Cannabidiol prevents LPS-induced microglial inflammation by inhibiting ROS/NF-kappa B-dependent signaling and glucose consumption

Autor(es)

dos-Santos-Pereira, Mauricio ^{[1, 2, 3]} ; Guimaraes, Franscisco S. ^{[1, 4]} ; Del-Bel, Elaine ^{[1, 2]} ; Raisman-Vozari, Rita ^[3] ; Michel, Patrick P. ^[3]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, NAPNA, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Morfol Fisiol & Patol Basica, Fac Odontol, Ribeirao Preto - Brazil

^[3] Sorbonne Univ, Inst Cerveau & Moelle Epiniere ICM, CNRS, INSERM, UMR 7225, U1127, Paris - France

^[4] Univ Sao Paulo, Dept Farmacol, Fac Med, Ribeirao Preto - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Glia; v. 68, n. 3, p. 561-573, MAR 2020.
• Citações Web of Science: 0

Resumo

We used mouse microglial cells in culture activated by lipopolysaccharide (LPS, 10 ng/ml) to study the anti-inflammatory potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis. Under LPS stimulation, CBD (1-10 mu M) potently inhibited the release of prototypical proinflammatory cytokines (TNF-alpha and IL-1 beta) and that of glutamate, a noncytokine mediator of inflammation. The effects of CBD were predominantly receptor-independent and only marginally blunted by blockade of CB2 receptors. We established that CBD inhibited a mechanism involving, sequentially, NADPH oxidase-mediated ROS production and NF-kappa B-dependent signaling events. In line with these observations, active concentrations of CBD demonstrated an intrinsic free-radical scavenging capacity in the cell-free DPPH assay. Of interest, CBD also prevented the rise in glucose uptake observed in microglial cells challenged with LPS, as did the inhibitor of NADPH oxidase apocynin and the inhibitor of I kappa B kinase-2, TPCA-1. This indicated that the capacity of CBD to prevent glucose uptake also contributed to its anti-inflammatory activity. Supporting this view, the glycolytic inhibitor 2-deoxy-d-glucose (2-DG) mimicked the antioxidant/immunosuppressive effects of CBD. Interestingly, CBD and 2-DG, as well as apocynin and TPCA-1 caused a reduction in glucose-derived NADPH, a cofactor required for NADPH oxidase activation and ROS generation. These different observations suggest that CBD exerts its anti-inflammatory effects towards microglia through an intrinsic antioxidant effect, which is amplified through inhibition of glucose-dependent NADPH synthesis. These results also further confirm that CBD may have therapeutic utility in conditions where neuroinflammatory processes are prominent. (AU)

• Processo FAPESP: 18/03482-0 - A ação de fármacos canabinóides no processo de neuroinflamação dependente de glia: um link com a discinesia induzida por l-dopa
• Beneficiário: Maurício dos Santos Pereira
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 14/25029-4 - Estudo da contribuição do processo inflamatório na discinesia induzida por L-DOPA na Doença de Parkinson
• Beneficiário: Elaine Aparecida Del Bel Belluz Guimarães
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/14207-7 - A ação de fármacos canabinóides na discinesia induzida por l-dopa: análise da neuroinflamação e liberação de glutamato em células gliais
• Beneficiário: Maurício dos Santos Pereira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado