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Molecular Pharmacology

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Research ArticleArticle

Cannabidiol and Other Cannabinoids Reduce Microglial Activation In Vitro and In Vivo: Relevance to Alzheimer's Disease

Ana María Martín-Moreno, David Reigada, Belén G. Ramírez, R. Mechoulam, Nadia Innamorato, Antonio Cuadrado and María L. de Ceballos
Molecular Pharmacology June 2011, 79 (6) 964-973; DOI: https://doi.org/10.1124/mol.111.071290
Ana María Martín-Moreno
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David Reigada
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Belén G. Ramírez
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R. Mechoulam
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Nadia Innamorato
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Antonio Cuadrado
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María L. de Ceballos
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Abstract

Microglial activation is an invariant feature of Alzheimer's disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study, we compared the effects of CBD with those of other cannabinoids on microglial cell functions in vitro and on learning behavior and cytokine expression after Aβ intraventricular administration to mice. CBD, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone [WIN 55,212-2 (WIN)], a mixed CB1/CB2 agonist, and 1,1-dimethylbutyl-1-deoxy-Δ9-tetrahydrocannabinol [JWH-133 (JWH)], a CB2-selective agonist, concentration-dependently decreased ATP-induced (400 μM) increase in intracellular calcium ([Ca2+]i) in cultured N13 microglial cells and in rat primary microglia. In contrast, 4-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-2-ene-2-methanol [HU-308 (HU)], another CB2 agonist, was without effect. Cannabinoid and adenosine A2A receptors may be involved in the CBD action. CBD- and WIN-promoted primary microglia migration was blocked by CB1 and/or CB2 antagonists. JWH and HU-induced migration was blocked by a CB2 antagonist only. All of the cannabinoids decreased lipopolysaccharide-induced nitrite generation, which was insensitive to cannabinoid antagonism. Finally, both CBD and WIN, after subchronic administration for 3 weeks, were able to prevent learning of a spatial navigation task and cytokine gene expression in β-amyloid-injected mice. In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD. Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.

Footnotes

  • This work was supported by the Spanish Ministry of Science and Technology [Grant SAF 2005-02845]; the National Institutes of Health National Institute on Drug Abuse [Grant DA9789]; a fellowship from the Community of Madrid (to B.G.R.); and a fellowship from the Ministry of Science and Innovation (to A.M.M.-M.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.071290.

  • ABBREVIATIONS:

    AD
    Alzheimer's disease
    Aβ
    β-amyloid peptide
    IL-6
    interleukin 6
    TNF-α
    tumor necrosis factor-α
    WIN
    WIN 55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone
    JWH
    JWH-133
    JWH-133
    1,1-dimethylbutyl-1-deoxy-Δ9-tetrahydrocannabinol
    HU
    HU-308, 4-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-2-ene-2-methanol
    LPS
    lipopolysaccharide
    iNOS
    inducible nitric-oxide synthase
    SCR
    scrambled peptide
    FCS
    fetal calf serum
    PCR
    polymerase chain reaction
    ANOVA
    analysis of variance
    SR1
    SR141716, N-piperidino-5-(4-chlorophenyl)-l-(2, 4-dichlorophenyl)-4-methylpyrazole-3-carboxamide
    SR2
    SR144528, N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide
    CGS
    CGS21680, 2-[p-(2-carboxyethyl)phenethylamino]-5′-N-ethylcarboxamidoadenosine
    ZM
    ZM241385, 4-{2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol
    VDM11
    N-(4-hydroxy-2-methylphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide.

  • Received January 18, 2011.
  • Accepted February 11, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (6)
Molecular Pharmacology
Vol. 79, Issue 6
1 Jun 2011
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Research ArticleArticle

Cannabidiol and Other Cannabinoids Reduce Microglial Activation In Vitro and In Vivo: Relevance to Alzheimer's Disease

Ana María Martín-Moreno, David Reigada, Belén G. Ramírez, R. Mechoulam, Nadia Innamorato, Antonio Cuadrado and María L. de Ceballos
Molecular Pharmacology June 1, 2011, 79 (6) 964-973; DOI: https://doi.org/10.1124/mol.111.071290

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Research ArticleArticle

Cannabidiol and Other Cannabinoids Reduce Microglial Activation In Vitro and In Vivo: Relevance to Alzheimer's Disease

Ana María Martín-Moreno, David Reigada, Belén G. Ramírez, R. Mechoulam, Nadia Innamorato, Antonio Cuadrado and María L. de Ceballos
Molecular Pharmacology June 1, 2011, 79 (6) 964-973; DOI: https://doi.org/10.1124/mol.111.071290
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