Thiacremonone Potentiates Anti-Oxidant Effects to Improve Memory Dysfunction in an APP/PS1 Transgenic Mice Model.

Alzheimer's disease (AD) is pathologically characterized by excessive accumulation of amyloid-beta (Aß) peptide. Evidence suggests that amyloid accumulation can be caused by oxidative stress and inflammatory responses. In this study, we examined neuroprotective effects of thiacremonone, an anti-oxidant and anti-inflammatory compound isolated from garlic. Treatment of thiacremonone significantly attenuated cognitive impairments in amyloid precursor protein (APP)/presenilin 1 (PS1) double-mutant transgenic mice. In addition, activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and extracellular signal-regulated kinase (ERK) pathways in the brain was potently inhibited by thiacremonone. We also observed that thiacremonone significantly inhibited activation of NF-κB and ERK pathways induced by H2O2 and Aß1-42 in embryonic neuronal cells. Furthermore, thiacremonone augmented peroxiredoxin 6 (PRDX6) expression in vivo and in vitro associated with reduced oxidative stress of macromolecules such as protein and lipids. This study indicates that thiacremonone might exert memory improvement via stimulating anti-oxidant system. These multiple properties could attenuate Aß accumulation and oxidative stress in Alzheimer's brains. Thus, these results suggest that thiacremonone might be useful to intervene development or progression of neurodegeneration in AD.

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.

BACKGROUND: Neuroinflammation 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. METHODS: We 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). RESULTS: Oral 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-1ß 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 Aß1-42 generation, ß- 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. CONCLUSION: These 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.