The Chemically-Modified Tetracycline COL-3 and Its Parent Compound Doxycycline Prevent Microglial Inflammatory Responses by Reducing Glucose-Mediated Oxidative Stress

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Ferreira Junior, Nilson Carlos ^{[1, 2, 3]} ; Pereira, Mauricio dos Santos ^{[1, 2, 3]} ; Francis, Nour ^[1] ; Ramirez, Paola ^[1] ; Martorell, Paula ^[1] ; Gonzalez-Lizarraga, Florencia ^[4] ; Figadere, Bruno ^[5] ; Chehin, Rosana ^[4] ; Del Bel, Elaine ^{[2, 3]} ; Raisman-Vozari, Rita ^[1] ; Michel, Patrick Pierre ^[1]

Afiliação do(s) autor(es)

^[1] Sorbonne Univ, Hop Pitie Salpetriere, AP HP, Paris Brain Inst ICM, INSERM, CNRS, F-75013 Paris - France

^[2] Univ Sao Paulo, Dept Basic & Oral Biol, FORP, Campus USP, Av Cafe S, BR-14040904 Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, BR-05508220 Sao Paulo - Brazil

^[4] Inst Invest Med Mol & Celular Aplicada IMMCA CONI, RA-4000 San Miguel De Tucuman - Argentina

^[5] Univ Paris Saclay, CNRS, BioCIS, F-92290 Chatenay Malabry - France

• Tipo de documento: Artigo Científico
• Fonte: CELLS; v. 10, n. 8 AUG 2021.
• Citações Web of Science: 0

Resumo

We used mouse microglial cells in culture activated by lipopolysaccharide (LPS) or alpha-synuclein amyloid aggregates (alpha Sa) to study the anti-inflammatory effects of COL-3, a tetracycline derivative without antimicrobial activity. Under LPS or alpha Sa stimulation, COL-3 (10, 20 mu M) efficiently repressed the induction of the microglial activation marker protein Iba-1 and the stimulated-release of the pro-inflammatory cytokine TNF-alpha. COL-3 ` s inhibitory effects on TNF-alpha were reproduced by the tetracycline antibiotic doxycycline (DOX; 50 mu M), the glucocorticoid dexamethasone, and apocynin (APO), an inhibitor of the superoxide-producing enzyme NADPH oxidase. This last observation suggested that COL-3 and DOX might also operate themselves by restraining oxidative stress-mediated signaling events. Quantitative measurement of intracellular reactive oxygen species (ROS) levels revealed that COL-3 and DOX were indeed as effective as APO in reducing oxidative stress and TNF-alpha release in activated microglia. ROS inhibition with COL-3 or DOX occurred together with a reduction of microglial glucose accumulation and NADPH synthesis. This suggested that COL-3 and DOX might reduce microglial oxidative burst activity by limiting the glucose-dependent synthesis of NADPH, the requisite substrate for NADPH oxidase. Coherent with this possibility, the glycolysis inhibitor 2-deoxy-D-glucose reproduced the immunosuppressive action of COL-3 and DOX in activated microglia. Overall, we propose that COL-3 and its parent compound DOX exert anti-inflammatory effects in microglial cells by inhibiting glucose-dependent ROS production. These effects might be strengthened by the intrinsic antioxidant properties of DOX and COL-3 in a self-reinforcing manner. (AU)

• 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