Skip to main content
SpringerLink
Log in

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

  • Chapter
Endocannabinoids

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 231))

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 379.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

2-AG:

2-Arachidonoyl-glycerol

3NP:

3-Nitropropionate

5HT1A :

Serotonin 1A receptor type

AD:

Alzheimer’s disease

AEA:

Anandamide

AMPA:

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

BACE1:

β-site amyloid precursor protein cleaving enzyme 1

BBB:

Blood brain barrier

CAG:

Cytosine-adenine-guanine

CB:

Cannabinoid

CB1 :

Cannabinoid receptor type 1

CB2,:

Cannabinoid receptor type 2

CBD:

Cannabidiol

CBN:

Cannabinol

CNS:

Central Nervous System

COX-2:

Cyclooxygenase-2

DAGL:

Diacylglycerol lipase

eCB:

Endocannabinoid

FAAH:

Fatty acid amide hydrolase

HD:

Huntington’s disease

HU-211:

Dexanabinol

IL-10:

Interleukin-10

iNOS:

Inducible nitric oxide synthase

LPS:

Lipopolysaccharide

MAGL:

Monoacylglycerol lipase

MPTP:

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

NADPH:

Nicotinamide adenine dinucleotide phosphate

NMDA:

N-methyl-D-aspartate

PD:

Parkinson’s disease

PPAR:

Peroxisome proliferator-activated receptor

ROS:

Reactive oxygen species

SCA:

Spinocerebellar ataxia

TNF-α:

Tumor necrosis factor-α

TRPV1:

Transient receptor potential vanilloid type 1

Δ9-THC:

Δ9-tetrahydrocannabinol

Δ9-THCV:

Δ9-tetrahydrocannabivarin

References

  • Abood ME, Rizvi G, Sallapudi N, McAllister SD (2001) Activation of the CB1 cannabinoid receptor protects cultured mouse spinal neurons against excitotoxicity. Neurosci Lett 309:197–201

    Article  CAS  PubMed  Google Scholar 

  • 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 30:439–459

    CAS  PubMed  Google Scholar 

  • Aso E, Juvés S, Maldonado R, Ferrer I (2013) CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AβPP/PS1 mice. J Alzheimers Dis 35:847–858

    PubMed  Google Scholar 

  • Athauda D, Foltynie T (2014) The ongoing pursuit of neuroprotective therapies in Parkinson’s disease. Nat Rev Neurol 11:25–40

    Article  PubMed  CAS  Google Scholar 

  • 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 23:11136–11141

    CAS  PubMed  Google Scholar 

  • 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 166:1474–1489

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Berk C, Paul G, Sabbagh M (2014) Investigational drugs in Alzheimer’s disease: current progress. Expert Opin Investig Drugs 23:837–846

    Article  CAS  PubMed  Google Scholar 

  • 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 134:845–852

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 134:119–136

    Article  PubMed  Google Scholar 

  • 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 32:18259–18268

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 65:999–1007

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Carta AR, Simuni T (2014) Thiazolidinediones under preclinical and early clinical development for the treatment of Parkinson’s disease. Expert Opin Investig Drugs 17:1–9

    Google Scholar 

  • 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 35:525–539

    CAS  PubMed  Google Scholar 

  • 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 37:434–440

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, McCarron RM, Ohara Y et al (2000) Human brain capillary endothelium: 2-arachidonoglycerol (endocannabinoid) interacts with endothelin-1. Circ Res 87:323–327

    Article  CAS  PubMed  Google Scholar 

  • Chen R, Zhang J, Wu Y et al (2012) Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Rep 2:1329–1339

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen R, Zhang J, Fan N et al (2013) Δ9-THC-Caused synaptic and memory impairments are mediated through COX-2 signaling. Cell 155:1154–1165

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 111:8257–8262

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 182:928–939

    Article  CAS  PubMed  Google Scholar 

  • 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 187:6508–6517

    Article  CAS  PubMed  Google Scholar 

  • D’Addario C, Di Francesco A, Arosio B et al (2012) Epigenetic regulation of fatty acid amide hydrolase in Alzheimer disease. PLoS One 7:e39186

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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 27:9537–9544

    Article  CAS  PubMed  Google Scholar 

  • 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 59–60:62–71

    Article  PubMed  CAS  Google Scholar 

  • 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 60:1–8

    Article  CAS  PubMed  Google Scholar 

  • 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 163:1997–2008

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 399:91–95

    Article  CAS  PubMed  Google Scholar 

  • 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 84:253–258

    Article  CAS  PubMed  Google Scholar 

  • 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 151:1272–1279

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Esposito G, Scuderi C, Valenza M et al (2011) Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One 6:e28668

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 3:773–777

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fagan SG, Campbell VA (2014) The influence of cannabinoids on generic traits of neurodegeneration. Br J Pharmacol 171:1347–1360

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 63:653–666

    Article  CAS  PubMed  Google Scholar 

  • Fernández-Ruiz J (2009) The endocannabinoid system as a target for the treatment of motor dysfunction. Br J Pharmacol 156:1029–1040

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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 79–109

    Chapter  Google Scholar 

  • Fernández-Ruiz J, Romero J, Velasco G et al (2007) Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol Sci 28:39–45

    Article  PubMed  CAS  Google Scholar 

  • 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 14:387–404

    Article  PubMed  Google Scholar 

  • 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 75:323–333

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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 505–525

    Chapter  Google Scholar 

  • 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 21:2803–2821

    Article  CAS  PubMed  Google Scholar 

  • Fowler CJ, Rojo ML, Rodriguez-Gaztelumendi A (2010) Modulation of the endocannabinoid system: neuroprotection or neurotoxicity? Exp Neurol 224:37–47

    Article  CAS  PubMed  Google Scholar 

  • 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 342:101–106

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 163:1495–1506

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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 587:1–4

    Article  PubMed  CAS  Google Scholar 

  • 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 1134:162–170

    Article  PubMed  CAS  Google Scholar 

  • García-Arencibia M, García C, Fernández-Ruiz J (2009) Cannabinoids and Parkinson’s disease. CNS Neurol Disord Drug Targets 8:432–439

    Article  PubMed  Google Scholar 

  • 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 https://clinicaltrials.gov/ct2/show/NCT01502046

  • Geldenhuys WJ, Van der Schyf CJ (2013) Rationally designed multi-targeted agents against neurodegenerative diseases. Curr Med Chem 20:1662–1672

    Article  CAS  PubMed  Google Scholar 

  • 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 97:505–519

    Article  CAS  PubMed  Google Scholar 

  • Gómez O, Arévalo-Martin A, García-Ovejero D et al (2010) The constitutive production of the endocannabinoid 2-arachidonoylglycerol participates in oligodendrocyte differentiation. Glia 58:1913–1927

    Article  PubMed  Google Scholar 

  • 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 163:1520–1532

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Gowran A, Noonan J, Campbell VA (2011) The multiplicity of action of cannabinoids: implications for treating neurodegeneration. CNS Neurosci Ther 17:637–644

    Article  CAS  PubMed  Google Scholar 

  • Gubellini P, Picconi B, Bari M et al (2002) Experimental parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission. J Neurosci 22:6900–6907

    CAS  PubMed  Google Scholar 

  • Hampson AJ, Bornheim LM, Scanziani M et al (1998) Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission. J Neurochem 70:671–676

    Article  CAS  PubMed  Google Scholar 

  • 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 89:134–141

    Article  CAS  PubMed  Google Scholar 

  • Iuvone T, Esposito G, De Filippis D, Scuderi C, Steardo L (2009) Cannabidiol: a promising drug for neurodegenerative disorders? CNS Neurosci Ther 15:65–75

    Article  CAS  PubMed  Google Scholar 

  • 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 2014:893516

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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 61:404–411

    Article  PubMed  CAS  Google Scholar 

  • 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 33:1522–1532

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 61:1822–1831

    Article  PubMed  Google Scholar 

  • Karl T, Cheng D, Garner B, Arnold JC (2012) The therapeutic potential of the endocannabinoid system for Alzheimer’s disease. Expert Opin Ther Targets 16:407–420

    Article  CAS  PubMed  Google Scholar 

  • Klein TW, Newton CA (2007) Therapeutic potential of cannabinoid-based drugs. Adv Exp Med Biol 601:395–413

    Article  PubMed  Google Scholar 

  • 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 285:1616–1626

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 25:97–104

    Article  CAS  PubMed  Google Scholar 

  • 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 14:1827–1832

    Article  CAS  PubMed  Google Scholar 

  • 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 929:236–242

    Article  CAS  PubMed  Google Scholar 

  • 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 19:96–107

    Article  CAS  PubMed  Google Scholar 

  • Leweke FM, Piomelli D, Pahlisch F et al (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2:e94

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 42:761–766

    CAS  PubMed  Google Scholar 

  • Marsicano G, Moosmann B, Hermann H, Lutz B, Behl C (2002) Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J Neurochem 80:448–456

    Article  CAS  PubMed  Google Scholar 

  • Marsicano G, Goodenough S, Monory K et al (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88

    Article  CAS  PubMed  Google Scholar 

  • 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 9:8

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Mechoulam R, Spatz M, Shohami E (2002) Endocannabinoids and neuroprotection. Sci STKE 2002(129):re5

    CAS  PubMed  Google Scholar 

  • 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 23:6470–6474

    CAS  PubMed  Google Scholar 

  • 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 622:79–85

    Article  CAS  PubMed  Google Scholar 

  • Nagayama T, Sinor AD, Simon RP et al (1999) Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci 19:2987–2995

    CAS  PubMed  Google Scholar 

  • Nomura DK, Morrison BE, Blankman JL et al (2011) Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334:809–813

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 151:104–110

    Article  PubMed  CAS  Google Scholar 

  • 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 474:148–153

    Article  CAS  PubMed  Google Scholar 

  • Ohno-Shosaku T, Kano M (2014) Endocannabinoid-mediated retrograde modulation of synaptic transmission. Curr Opin Neurobiol 29C:1–8

    Article  CAS  Google Scholar 

  • Pacher P, Mechoulam R (2011) Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res 50:193–211

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Palazuelos J, Aguado T, Pazos MR et al (2009) Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain 132:3152–3164

    Article  PubMed  Google Scholar 

  • Panikashvili D, Simeonidou C, Ben-Shabat S et al (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413:527–531

    Article  CAS  PubMed  Google Scholar 

  • 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 71:282–291

    Article  CAS  PubMed  Google Scholar 

  • Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol 153:199–215

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Petrosino S, Ménard B, Zsürger N, Di Marzo V, Chabry J (2011) Alteration of the endocannabinoid system in mouse brain during prion disease. Neuroscience 177:292–297

    Article  CAS  PubMed  Google Scholar 

  • 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 51:1004–1012

    Article  CAS  PubMed  Google Scholar 

  • 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 1:617–623

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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 57:777–779

    Article  PubMed  Google Scholar 

  • 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 29:2177–2186

    Article  PubMed Central  PubMed  Google Scholar 

  • 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 25:1904–1913

    Article  PubMed  CAS  Google Scholar 

  • 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 171:1472–1489

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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 81:149–159

    Article  PubMed  CAS  Google Scholar 

  • Rossi M, Perez-Lloret S, Doldan L et al (2014) Autosomal dominant cerebellar ataxias: a systematic review of clinical features. Eur J Neurol 21:607–615

    Article  CAS  PubMed  Google Scholar 

  • 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 8:5

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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 26:843–851

    Article  PubMed  Google Scholar 

  • 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 57:1154–1167

    Article  PubMed Central  PubMed  Google Scholar 

  • 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 89:1509–1518

    Article  CAS  PubMed  Google Scholar 

  • 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 7:41–48

    Article  CAS  PubMed  Google Scholar 

  • Sampaio C, Borowsky B, Reilmann R (2014) Clinical trials in Huntington’s disease: interventions in early clinical development and newer methodological approaches. Mov Disord 29:1419–1428

    Article  PubMed  Google Scholar 

  • 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 102:1966–1977

    Article  CAS  PubMed  Google Scholar 

  • 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 28:1007–1013

    Article  CAS  PubMed  Google Scholar 

  • Shen M, Thayer SA (1998) Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol Pharmacol 54:459–462

    CAS  PubMed  Google Scholar 

  • 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 4:244–248

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shohami E, Mechoulam R (2000) A non-psychotropic cannabinoid with neuroprotective properties. Drug Dev Res 50:211–215

    Article  CAS  Google Scholar 

  • 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 293:136–150

    CAS  PubMed  Google Scholar 

  • Stahel PF, Smith WR, Bruchis J, Rabb CH (2008) Peroxisome proliferator-activated receptors: “key” regulators of neuroinflammation after traumatic brain injury. PPAR Res 2008:538141

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Stella N (2010) Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia 58:1017–1030

    Article  PubMed Central  PubMed  Google Scholar 

  • Takada LT, Geschwind MD (2013) Prion diseases. Semin Neurol 33:348–356

    Article  PubMed  Google Scholar 

  • 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–e16

    PubMed  Google Scholar 

  • 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 1283:148–154

    Article  PubMed  CAS  Google Scholar 

  • 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 3:400–406

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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:e862

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):185–199

    Article  PubMed Central  CAS  Google Scholar 

  • 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 21:6475–6579

    PubMed  Google Scholar 

  • 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 63:1410–1424

    Article  PubMed  CAS  Google Scholar 

  • 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 79:41–50

    Article  PubMed  CAS  Google Scholar 

  • 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 16:620–642

    Article  CAS  PubMed  Google Scholar 

  • Walter L, Franklin A, Witting A et al (2003) Non-psychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 23:1398–1405

    CAS  PubMed  Google Scholar 

  • 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 57:201–208

    Article  CAS  PubMed  Google Scholar 

  • 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 63:637–652

    Article  CAS  PubMed  Google Scholar 

  • 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 32:17321–17331

    Article  CAS  PubMed  Google Scholar 

  • Ziemka-Nałęcz M, Zalewska T (2012) Endogenous neurogenesis induced by ischemic brain injury or neurodegenerative diseases in adults. Acta Neurobiol Exp 72:309–324

    Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

  1. Facultad de Medicina, Departamento de Bioquímica y Biología Molecular III, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Ciudad Universitaria s/n, 28040, Madrid, Spain

    Javier Fernández-Ruiz & José A. Ramos

  2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    Javier Fernández-Ruiz & José A. Ramos

  3. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain

    Javier Fernández-Ruiz & José A. Ramos

  4. Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Madrid, Spain

    Julián Romero

  5. Departamento de Ciencias Biosanitarias, Universidad Francisco de Vitoria, Madrid, Spain

    Julián Romero

Authors
  1. Javier Fernández-Ruiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julián Romero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. José A. Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Javier Fernández-Ruiz .

Editor information

Editors and Affiliations

  1. Professor of Neuropharmacology, University of Aberdeen Institute of Medical Sciences, Aberdeen, United Kingdom

    Roger G. Pertwee

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Fernández-Ruiz, J., Romero, J., Ramos, J.A. (2015). Endocannabinoids and Neurodegenerative Disorders: Parkinson’s Disease, Huntington’s Chorea, Alzheimer’s Disease, and Others. In: Pertwee, R. (eds) Endocannabinoids. Handbook of Experimental Pharmacology, vol 231. Springer, Cham. https://doi.org/10.1007/978-3-319-20825-1_8

Download citation

Publish with us

Policies and ethics

Search

Navigation