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Mitochondrial Uncouplers Confer Protection by Activating AMP-Activated Protein Kinase to Inhibit Neuroinflammation Following Intracerebral Hemorrhage.
- Source :
-
Biological & pharmaceutical bulletin [Biol Pharm Bull] 2020; Vol. 43 (8), pp. 1210-1219. - Publication Year :
- 2020
-
Abstract
- Intracerebral hemorrhage (ICH) is a disease with high disability and mortality rates. Currently, the efficacy of therapies available for ICH is limited. Microglia-mediated neuroinflammation substantially exacerbates brain damage following ICH. Here, we investigated whether mitochondrial uncouplers conferred protection by suppressing neuroinflammation following ICH. To mimic ICH-induced neuroinflammation in vitro, we treated microglia with red blood cell (RBC) lysate. RBC lysate enhanced the expression of pro-inflammatory cytokines in microglia. A clinically used uncoupler, niclosamide (Nic), reduced the RBC lysate-induced expression of pro-inflammatory cytokines in microglia. Moreover, Nic ameliorated brain edema, decreased neuroinflammation, and improved neurological deficits in a well-established mouse model of ICH. Like niclosamide, the structurally unrelated uncoupler carbonyl cyanide p-triflouromethoxyphenylhydrazone (FCCP) reduced brain edema, decreased neuroinflammation, and improved neurological deficits following ICH. It has been reported that mitochondrial uncouplers activate AMP-activated protein kinase (AMPK). Mechanistically, Nic enhanced AMPK activation following ICH, and AMPK knockdown abolished the beneficial effects of Nic following ICH. In conclusion, mitochondrial uncouplers conferred protection by activating AMPK to inhibit microglial neuroinflammation following ICH.
- Subjects :
- Animals
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone pharmacology
Cells, Cultured
Mice
Microglia drug effects
Niclosamide therapeutic use
AMP-Activated Protein Kinases physiology
Cerebral Hemorrhage drug therapy
Inflammation drug therapy
Neuroprotective Agents pharmacology
Niclosamide pharmacology
Uncoupling Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1347-5215
- Volume :
- 43
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Biological & pharmaceutical bulletin
- Publication Type :
- Academic Journal
- Accession number :
- 32741941
- Full Text :
- https://doi.org/10.1248/bpb.b20-00108