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.
Highlights
Neuroinflammation is important in the pathogenesis and progression of Alzheimer disease (AD)
To define the effect of 4-O-methylhonokiol against amyloid beta-peptide (Ab) accumulation via the prevention of neuroinflammation, we investigated the effect of 4-O-methylhonokiol on LPS-induced memory impairments and amyloidogenesis via anti-inflammatory reactions in LPS-injected mice brain, in cultured astrocytes and in microglial BV-2 cells
4-O-methylhonokiol inhibits LPS-induced inducible nitric oxide synthase (iNOS) and COX-2 expression To investigate the inhibitory effect of 4-O-methylhonokiol on memory impairment via inhibition of neuroinflammation, the expression of iNOS was determined by immunohistochemical analysis
Summary
Neuroinflammation is important in the pathogenesis and progression of Alzheimer disease (AD). We demonstrated that lipopolysaccharide (LPS)-induced neuroinflammation caused memory impairments. 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. AD is pathologically characterized by the presence of senile plaques and neurofibrillary tangles in the brain. Neuropathological studies in the human brains have demonstrated that the activation of glial cells excessively releases proinflammatory mediators and cytokines, which in turn trigger a neurodegenerative cascades via neuroinflammation [4,5,6,7,8]. Numerous investigators have reported that neuroinflammatory processes contribute to the pathogenesis and progression of AD. Various cytokines, chemokines, oxygen free radicals, and reactive nitrogen species [9], as well as prostaglandin E2 (PGE2) [10], are important signaling molecules and components of neuroinflammatory responses [11]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have