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DMH-CBD, a cannabidiol analog with reduced cytotoxicity, inhibits TNF production by targeting NF-kB activity dependent on A(2A) receptor

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Autor(es):
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Silva, Rangel L. [1] ; Silveira, Gabriela T. [1] ; Wanderlei, Carlos W. [2, 1] ; Cecilio, Nerry T. [1] ; Maganin, Alexandre G. M. [1] ; Franchin, Marcelo [3] ; Marques, Lucas M. M. [4] ; Lopes, Norberto P. [4] ; Crippa, Jose A. [5] ; Guimaraes, Francisco S. [1] ; Alves, Jose C. F. [1] ; Cunha, Fernando Q. [1] ; Cunha, Thiago M. [1]
Número total de Autores: 13
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto - Brazil
[2] Univ Fed Ceara, Fac Med, Dept Physiol & Pharmacol, Fortaleza, Ceara - Brazil
[3] Univ Estadual Campinas, Piracicaba Dent Sch, BR-13414903 Piracicaba, SP - Brazil
[4] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto, Dept Phys Chem, Ribeirao Preto - Brazil
[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Neurosci & Behav, Ribeirao Preto - Brazil
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: Toxicology and Applied Pharmacology; v. 368, p. 63-71, APR 1 2019.
Citações Web of Science: 0
Resumo

Cannabidiol (CBD) is a natural compound with psychoactive therapeutic properties well described. Conversely, the immunological effects of CBD are still poorly explored. In this study, the potential anti-inflammatory effects and underlying mechanisms of CBD and its analog Dimethyl-Heptyl-Cannabidiol (DMH-CBD) were investigated using RAW 264.7 macrophages. CBD and DMH-CBD suppressed LPS-induced TNF production and NF-kB activity in a concentration-dependent manner. Both compounds reduced the NF-kB activity in a mu M concentration range: CBD (IC50 = 15 mu M) and DMH-CBD (IC50 = 38 mu M). However, the concentrations of CBD that mediated NF-kB inhibition were similar to those that cause cytotoxicity (LC50 = 58 mu M). Differently, DMH-CBD inhibited the NF-kB activation without cytotoxic effects at the same concentrations, although it provokes cytotoxicity at long-term exposure. The inhibitory action of the DMH-CBD on NF-kB activity was not related to the reduction in IkB alpha degradation or either p65 (NF-kB) translocation to the nucleus, although it decreased p38 MAP kinase phosphorylation. Additionally, 8-(3-Chlorostyryl) caffeine (CSC), an A(2A) antagonist, reversed the effect of DMH-CBD on NF-kB activity in a concentration-dependent manner. Collectively, our results demonstrated that CBD reduces NF-kB activity at concentrations intimately associated with those that cause cell death, whereas DMH-CBD decreases NF-kB activity at non-toxic concentrations in an A(2A) receptor dependent-manner. (AU)

Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
Beneficiário:Fernando de Queiroz Cunha
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs