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Dasatinib regulates LPS-induced microglial and astrocytic neuroinflammatory responses by inhibiting AKT/STAT3 signaling

Title
Dasatinib regulates LPS-induced microglial and astrocytic neuroinflammatory responses by inhibiting AKT/STAT3 signaling
Authors
Ryu, Ka-YoungLee, Hyun-JuWoo, HanwoongKang, Ri-JinHan, Kyung-MinPark, HyunHeeLee, Sang MinLee, Ju-YoungJeong, Yoo JooNam, Hyun-WookNam, YoungpyoHoe, Hyang-Sook
Issue Date
2019-10
Citation
Journal of Neuroinflammation, 16(1)
Type
Article
Article Type
Article
Author Keywords
LPSNeuroinflammationSTAT3AKTMicrogliaAstrocytes
Keywords
KAPPA-B ACTIVATIONTYROSINE KINASE INHIBITORSCHRONIC MYELOID-LEUKEMIAC-ABL KINASEMOUSE MODELINFLAMMATORY RESPONSESNLRP3 INFLAMMASOMEIMATINIBCELLSAPOPTOSIS
ISSN
1742-2094
Abstract
Background: The FDA-approved small-molecule drug dasatinib is currently used as a treatment for chronic myeloid leukemia (CML). However, the effects of dasatinib on microglial and/or astrocytic neuroinflammatory responses and its mechanism of action have not been studied in detail. Methods: BV2 microglial cells, primary astrocytes, or primary microglial cells were treated with dasatinib (100 or 250 nM) or vehicle (1% DMSO) for 30 min or 2 h followed by lipopolysaccharide (LPS; 200 ng/ml or 1 μg/ml) or PBS for 5.5 h. RT-PCR, real-time PCR; immunocytochemistry; subcellular fractionation; and immunohistochemistry were subsequently conducted to determine the effects of dasatinib on LPS-induced neuroinflammation. In addition, wild-type mice were injected with dasatinib (20 mg/kg, intraperitoneally (i.p.) daily for 4 days or 20 mg/kg, orally administered (p.o.) daily for 4 days or 2 weeks) or vehicle (4% DMSO + 30% polyethylene glycol (PEG) + 5% Tween 80), followed by injection with LPS (10 mg/kg, i.p.) or PBS. Then, immunohistochemistry was performed, and plasma IL-6, IL-1β, and TNF-α levels were analyzed by ELISA. Results: Dasatinib regulates LPS-induced proinflammatory cytokine and anti-inflammatory cytokine levels in BV2 microglial cells, primary microglial cells, and primary astrocytes. In BV2 microglial cells, dasatinib regulates LPS-induced proinflammatory cytokine levels by regulating TLR4/AKT and/or TLR4/ERK signaling. In addition, intraperitoneal injection and oral administration of dasatinib suppress LPS-induced microglial/astrocyte activation, proinflammatory cytokine levels (including brain and plasma levels), and neutrophil rolling in the brains of wild-type mice. Conclusions: Our results suggest that dasatinib modulates LPS-induced microglial and astrocytic activation, proinflammatory cytokine levels, and neutrophil rolling in the brain. © 2019 The Author(s).
URI
http://hdl.handle.net/20.500.11750/10925
DOI
10.1186/s12974-019-1561-x
Publisher
BioMed Central
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