nitrophenols and Alzheimer-Disease

Two novel reversible enzyme inhibitors involved in monoamine metabolism are described. The novel and reversible inhibitors are the catechol-O-methyl-transferase (COMT) inhibitors, Ro 40-7592 (3,4-dihydroxy-4'-methyl-5-nitrobenzophenone), and the monoamine oxidase type-B (MAO-B) inhibitor, Ro 19-6327 (N-(2-aminoethyl)-5-chloro-2-pyridine carboxamide HC1). These may be of special therapeutic benefit in Parkinson's and Alzheimer's diseases.

Topics: Aging; Alzheimer Disease; Benserazide; Benzophenones; Catechol O-Methyltransferase Inhibitors; Drug Combinations; Enzyme Inhibitors; Humans; Levodopa; Monoamine Oxidase Inhibitors; Nitrophenols; Parkinson Disease; Picolinic Acids; Tolcapone

Alzheimer's disease (AD) is a complex multifactorial syndrome. Metal chelator and Aβ inhibitor are showing promise against AD. In this report, three small hybrid compounds (1, 2, and 3) have been designed and synthesized utilizing salicylaldehyde (SA) based Schiff bases as the chelators and benzothiazole (BT) as the recognition moiety for AD treatment. These conjugates can capture Cu(2+) from Aβ and become dimers upon Cu(2+) coordination and show high efficiency for both Cu(2+) elimination and Aβ assembly inhibition. Besides, the complexes have superoxide dismutase (SOD) activity and significant antioxidant capacity and are capable of decreasing intracellular reactive oxygen species (ROS) and increasing cell viability. All these results indicate that the multifunctional metal complexes which have Aβ specific recognition moiety and metal ion chelating elements show the potential for AD treatment. Therefore, our work will provide new insights into exploration of more potent amyloid inhibitors.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzothiazoles; Blood-Brain Barrier; Cell Survival; Chelating Agents; Chlorophenols; Coordination Complexes; Copper; Dimerization; Nitrophenols; PC12 Cells; Phenols; Plaque, Amyloid; Rats; Reactive Oxygen Species; Stereoisomerism; Structure-Activity Relationship; Superoxide Dismutase

We have previously characterized a number of small molecule organic compounds that prevent the aggregation of the beta-amyloid peptide and its neurotoxicity in hippocampal neuronal cultures. We have now evaluated the effects of such compounds on amyloid precursor protein (APP) accumulation in the CTb immortalized cell line derived from the cerebral cortex of a trisomy 16 mouse, an animal model of Down's syndrome. Compared to a non-trisomic cortical cell line (CNh), CTb cells overexpress APP and exhibit slightly elevated resting intracellular Ca2+ levels ([Ca2+] inverted exclamation mark). Here, we show that the compounds 2,4-dinitrophenol, 3-nitrophenol and 4-anisidine decreased intracellular accumulation of APP in CTb cells. Those compounds were non-toxic to the cells, and slightly increased the basal [Ca2+] inverted exclamation mark. Results indicate that the compounds tested can be leads for the development of drugs to decrease intracellular vesicular accumulation of APP in trisomic cells.

Topics: 2,4-Dinitrophenol; Alzheimer Disease; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Cell Line; Cerebral Cortex; Disease Models, Animal; Down Syndrome; Mice; Nitrophenols

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cells, Cultured; Hippocampus; Humans; Microinjections; Neurons; Neuroprotective Agents; Nitrophenols; Protein Structure, Tertiary; Rats