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The Chemically-Modified Tetracycline COL-3 and Its Parent Compound Doxycycline Prevent Microglial Inflammatory Responses by Reducing Glucose-Mediated Oxidative Stress
- Source :
- Cells, Volume 10, Issue 8, Cells, MDPI, 2021, 10 (8), pp.2163. ⟨10.3390/cells10082163⟩, Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual), Universidade de São Paulo (USP), instacron:USP, Cells, 2021, 10 (8), pp.2163. ⟨10.3390/cells10082163⟩, Cells, Vol 10, Iss 2163, p 2163 (2021)
- Publication Year :
- 2021
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2021.
-
Abstract
- We used mouse microglial cells in culture activated by lipopolysaccharide (LPS) or α-synuclein amyloid aggregates (αSa) to study the anti-inflammatory effects of COL-3, a tetracycline derivative without antimicrobial activity. Under LPS or αSa stimulation, COL-3 (10, 20 µM) efficiently repressed the induction of the microglial activation marker protein Iba-1 and the stimulated-release of the pro-inflammatory cytokine TNF-α. COL-3′s inhibitory effects on TNF-α were reproduced by the tetracycline antibiotic doxycycline (DOX<br />50 µM), 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-α 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.
- Subjects :
- Lipopolysaccharide
Neuroimmunomodulation
QH301-705.5
glucose metabolism
Fluorescent Antibody Technique
microglia
Oxidative phosphorylation
macromolecular substances
Pharmacology
medicine.disease_cause
Article
neuroinflammation
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Microscopy, Electron, Transmission
medicine
Animals
oxidative stress
[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Biology (General)
Cells, Cultured
COL-3
030304 developmental biology
Doxycycline
0303 health sciences
NADPH oxidase
biology
Microglia
Chemistry
General Medicine
FARMACOLOGIA EXPERIMENTAL
tetracyclines
equipment and supplies
3. Good health
Respiratory burst
Glucose
medicine.anatomical_structure
Apocynin
biology.protein
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
030217 neurology & neurosurgery
Oxidative stress
Signal Transduction
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 20734409
- Database :
- OpenAIRE
- Journal :
- Cells
- Accession number :
- edsair.doi.dedup.....55df4114fa384166095e5c57f2eb1940
- Full Text :
- https://doi.org/10.3390/cells10082163