Abstract
BackgroundThe 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.MethodsBV2 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.ResultsDasatinib 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.ConclusionsOur results suggest that dasatinib modulates LPS-induced microglial and astrocytic activation, proinflammatory cytokine levels, and neutrophil rolling in the brain.
Highlights
The FDA-approved small-molecule drug dasatinib is currently used as a treatment for chronic myeloid leukemia (CML)
Subcellular fractionation To test whether dasatinib affects LPS-induced cytosolic and nuclear p-Signal transducer and activator of transcription 3 (STAT3) levels, BV2 microglial cells were treated with dasatinib (250 nΜ) or vehicle (1% DMSO) for 30 min followed by LPS (1 μg/ml) or PBS for 5.5 h
To investigate whether dasatinib affects LPS-induced proinflammatory responses, BV2 microglial cells were treated with vehicle (1% DMSO) or dasatinib (100 nM) for 30 min followed by LPS (1 μg/ml) or PBS for 5.5 h, and proinflammatory cytokine levels were measured using Reverse transcription-polymerase chain reaction (RT-PCR)
Summary
The FDA-approved small-molecule drug dasatinib is currently used as a treatment for chronic myeloid leukemia (CML). The effects of dasatinib on microglial and/or astrocytic neuroinflammatory responses and its mechanism of action have not been studied in detail. The human brain comprises numerous cell types, including microglia, astrocytes, and neuronal cells. As an FDAapproved drug, dasatinib is currently used as a treatment for imatinib-resistant chronic myeloid leukemia (CML) [6,7,8]. Fraser et al demonstrated that orally administered dasatinib significantly downregulates LPS-induced serum levels of TNF-α but not other proinflammatory cytokines in the lung [12]. Few studies have examined whether dasatinib can alter LPS-induced neuroinflammatory responses in vitro and in vivo and its molecular mechanism of action
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