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Several clinical studies reported that the elevated expression of Chitinase-3-like 1 (CHI3L1) was observed in patients suffering from a wide range of diseases: cancer, metabolic, and neurological diseases. However, the role of CHI3L1 in AD is still unclear. Our previous study demonstrated that 2-({3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}culfanyl)-N-(4-ethylphenyl)butanamide, a CHI3L1 inhibiting compound, alleviates memory and cognitive impairment and inhibits neuroinflammation in AD mouse models. In this study, we studied the detailed correlation of CHI3L1 and AD using serum from AD patients and using CHI3L1 knockout (KO) mice with Aβ infusion (300 pmol/day, 14 days). Serum levels of CHI3L1 were significantly elevated in patients with AD compared to normal subjects, and receiver operating characteristic (ROC) analysis data based on serum analysis suggested that CHI3L1 could be a significant diagnostic reference for AD. To reveal the role of CHI3L1 in AD, we investigated the CHI3L1 deficiency effect on memory impairment in Aβ-infused mice and microglial BV-2 cells. In CHI3L1 KO mice, Aβ infusion resulted in lower levels of memory dysfunction and neuroinflammation compared to that of WT mice. CHI3L1 deficiency selectively inhibited phosphorylation of ERK and IκB as well as inhibition of neuroinflammation-related factors in vivo and in vitro. On the other hand, treatment with recombinant CHI3L1 increased neuroinflammation-related factors and promoted phosphorylation of IκB except for ERK in vitro. Web-based gene network analysis and our results showed that CHI3L1 is closely correlated with PTX3. Moreover, in AD patients, we found that serum levels of PTX3 were correlated with serum levels of CHI3L1 by Spearman correlation analysis. These results suggest that CHI3L1 deficiency could inhibit AD development by blocking the ERK-dependent PTX3 pathway. [ABSTRACT FROM AUTHOR]

Chronic stress is thought to be a major contributor to the onset of mental disorders such as anxiety disorders. Several studies have demonstrated a correlation between anxiety state and neuroinflammation, but the detailed mechanism is unclear. Chitinase-3-like 1 (CHI3L1) is expressed in several chronic inflammatorily damaged tissues and is well known to play a major role in mediating inflammatory responses. In the present study, we investigated the anxiolytic-like effect of N-Allyl-2-[(6-butyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)sulfanyl]acetamide (G721-0282), an inhibitor of CHI3L1, on mice treated with chronic unpredictable mild stress (CUMS), as well as the mechanism of its action. We examined the anxiolytic-like effect of G721-0282 by conducting several behavioral tests with oral administration of G721-0282 to CUMS-treated BALB/c male mice. We found that administration of G721-0282 relieves CUMS-induced anxiety. Anxiolytic-like effects of G721-0282 have been shown to be associated with decreased expressions of CUMS-induced inflammatory proteins and cytokines in the hippocampus. The CUMS-elevated levels of CHI3L1 and IGFBP3 were inhibited by treatment with G721-0282 in vivo and in vitro. However, CHI3L1 deficiency abolished the anti-inflammatory effects of G721-0282 in microglial BV-2 cells. These results suggest that G721-0282 could lower CUMS-induced anxiety like behaviors by regulating IGFBP3-mediated neuroinflammation via inhibition of CHI3L1. [ABSTRACT FROM AUTHOR]

Neuroinflammation is important in the pathogenesis and development of Alzheimer's disease (AD). In the AD brain, microglial activation and upregulation of pro-inflammatory mediators both induce amyloid beta (Aβ) accumulation. Regulatory T cells (Tregs) and nuclear factor-kappa B (NF-κB) signaling have been implicated in AD development through their effects on neuroinflammation and microglial activation. The bee venom soluble phospholipase A2 (bv-sPLA2) enzyme is known to exert anti-inflammatory and anti-immune effects. Here, we investigated the inhibitory effects of bv-sPLA2 on memory deficiency in a lipopolysaccharide (LPS)-induced mouse model of AD. We examined whether bv-sPLA2 (0.02, 0.2, and 2 mg/kg by i.p. injection three times for 1 week) could inhibit neuroinflammation and memory impairment in LPS-treated mice (250 μg/kg by i.p. injection daily for 1 week). We also assessed the effects of bv-sPLA2 administration (0.01, 0.1, and 1 μg/ml) on LPS (1 μg/ml)-treated microglial BV-2 cells. In the LPS-injected mouse brain, sPLA2 treatment rescued memory dysfunction and decreased Aβ levels, through the downregulation of amyloidogenic proteins, and decreased the expression of inflammatory proteins and pro-inflammatory cytokines. Moreover, the LPS-mediated increase in inflammatory protein expression was attenuated bv-sPLA2 treatment in BV-2 cells. Treatment with bv-sPLA2 also downregulated signaling by NF-κB, which is considered to be an important factor in the regulation of neuroinflammatory and amyloidogenic responses, both in vivo and in vitro. Additionally, co-treatment with NF-κB (5 μM) and bv-sPLA2 (0.1 μg/ml) exerted more marked anti-inflammatory effects, compared to bv-sPLA2 treatment alone. These results indicate that bv-sPLA2 inhibits LPS-induced neuroinflammation and amyloidogenesis via inhibition of NF-κB. [ABSTRACT FROM AUTHOR]

Highlights • Aβ infusion induced memory deficit and neuroinflammation in ovariectomized mice. • β-Estradiol treatment prevented Aβ-induced neuroinflammation. • Aβ-induced NF-ĸB activation was inhibited by estrogen treatment. • Estrogen deficiency promoted Alzheimer’s disease pathology via NF-ĸB. Abstract Estrogen is well known to have a preventative effect in Alzheimer’s disease (AD) pathology. Several studies have demonstrated that nuclear factor kappa-B (NF-ĸB) can contribute to the effects of estrogen on the development of AD. We investigated whether NF-ĸB affects amyloid-beta (Aβ)-induced memory impairment in an estrogen-lacking condition. In the present study, nine-week-old Institute cancer research (ICR) mice were ovariectomized to block estrogen stimulation. Ten weeks after the ovariectomization, mice were administered with Aβ (300 pmol) via intracerebroventricular (ICV) infusion for 2 weeks. Memory impairment, neuroinflammatory protein expression, and amyloidogenic pathways were then measured. Ovariectomized mice demonstrated severe memory impairment, Aβ accumulation, neprilysin downregulation, and activation of NF-ĸB signaling compared to sham-control mice. In vitro experiments demonstrated that β-estradiol (10 μM) inhibited Aβ (1 μM)-induced neuroinflammation in microglial BV-2 cells and prevented Aβ-induced cell death in primary cultured neuronal cells. As in in vivo experiments, NF-ĸB activation was significantly upregulated in in vitro experiments. Furthermore β-estradiol treatment inhibited NF-ĸB activation in both of microglial BV-2 cells and cultured neuronal cells. These findings suggest that estrogen may protect against memory impairment through the regulation of Aβ accumulation and neurogenic inflammation by inhibiting NF-κB activity. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic, autoimmune and neurodegenerative disease in which demyelination sporadically and repeatedly occurs in the central nervous system (CNS). The activity of nuclear factor kappa B (NF-κB), a family of transcription factors, was increased in the cerebrospinal fluid (CSF) and/or the serum and brain and/or spinal cord of MS patients than in a healthy donors. In our study, we investigated whether piperlongumine (PL), which is known to have inhibitory effect on activity of NF-κB, can alleviate an experimental autoimmune encephalomyelitis (EAE). The mice were immunized with myelin oligodendrocyte glycoprotein 35–55 (MOG 35–55 ), and then we injected PL (1.5 mg/kg/day or 3.0 mg/kg/day) into the mice intraperitoneally on every second day from days 2 to 28. For in vitro study, we treated PL (0.5, 1 and 2.5 μM) to RAW 264.7 and Jurkat cells with each stimulator. We observed that the paralytic severity and neuropathology of EAE in PL-treated group were decreased compared with the EAE group. PL showed a suppressed effect on demyelination, immune cells infiltration, astrocytes/microglials activation, level of inflammatory cytokines and proteins as well as NF-κB activity. Production of inflammatory cytokines and proteins as well as translocation of NF-κB into nucleus by treatment stimulators in RAW 264.7 and Jurkat cells were reduced by PL. Moreover, treatment of NF-κB inhibitor further inhibited production of inflammatory cytokines and proteins. These results suggest that PL can mitigate MOG-induced EAE symptoms and activation of macrophages and T cells by inhibiting NF-κB signaling. Therefore, PL could be useful for the treatment for MS. [ABSTRACT FROM AUTHOR]

Neuroinflammation is implicated in dopaminergic neurodegeneration. We have previously demonstrated that (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a selective signal transducer and activator of transcription 3 (STAT3) inhibitor, has anti-inflammatory properties in several inflammatory disease models. We investigated whether MMPP could protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell loss and behavioral impairment. Imprinting control region (ICR) mice (8 weeks old, n = 10 per group) were administered MMPP (5 mg/kg) in drinking water for 1 month, and injected with MPTP (15 mg/kg, four times with 2 h intervals) during the last 7 days of treatment. MMPP decreased MPTP-induced behavioral impairments in rotarod, pole, and gait tests. We also showed that MMPP ameliorated dopamine depletion in the striatum and inflammatory marker elevation in primary cultured neurons by high-performance liquid chromatography and immunohistochemical analysis. Increased activation of STAT3, p38, and monoamine oxidase B (MAO-B) were observed in the substantia nigra and striatum after MPTP injection, effects that were attenuated by MMPP treatment. Furthermore, MMPP inhibited STAT3 activity and expression of neuroinflammatory proteins, including ionized calcium binding adaptor molecule 1 (Iba1), inducible nitric oxide synthase (iNOS), and glial fibrillary acidic protein (GFAP) in 1-methyl-4-phenylpyridinium (MPP+; 0.5 mM)-treated primary cultured cells. However, mitogen-activated protein kinase (MAPK) inhibitors augmented the activity of MMPP. Collectively, our results suggest that MMPP may be an anti-inflammatory agent that attenuates dopaminergic neurodegeneration and neuroinflammation through MAO-B and MAPK pathway-dependent inhibition of STAT3 activation. [ABSTRACT FROM AUTHOR]

• The ethanol extract of Magnolia obovata leaf attenuate anxiety-like behavior in mice. • The ethanol extract of M. obovata leaf inhibits neuroinflammation in vivo and in vitro. • The ethanol extract of M. obovata leaf anxiolytic effect through the GABA A receptor. Recently, there have been studies that examined the relationship between neuroinflammation and anxiety disorder. Herein, we investigated the anxiolytic effect of a well-studied medicinal plant with anti-inflammatory properties, Magnolia obovata , by conducting cellular and animal studies. At the cellular level, the ethanol extract of M. obovata leaves demonstrated inhibitory effects on the production of nitric oxide and inflammatory cytokines and proteins in cultured BV-2 cells. The extract also enhanced GABA-benzodiazepine receptor activity by increasing chloride ion influx in primary cultured neuronal cells. We also examined the anxiolytic effect of the extract in imprinting control region male mice by conducting several behavioral tests. The mice were administered daily oral dose of M. obovata extract (25 mg/kg and 50 mg/kg) for 2 weeks. The extract increased the number of entries and time spent in open arms in the elevated plus maze test and decreased locomotor activity in the spontaneous locomotor activity test, thus implying that the extract ameliorated anxiety levels in mice. Furthermore, we found that the extract inhibited the expression of inflammatory proteins and cytokines and enhanced the expression of GABA-benzodiazepine receptor. These results suggest that the ethanol extract of M. obovata leaves may have an anxiolytic effect through enhancement of the GABAergic system and anti-neuroinflammatory mechanisms. [ABSTRACT FROM AUTHOR]