaches. Mov Disord 29:1419–1428PubMedCrossRefGoogle Scholar
  101. Sang N, Zhang J, Chen C (2007) COX-2 oxidative metabolite of endocannabinoid 2-AG enhances excitatory glutamatergic synaptic transmission and induces neurotoxicity. J Neurochem 102:1966–1977PubMedCrossRefGoogle Scholar
  102. Scuderi C, Steardo L, Esposito G (2014) Cannabidiol promotes amyloid precursor protein ubiquitination and reduction of β-amyloid expression in SHSY5YAPP+ cells through PPARγ involvement. Phytother Res 28:1007–1013PubMedCrossRefGoogle Scholar
  103. Shen M, Thayer SA (1998) Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol Pharmacol 54:459–462PubMedGoogle Scholar
  104. Sheng WS, Hu S, Ni HT, Rock RB, Peterson PK (2009) WIN55,212-2 inhibits production of CX3CL1 by human astrocytes: involvement of p38 MAP kinase. J Neuroimmune Pharmacol 4:244–248PubMedCentralPubMedCrossRefGoogle Scholar
  105. Shohami E, Mechoulam R (2000) A non-psychotropic cannabinoid with neuroprotective properties. Drug Dev Res 50:211–215CrossRefGoogle Scholar
  106. Smith SR, Terminelli C, Denhardt G (2000) Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin-10 in endotoxemic mice. J Pharmacol Exp Ther 293:136–150PubMedGoogle Scholar
  107. Stahel PF, Smith WR, Bruchis J, Rabb CH (2008) Peroxisome proliferator-activated receptors: “key” regulators of neuroinflammation after traumatic brain injury. PPAR Res 2008:538141PubMedCentralPubMedCrossRefGoogle Scholar
  108. Stella N (2010) Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia 58:1017–1030PubMedCentralPubMedCrossRefGoogle Scholar
  109. Takada LT, Geschwind MD (2013) Prion diseases. Semin Neurol 33:348–356PubMedCrossRefGoogle Scholar
  110. Ternianov A, Pérez-Ortiz JM, Solesio ME et al (2012) Overexpression of CB2 cannabinoid receptors results in neuroprotection against behavioral and neurochemical alterations induced by intracaudate administration of 6-hydroxydopamine. Neurobiol Aging 33(421):e1–e16PubMedGoogle Scholar
  111. Tolón RM, Núñez E, Pazos MR et al (2009) The activation of cannabinoid CB2 receptors stimulates in situ and in vitro β-amyloid removal by human macrophages. Brain Res 1283:148–154PubMedCrossRefGoogle Scholar
  112. Valdeolivas S, Satta V, Pertwee RG, Fernández-Ruiz J, Sagredo O (2012) Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington’s disease: role of CB1 and CB2 receptors. ACS Chem Neurosci 3:400–406PubMedCentralPubMedCrossRefGoogle Scholar
  113. Valdeolivas S, Pazos MR, Bisogno T et al (2013) The inhibition of 2-arachidonoyl-glycerol (2-AG) biosynthesis, rather than enhancing striatal damage, protects striatal neurons from malonate-induced death: a potential role of cyclooxygenase-2-dependent metabolism of 2-AG. Cell Death Dis 4:e862PubMedCentralPubMedCrossRefGoogle Scholar
  114. Valdeolivas S, Navarrete C, Cantarero I et al (2014) Neuroprotective properties of cannabigerol in Huntington’s disease: studies in R6/2 mice and 3-nitropropionate-lesioned mice. Neurotherapeutics 12(1):185–199PubMedCentralCrossRefGoogle Scholar
  115. van der Stelt M, Veldhuis WB, Bar PR et al (2001) Neuroprotection by Δ9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. J Neurosci 21:6475–6579PubMedGoogle Scholar
  116. van der Stelt M, Mazzola C, Esposito G et al (2006) Endocannabinoids and β-amyloid-induced neurotoxicity in vivo: effect of pharmacological elevation of endocannabinoid levels. Cell Mol Life Sci 63:1410–1424PubMedCrossRefGoogle Scholar
  117. Vázquez C, Tolón RM, Pazos MR et al (2015) Endocannabinoids regulate the activity of astrocytic hemichannels and the microglial response against an injury: in vivo studies. Neurobiol Dis 79:41–50PubMedCrossRefGoogle Scholar
  118. Vendel E, de Lange EC (2014) Functions of the CB1 and CB2 receptors in neuroprotection at the level of the blood-brain barrier. Neuromolecular Med 16:620–642PubMedCrossRefGoogle Scholar
  119. Walter L, Franklin A, Witting A et al (2003) Non-psychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 23:1398–1405PubMedGoogle Scholar
  120. Wang Y, Ma S, Wang Q et al (2014) Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart. Sci China Life Sci 57:201–208PubMedCrossRefGoogle Scholar
  121. Westlake TM, Howlett AC, Bonner TI, Matsuda LA, Herkenham M (1994) Cannabinoid receptor binding and messenger RNA expression in human brain: an in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer’s brains. Neuroscience 63:637–652PubMedCrossRefGoogle Scholar
  122. Yamanaka M, Ishikawa T, Griep A et al (2012) PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci 32:17321–17331PubMedCrossRefGoogle Scholar
  123. Ziemka-Nałęcz M, Zalewska T (2012) Endogenous neurogenesis induced by ischemic brain injury or neurodegenerative diseases in adults. Acta Neurobiol Exp 72:309–324Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Javier Fernández-Ruiz
    • 1
    • 2
    • 3
    Email author
  • Julián Romero
    • 4
    • 5
  • José A. Ramos
    • 1
    • 2
    • 3
  1. 1.Facultad de Medicina, Departamento de Bioquímica y Biología Molecular III, Instituto Universitario de Investigación en NeuroquímicaUniversidad ComplutenseMadridSpain
  2. 2.Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)MadridSpain
  3. 3.Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain
  4. 4.Laboratorio de Apoyo a la InvestigaciónHospital Universitario Fundación AlcorcónMadridSpain
  5. 5.Departamento de Ciencias BiosanitariasUniversidad Francisco de VitoriaMadridSpain

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