Nilotinib modulates LPS-induced cognitive impairment and neuroinflammatory responses by regulating P38/STAT3 signaling

Abstract

Background In chronic myelogenous leukemia, reciprocal translocation between chromosome 9 and chromosome 22 generates a chimeric protein, Bcr-Abl, that leads to hyperactivity of tyrosine kinase-linked signaling transduction. The therapeutic agent nilotinib inhibits Bcr-Abl/DDR1 and can cross the blood–brain barrier, but its potential impact on neuroinflammatory responses and cognitive function has not been studied in detail. Methods The effects of nilotinib in vitro and in vivo were assessed by a combination of RT-PCR, real-time PCR, western blotting, ELISA, immunostaining, and/or subcellular fractionation. In the in vitro experiments, the effects of 200 ng/mL LPS or PBS on BV2 microglial cells, primary microglia or primary astrocytes pre- or post-treated with 5 µM nilotinib or vehicle were evaluated. The in vivo experiments involved wild-type mice administered a 7-day course of daily injections with 20 mg/kg nilotinib (i.p.) or vehicle before injection with 10 mg/kg LPS (i.p.) or PBS. Results In BV2 microglial cells, pre- and post-treatment with nilotinib altered LPS-induced proinflammatory/anti-inflammatory cytokine mRNA levels by suppressing AKT/P38/SOD2 signaling. Nilotinib treatment also significantly downregulated LPS-stimulated proinflammatory cytokine levels in primary microglia and primary astrocytes by altering P38/STAT3 signaling. Experiments in wild-type mice showed that nilotinib administration affected LPS-mediated microglial/astroglial activation in a brain region-specific manner in vivo. In addition, nilotinib significantly reduced proinflammatory cytokine IL-1β, IL-6 and COX-2 levels and P38/STAT3 signaling in the brain in LPS-treated wild-type mice. Importantly, nilotinib treatment rescued LPS-mediated spatial working memory impairment and cortical dendritic spine number in wild-type mice. Conclusions Our results indicate that nilotinib can modulate neuroinflammatory responses and cognitive function in LPS-stimulated wild-type mice.

L-Type Ca2+ Channel Inhibition Rescues the LPS-Induced Neuroinflammatory Response and Impairments in Spatial Memory and Dendritic Spine Formation

“…Recent studies have reported that chronic LPS administration promotes neuroinflammation-mediated cognitive disruption [ 42 , 43 , 44 , 45 ] and that low-dose (250 μg/mL) chronic LPS administration induces motor and short-term working memory impairment in wild-type mice [ 46 ]. Based on these observations, we used a low dose of LPS to evaluate the effects of the L-type CCB felodipine on chronic neuroinflammation-mediated learning and memory impairments.…”

“…No. DYC4198-5, R&D Systems, Minneapolis, MN, USA) as previously described [ 46 ]. The conditioned medium used in the ELISA was harvested from cells and treated successively with 5 μM felodipine or vehicle for 30 min and with 200 ng/mL LPS or PBS for 5.5 h. The ELISA was conducted according to the provided protocol.…”

CXCR4-BTK axis mediate pyroptosis and lipid peroxidation in early brain injury after subarachnoid hemorrhage via NLRP3 inflammasome and NF-κB pathway

“…Primary microglia were isolated and purified from C57BL6/J mice within 3 days of birth as described previously [ 39 ]. Briefy, cerebral cortex was isolated, fltered through a 70-μm nylon mesh, and then cultured in low-glucose DMEM medium supplemented with 10% FBS and 1% penicillin/streptomycin at 37°C under 5% CO2 incubator.…”

Inhibiting EGFR/HER-2 ameliorates neuroinflammatory responses and the early stage of tau pathology through DYRK1A

“…To assess the effects of varlitinib on glial activation, we measured Iba-l and GFAP fluorescence intensity. In addition, to investigate the effects of varlitinib on glial migration and morphology, we quantified the number of GFAP-positive cells and the percent GFAP-positive area, respectively ( 16 , 21 ).…”