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.Electronic supplementary materialThe online version of this article (10.1186/s12974-019-1561-x) contains supplementary material, which is available to authorized users.

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Adpsin is an adipokine that stimulates insulin secretion from β-cells and improves glucose tolerance. Its expression has been found to be markedly reduced in obese animals. However, it remains unclear what factors lead to downregulation of adipsin in the context of obesity. Endoplasmic reticulum (ER) stress response is activated in various tissues under obesity-related conditions and can induce transcriptional reprogramming. Therefore, we aimed to investigate the relationship between adipsin expression and ER stress in adipose tissues during obesity. We observed that obese mice exhibited decreased levels of adipsin in adipose tissues and serum and increased ER stress markers in adipose tissues compared to lean mice. We also found that ER stress suppressed adipsin expression via adipocytes-intrinsic mechanisms. Moreover, the ER stress-mediated downregulation of adipsin was at least partially attributed to decreased expression of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor in the regulation of adipocyte function. Finally, treatment with chemical chaperones recovered the ER stress-mediated downregulation of adipsin and PPARγ in vivo and in vitro. Our findings suggest that activated ER stress in adipose tissues is an important cause of the suppression of adipsin expression in the context of obesity.

Recently, we reported that ALWPs, which we developed by combining Liuwei Dihuang pills (LWPs) with antler, regulate the LPS-induced neuroinflammatory response and rescue LPS-induced short- and long-term memory impairment in wild-type (WT) mice. In the present study, we examined the effects of ALWPs on Alzheimer’s disease (AD) pathology and cognitive function in WT mice as well as 5x FAD mice (a mouse model of AD). We found that administration of ALWPs significantly reduced amyloid plaque levels in 5x FAD mice and significantly decreased amyloid β (Aβ) levels in amyloid precursor protein (APP)-overexpressing H4 cells. In addition, ALWPs administration significantly suppressed tau hyperphosphorylation in 5x FAD mice. Oral administration of ALWPs significantly improved long-term memory in scopolamine (SCO)-injected WT mice and 5x FAD mice by altering dendritic spine density. Importantly, ALWPs promoted spinogenesis in primary hippocampal neurons and WT mice and modulated the dendritic spine number in an extracellular signal-regulated kinase (ERK)-dependent manner. Taken together, our results suggest that ALWPs are a candidate therapeutic drug for AD that can modulate amyloid plaque load, tau phosphorylation, and synaptic/cognitive function.