ABSTRACT
OBJECTIVE: The aim of the study was to investigate the effects of nicotine on learning and memory deficits induced by intracerebroventricular infusion of amyloid-ß peptide (Aß) in rats. MATERIALS AND METHODS: Neuronal dysfunction in rats was induced by an infusion of Aß(1-42) (20 µg/body, over 3 days) into right ventricle. Nicotine was administered intraperitoneally to the rats at 0.2 mg/kg, once a day for 9 weeks beginning 3 weeks after the Aß infusion. Learning and memory functions were examined by behavioral tests including Morris water maze task performed on days 87-90. As biochemical analyses, choline acetyltransferase (ChAT) activity and hemicholinium-3 (HC-3) binding were measured in brain tissues after the behavioral examination. RESULTS: The Aß infusion induced significant learning and memory deficits in rats, judging from the behavioral tests. Treatment of the rats with nicotine significantly improved the Aß-induced learning and memory deficits in water maze task. The Aß infusion also decreased significantly not only the level of ChAT activity in posterior cortex and striatum, but the HC-3 binding in anterior cortex, posterior cortex, and hippocampus. The nicotine treatment did not reverse the level of ChAT but significantly inhibited the decrease in HC-3 binding, indicating improvement of cholinergic function without affecting the number of ACh terminals. CONCLUSIONS: Nicotine ameliorated learning and memory deficits in the Aß(1-42)-induced animal model, which is mediated, at least in part, by enhancement of cholinergic neurotransmission. nAChR ligands including nicotine is thought to be useful as a treatment for Alzheimer's disease.
Subject(s)
Amyloid beta-Peptides/metabolism , Neurons/drug effects , Nicotine/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Choline O-Acetyltransferase/metabolism , Disease Models, Animal , Infusions, Intraventricular , Male , Maze Learning/drug effects , Memory/drug effects , Memory Disorders/chemically induced , Nicotinic Agonists/pharmacology , Rats , Rats, Inbred F344ABSTRACT
Natural products from plants are expected to play significant roles in creating new, safe and improved chemopreventive and therapeutic antitumor agents. Selectivity is also an important issue in cancer prevention and therapy. The present study was designed to extend our previous study on the c-Ha-ras and c-myc-induced tumor cell-selective antiproliferative effects of a licorice component, glycyrrhetinic acid (GA). An in silico ligand-receptor docking simulation revealed that GA acts as an 11ß-hydroxysteroid dehydrogenase type 2 inhibitor. GA disrupted the redox balance in tumor cells through upregulation of reactive oxygen species and downregulation of glutathione (GSH). The GA-induced GSH reduction and cytotoxicity were enhanced by an inhibitor of GSH, l-buthionine-[S,R]-sulfoximine. N-acetyl-l-cysteine, an antioxidant and precursor of GSH, restored the GA-induced GSH reduction and cytotoxicity in tumor cells. Taken together, these data highlighting the downregulation of GSH by GA and the efficacy of GSH in ameliorating GA-mediated cytotoxicity support the notion that GSH is involved in the selective toxicity of GA toward tumor cells.
Subject(s)
Cell Proliferation/drug effects , Down-Regulation/drug effects , Glutathione/metabolism , Glycyrrhetinic Acid/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 2/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Acetylcysteine/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Buthionine Sulfoximine/pharmacology , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Free Radical Scavengers/pharmacology , Glycyrrhetinic Acid/chemistry , Glycyrrhetinic Acid/metabolism , Inhibitory Concentration 50 , Models, Molecular , Molecular Conformation , Neoplasms/metabolism , Neoplasms/pathology , Oxidation-Reduction/drug effects , Protein Binding , Protein Conformation , Reactive Oxygen Species/metabolism , Up-Regulation/drug effectsABSTRACT
The behavioral, neurochemical and histological changes of rats subjected to 3 days treatment with intracerebroventricular infusion of beta-amyloid peptides(Abeta)(1-42) were investigated 20 days and 80 days after the surgery. Abeta(1-42) produced a dose-dependent and a time-dependent impairment in the spontaneous alternation performance in the Y-maze (spatial working memory), place navigation task in a water maze (spatial reference memory) and passive avoidance retention (non-spatial long-term memory) at doses of 10 and 20 microg/rat. The learning impairments were more severe at 80 days than 20 days after infusion of Abeta(1-42). At 25 days after the infusion, a significant decrease in hemicholinium-3 (HC-3) binding was observed only in the hippocampus, although choline acetyltransferase (ChAT) activity was unchanged in the brain regions tested as compared with the vehicle (Abeta(40-1)) treatment. In contrast, the reduction in ChAT activity 85 days after Abeta(1-42) infusion was significant in hippocampus and striatum. HC-3 binding was also significantly decreased in the posterior cortex, hippocampus and striatum. In the histological analysis, brain atrophy was observed inasmuch as ventricular enlargement and neuronal damage in the CA1 area of the hippocampus were seen 85 days after Abeta(1-42) infusion. These results suggest that the rats subjected to intracerebroventricular infusion of Abeta(1-42) suffered from progressive brain dysfunction, and could be useful as an animal model for evaluating the developmental processes at the early and/or middle stage of Alzheimer's-type dementia.
Subject(s)
Alzheimer Disease/enzymology , Amyloid beta-Peptides/pharmacology , Hippocampus/drug effects , Memory Disorders/chemically induced , Nerve Degeneration/chemically induced , Neurons/drug effects , Peptide Fragments/pharmacology , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Animals , Avoidance Learning/drug effects , Avoidance Learning/physiology , Choline O-Acetyltransferase/metabolism , Cholinergic Agents/pharmacokinetics , Dose-Response Relationship, Drug , Hemicholinium 3/pharmacokinetics , Hippocampus/enzymology , Hippocampus/pathology , Injections, Intraventricular , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory Disorders/enzymology , Memory Disorders/pathology , Memory, Short-Term/drug effects , Memory, Short-Term/physiology , Neocortex/drug effects , Neocortex/enzymology , Neocortex/pathology , Neostriatum/drug effects , Neostriatum/metabolism , Neostriatum/pathology , Nerve Degeneration/enzymology , Nerve Degeneration/pathology , Neurons/enzymology , Neurons/pathology , Psychomotor Performance/drug effects , Psychomotor Performance/physiology , Rats , Rats, Inbred F344 , Space Perception/physiologyABSTRACT
Orixajaponica (Rutaceae) is a shrub widely distributed in Japan, and has been found to contain various quinoline alkaloids. We investigated the alkaloidal constituents of O. japonica, and four quinoline alkaloids were isolated and characterized. Three of these alkaloids are new natural products.
Subject(s)
Alkaloids/chemistry , Dioxoles/chemistry , Plants/chemistry , Quinolines/chemistry , Quinolones/chemistry , Alkaloids/classification , Alkaloids/isolation & purification , Dioxoles/isolation & purification , Insecticides , Molecular Structure , Plant Extracts , Plant Leaves/chemistry , Plant Stems/chemistry , Quinolines/classification , Quinolines/isolation & purification , Quinolones/isolation & purificationABSTRACT
Two quinoline alkaloids, japonine (1) and eduline (2) were isolated from the methanol extract of the leaves of Orixa japonica as relaxants against rat small intestine muscle. The activity of these alkaloids was comparable to that of the typical muscle relaxant papaverine (4). This is also the first report of the isolation of eduline (2) from O. japonica.
Subject(s)
Alkaloids/pharmacology , Jejunum/drug effects , Quinolines/pharmacology , Rosales/chemistry , Alkaloids/isolation & purification , Animals , Jejunum/physiology , Muscle Relaxation/drug effects , PC12 Cells , Quinolines/isolation & purification , Rats , Spectrum AnalysisABSTRACT
Adxanthromycins A and B are new inhibitors of ICAM-1/LFA-1 mediated cell adhesion molecule isolated from the fermentation broth of Streptomyces sp. NA-148. The molecular formula of adxanthromycins A and B were determined as C42H40O17 and C48H50O22, respectively by FAB-MS and NMR spectral analyses, and the structures of both compounds were elucidated to be a dimeric anthrone peroxide skeleton containing alpha-D-galactose by various NMR spectral analyses and chemical degradation.
Subject(s)
Anti-Bacterial Agents/chemistry , Streptomyces/chemistry , Anti-Bacterial Agents/pharmacology , Drug Evaluation, Preclinical , Fermentation , Intercellular Adhesion Molecule-1/drug effects , Lymphocyte Function-Associated Antigen-1/drug effects , Magnetic Resonance Spectroscopy , Molecular Structure , Peroxides/chemistry , Peroxides/pharmacology , Spectrometry, Mass, Fast Atom Bombardment , Streptomyces/metabolism , Xanthenes/chemistry , Xanthenes/pharmacologyABSTRACT
Four steroidal alkaloids, epipachysamines B (1) and E (2), pachystermine A (3) and pachysamine E (4), were isolated as cytotoxic principles from the MeOH extract of the stems of Pachysandra terminalis SIEB. et ZUCC. (Buxaceae). These alkaloids showed cytotoxic activity against P388 and P388/ADR leukemia cells in vitro. Three of the alkaloids (1-3) were previously isolated from this plant material, and this is the first report of their cytotoxic activity. Pachysamine E (4) is a new alkaloid.
