Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models

Abstract

BackgroundNeuroinflammation is important in the pathogenesis and progression of Alzheimer disease (AD). Previously, we demonstrated that lipopolysaccharide (LPS)-induced neuroinflammation caused memory impairments. In the present study, we investigated the possible preventive effects of 4-O-methylhonokiol, a constituent of Magnolia officinalis, on memory deficiency caused by LPS, along with the underlying mechanisms.MethodsWe investigated whether 4-O-methylhonokiol (0.5 and 1 mg/kg in 0.05% ethanol) prevents memory dysfunction and amyloidogenesis on AD model mice by intraperitoneal LPS (250 μg/kg daily 7 times) injection. In addition, LPS-treated cultured astrocytes and microglial BV-2 cells were investigated for anti-neuroinflammatory and anti-amyloidogenic effect of 4-O-methylhonkiol (0.5, 1 and 2 μM).ResultsOral administration of 4-O-methylhonokiol ameliorated LPS-induced memory impairment in a dose-dependent manner. In addition, 4-O-methylhonokiol prevented the LPS-induced expression of inflammatory proteins; inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as activation of astrocytes (expression of glial fibrillary acidic protein; GFAP) in the brain. In in vitro study, we also found that 4-O-methylhonokiol suppressed the expression of iNOS and COX-2 as well as the production of reactive oxygen species, nitric oxide, prostaglandin E2, tumor necrosis factor-α, and interleukin-1β in the LPS-stimulated cultured astrocytes. 4-O-methylhonokiol also inhibited transcriptional and DNA binding activity of NF-κB via inhibition of IκB degradation as well as p50 and p65 translocation into nucleus of the brain and cultured astrocytes. Consistent with the inhibitory effect on neuroinflammation, 4-O-methylhonokiol inhibited LPS-induced Aβ1-42 generation, β- and γ-secretase activities, and expression of amyloid precursor protein (APP), BACE1 and C99 as well as activation of astrocytes and neuronal cell death in the brain, in cultured astrocytes and in microglial BV-2 cells.ConclusionThese results suggest that 4-O-methylhonokiol inhibits LPS-induced amyloidogenesis via anti-inflammatory mechanisms. Thus, 4-O-methylhonokiol can be a useful agent against neuroinflammation-associated development or the progression of AD.

A role for human brain pericytes in neuroinflammation

“…Interestingly, we did not see this with IFNγ treatment, which remains controversial in other studies [65,66]. Additionally, inhibition or blockade of the NFκB pathway has been shown to protect from LPS-induced neurotoxicity [67,68]. This uncovers potential targets for anti-inflammatory drug development, which is supported by in vitro evidence in human brain cells from our group and others [37].…”

Epigallocatechin-3-gallate prevents systemic inflammation-induced memory deficiency and amyloidogenesis via its anti-neuroinflammatory properties

“…In previous studies, we found that microglia were activated in brain of systemic inflammation inducing AD [79,80] and that several anti-inflammatory compounds inhibited the activation of microglia as well as prevented the development of AD inhibited the activation of microglia as well as prevented the development of AD [80,81]. The inhibitory effect of EGCG on microglial activation is also well known to be effective for other neuroinflammatory diseases such as ischemic stroke, Parkinson's disease (PD) and amyotrophic lateral sclerosis [82][83][84].…”

Upregulation of TREM2 Ameliorates Neuroinflammatory Responses and Improves Cognitive Deficits Triggered by Surgical Trauma in Appswe/PS1dE9 Mice

“…Synaptophysin plays an important role in the regulation of synaptic plasticity. Mounting evidence indicates that microglia-generated proinflammatory cytokines (e.g., IL-6 and TNF-α) are responsible for neuronal and synaptic losses, whereas anti-inflammatory therapies can effectively attenuate neuronal and synaptic damage and improve cognitive deficits in animal models of neuroinflammation and aging [45, 46]. TREM2 silencing led to the exacerbation of neuronal and synaptic losses in the cerebral cortex and hippocampus of P301S mice [47].…”