thiacremonone and Disease-Models--Animal

Alzheimer's disease (AD) is pathologically characterized by excessive accumulation of amyloid-beta (Aβ) 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 Aβ1-42 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 Aβ 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.

Topics: Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Antioxidants; Disease Models, Animal; DNA; Enzyme Activation; Glutathione; Lipid Peroxidation; Memory Disorders; Mice, Transgenic; Mitogen-Activated Protein Kinases; Mutation; Neurons; NF-kappa B; Oxidative Stress; Peroxiredoxin VI; Presenilin-1; Protein Binding; Protein Carbonylation; Rats, Sprague-Dawley; Thiophenes

Neuroinflammation is implicated for dopaminergic neurodegeneration. Sulfur compounds extracted from garlic have been shown to have anti-inflammatory properties. Previously, we have investigated that thiacremonone, a sulfur compound isolated from garlic has anti-inflammatory effects on several inflammatory disease models. To investigate the protective effect of thiacremonone against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment and dopaminergic neurodegeneration, 8 week old ICR mice were given thiacremonone (10 mg/kg) in drinking water for 1 month and received intraperitoneal injection of MPTP (15 mg/kg, four times with 2 h interval) during the last 7 days of treatment. Our data showed that thiacremonone decreased MPTP-induced behavioral impairments (Rotarod test, Pole test, and Gait test), dopamine depletion and microglia and astrocytes activations as well as neuroinflammation. Higher activation of p38 was found in the substantia nigra and striatum after MPTP injection, but p38 activation was reduced in thiacremonone treated group. In an in vitro study, thiacremonone (1, 2, and 5 μg/ml) effectively decreased MPP+ (0.5 mM)-induced glial activation, inflammatory mediators generation and dopaminergic neurodegeneration in cultured astrocytes and microglial BV-2 cells. Moreover, treatment of p38 MAPK inhibitor SB203580 (10 μM) further inhibited thiacremonone induced reduction of neurodegeneration and neuroinflammation. These results indicated that the anti-inflammatory compound, thiacremonone, inhibited neuroinflammation and dopaminergic neurodegeneration through inhibition of p38 activation.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Anti-Inflammatory Agents; Astrocytes; Behavioral Symptoms; Cell Line; Corpus Striatum; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Humans; Imidazoles; Inflammation; Male; Mice; Mice, Inbred ICR; Microglia; Neuroprotective Agents; p38 Mitogen-Activated Protein Kinases; Pyridines; Rats; Rats, Sprague-Dawley; Substantia Nigra; Thiophenes

Thiacremonone (2, 4-dihydroxy-2, 5-dimethyl-thiophene-3-one) is an antioxidant substance as a novel sulfur compound generated from High-Temperature-High-Pressure-treated garlic. Peroxiredoxin 6 (PRDX6) is a member of peroxidases, and has glutathione peroxidase and calcium-independent phospholipase A2 (iPLA2) activities. Several studies have demonstrated that PRDX6 stimulates lung cancer cell growth via an increase of glutathione peroxidase activity. A docking model study and pull down assay showed that thiacremonone completely fits on the active site (cys-47) of glutathione peroxidase of PRDX6 and interacts with PRDX6. Thus, we investigated whether thiacremonone inhibits cell growth by blocking glutathione peroxidase of PRDX6 in the human lung cancer cells, A549 and NCI-H460. Thiacremonone (0-50 μg/ml) inhibited lung cancer cell growth in a concentration dependent manner through induction of apoptotic cell death accompanied by induction of cleaved caspase-3, -8, -9, Bax, p21 and p53, but decrease of xIAP, cIAP and Bcl2 expression. Thiacremonone further inhibited glutathione peroxidase activity in lung cancer cells. However, the cell growth inhibitory effect of thiacremonone was not observed in the lung cancer cells transfected with mutant PRDX6 (C47S) and in the presence of dithiothreitol and glutathione. In an allograft in vivo model, thiacremonone (30 mg/kg) also inhibited tumor growth accompanied with the reduction of PRDX6 expression and glutathione peroxidase activity, but increased expression of cleaved caspase-3, -8, -9, Bax, p21 and p53. These data indicate that thiacremonone inhibits tumor growth via inhibition of glutathione peroxidase activity of PRDX6 through interaction. These data suggest that thiacremonone may have potentially beneficial effects in lung cancer.

Topics: Allografts; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Garlic; Gene Expression; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Mice; Models, Molecular; Molecular Conformation; Mutation; Neoplasms; Peroxiredoxin VI; Plant Extracts; Protein Binding; Thiophenes; Tumor Burden

Neuroinflammation is implicated for amyloidogenesis. Sulfur compounds extracted from garlic have been shown to have anti-inflammatory properties. Previously, we have investigated that thiacremonone, a sulfur compound isolated from garlic has anti-inflammatory effects. To investigate thiacremonone's potential effect on anti-neuroinflammation and anti-amyloidogenesis, 4 week old ICR mice were given different doses of thiacremonone (1, 3, and 10 mg/kg) in drinking water for 1 month and received intraperitoneal injection of lipopolysaccharide (LPS) (250 μg/kg/day) at last 7 days of treatment. Our data show thiacremonone decreased LPS-induced memory impairment, glial activation, pro-inflammatory mediators' expression, and amyloidogenesis. In an in vitro study, we obtained similar results, with thiacremonone (1, 2, and 5 μg/ml) effectively decreased LPS (1 μg/ml)-induced glial activation and inflammatory mediators generation which are implicated in amyloidogenesis. Our data also demonstrated that thiacremonone inhibited LPS-induced amyloidogenesis in cultured astrocytes and microglial BV-2 cells. NF-κB, a critical transcriptional factor regulating not only inflammation but also amyloid-β generation, was inhibited by thiacremonone via blocking of phosphorylation of IκBα in mice brain as well as cultured astrocytes and microglial BV-2 cells. These results indicated that the anti-inflammatory compound, thiacremonone, inhibited neuroinflammation and amyloidogenesis through inhibition of NF-κB activity, and thus could be applied for intervention of inflammation-related neurodegenerative disease including Alzheimer's disease.

Topics: Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Animals, Newborn; Anti-Inflammatory Agents; Astrocytes; Avoidance Learning; Brain; Cell Survival; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Electrophoretic Mobility Shift Assay; Exploratory Behavior; Gene Expression Regulation; Inflammation; Lipopolysaccharides; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Nitric Oxide; Peptide Fragments; Reactive Oxygen Species; Thiophenes