期刊
NANOMEDICINE
卷 7, 期 8, 页码 1149-1165出版社
FUTURE MEDICINE LTD
DOI: 10.2217/nnm.12.16
关键词
celastrol; inflammation; JNK; microglia; NF-kappa B; nitric oxide; p38; poly(amidoamine) dendrimers; TLR4 signaling; TNF-alpha
资金
- Canadian Institutes of Health Research (CIHR MOP) [89995, 119425]
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Alzheimer's Society of Canada
- CIHR
Aim: This study investigates the capacity of a potent anti-inflammatory nanomedicine, celastrol, incorporated into poly(amidoamine) dendrimers, to inhibit endotoxin-mediated signaling in microglia. Materials & methods: Celastrol was incorporated into amino (Cel/G4-NH2) and hydroxyl (Cel/G4-OH) terminus poly(amidoamine) (G4) dendrimers. Cell viability, release of nitric oxide, IL-6, TNF-alpha and activation of MAPK (e.g., p38 and JNK) and NF-kappa B were assessed in endotoxin (i.e., lipopolysaccharide) stimulated microglial cells. Results: G4-OH and G4-NH2 increased celastrol aqueous solubility by seven- and 12-fold, respectively. G4-OH and Cel/G4-OH suppressed lipopolysaccharide-mediated release of proinflammatory mediators, such as nitric oxide and IL-6, but not TNF-alpha, without reducing microglial cell viability, while Cel/G4-NH2 potentiated cytotoxicity and cytokine release. Blockade of proinflammatory signaling was accompanied by attenuation of p38 MAPK activation. Conclusion: This study supports the potential use of poly(amidoamine) dendrimers for effective anti-inflammatory therapy in the chronically inflamed CNS.
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