K284-6111 prevents the amyloid beta-induced neuroinflammation and impairment of recognition memory through inhibition of NF-κB-mediated CHI3L1 expression

Abstract

BackgroundAlzheimer’s disease, which is pathologically characterized by an excessive accumulation of amyloid beta (Aβ) fibrils, is a degenerative brain disease and the most common cause of dementia. In a previous study, it was reported that an increased level of CHI3L1 in plasma was found in AD patients. We investigated the inhibitory effect of 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), an inhibitor of chitinase 3 like 1 (CHI3L1), on memory impairment in Aβ1–42-infused mice, and microglial BV-2 cells and astrocytes.MethodsWe examined whether K284-6111 (3 mg/kg given orally for 4 weeks) prevents amyloidogenesis and memory loss in Aβ1–42-induced AD mice model. After intracerebroventrical (ICV) infusion of Aβ1–42 for 14 days, the cognitive function was assessed by the Morris water maze test and passive avoidance test. K284-6111 treatment was found to reduce Aβ1–42-induced memory loss.ResultsA memory recovery effect was found to be associated with the reduction of Aβ1–42-induced expression of inflammatory proteins (iNOS, COX-2, GFAP, and Iba-1) and the suppression of CHI3L1 expression in the brain. Additionally, K284-6111 reduced Aβ1–42-induced β-secretase activity and Aβ generation. Lipopolysaccharide (LPS)-induced (1 μg/mL) expression of inflammatory (COX-2, iNOS, GFAP, Iba-1) and amyloidogenic proteins (APP, BACE1) were decreased in microglial BV-2 cells and cultured astrocytes by the K284-6111 treatment (0.5, 1, and 2 μM). Moreover, K284-6111 treatment suppressed p50 and p65 translocation into the nucleus, and phosphorylation of IκB in vivo and in vitro.ConclusionThese results suggest that CHI3L1 inhibitor could be an applicable intervention drug in amyloidogenesis and neuroinflammation, thereby preventing memory dysfunction via inhibition of NF-κB.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1269-3) contains supplementary material, which is available to authorized users.

K284-6111 Alleviates Memory Impairment and Neuroinflammation in Tg2576 Mice by Inhibition of Chitinase-3-like 1 Regulating ERK Dependent PTX3 Pathway

“…Our previous study suggested that K284-6111 could act as an inhibitor of CHI3L1 by directly binding to CHI3L1 [33]. In this study, we also found that administration of K284-6111 markedly attenuated impaired cognitive function and memory in Tg2576 AD mouse model.…”

“…Pranzatelli et al reported that the CHI3L1 is increased in CSF and serum of in ammatory neurological disorders in children [47]. In our previous study, Aβ-induced AD mouse model showed higher level of CHI3L1 in brain compared to that of controls, and we also demonstrated that CHI3L1-knockdown reduced in ammatory proteins such as iNOS and COX-2 in LPS-stimulated BV-2 cells [33]. Consistent with our previous ndings, the present study showed that overexpression of CHI3L1 increased expression of pro-in ammatory cytokines, Cd86, one of the markers of M1 microglia, and in ammatory proteins in CHI3L1 overexpressing BV-2 cells.…”

“…In our previous study, we demonstrated that K284-6111 directly binds to CHI3L1 using computational docking study and that K284-6111 has anti-in ammatory effect on Aβ-infusion AD mouse model and BV-2 cells [33]. However, our previous study has not demonstrated whether CHI3L1 could cause neuroin ammation and whether K284-6111 could mitigate neuroin ammatory responses induced by CHI3L1.…”

“…In our previous study, we found that the 2-({3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111) alleviated memory dysfunction and neuroin ammation by inhibiting CHI3L1 in Αβ infusion AD mouse model [33]. However, studies of the detailed mechanisms of K284-6111 that inhibits neuroin ammation and memory impairment by inhibition of CHI3L1 function have not been performed yet.…”

G721-0282 inhibits cell growth and induces apoptosis in human osteosarcoma through down-regulation of the STAT3 pathway

“…Recently, chitinase 3 like 1 (Chi3L1) expression has been found in a variety of cancer cells such as breast, lung, prostate, colon, rectum, ovary, kidney, glioblastomas, and malignant melanoma (14)(15)(16)(17)(18)(19)(20). We also previously selected 20 chemicals as candidate compounds for the ligand of Chi3L1 by using 3D chemical database analysis with X-ray structure-based virtual screening (21), and G721-0282 was obtained from ChemiDiv Inc. (http://www.chemdiv.com). In the present study, we investigated whether G721-0282, a candidate ligand of Chi3L1 regulates in vitro effects on proliferation, apoptosis, migration, invasion, and colony formation in OS cells, and in vivo anti-tumor effects in a xenograft mouse model.…”