fumarates and Alzheimer-Disease

The neurotoxicity of amyloid-β (Aβ) and its deposition in neurons plays a critical role in the occurrence and development of Alzheimer's disease (AD). Several preclinical experiments have found that the renin inhibitor aliskiren has a wide range of physiological effects, including hindering the progression of atherosclerosis and anti-inflammatory. This study is aimed to explore the effect of aliskiren on neuronal toxic damage and the underlying mechanism. This study established an

Topics: Alzheimer Disease; Amides; Amyloid beta-Peptides; Apoptosis; Cell Line, Tumor; Fumarates; Humans; Molecular Docking Simulation; Neurons; Peptide Fragments; Renin

A dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT), RS-1259 (4-[1S)-methylamino-3-(4-nitrophenoxy)]propylphenyl N,N-dimethylcarbamate (fumaric acid)(1/2)salt), was newly synthesized. RS-1259 simultaneously inhibited AChE and SERT in the brain following an oral administration in mice and rats. Actual simultaneous elevation of extracellular levels of 5-HT and ACh in the rat hippocampus was confirmed by microdialysis. The compound was as effective as SERT inhibitors such as fluoxetine and fluvoxamine in a 5-hydroxytryptophan-enhancing test in mice. Spatial memory deficits in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake episodes in the daytime electroencephalogram of rats. Although RS-1259 was weaker than donepezil in enhancing central cholinergic transmission, as observed by ACh elevation in the hippocampus and memory enhancement in aged rats, the efficacy of RS-1259 on the consciousness level, which reflects the whole activity in the brain, was almost the same as that of donepezil. These results suggest that both cholinergic and serotonergic systems are involved in maintaining brain arousal and that a dual inhibitor of AChE and SERT may be useful for the treatment of cognitive disorders associated with reduced brain activity such as in Alzheimer's disease.

Topics: Acetylcholinesterase; Administration, Oral; Aging; Alzheimer Disease; Animals; Carbamates; Carrier Proteins; Cholinesterase Inhibitors; Fumarates; Hippocampus; Male; Maze Learning; Membrane Glycoproteins; Membrane Transport Proteins; Memory; Mice; Microdialysis; Motor Activity; Nerve Tissue Proteins; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Rats, Wistar; Serotonin Plasma Membrane Transport Proteins

Impaired oxidative and energy metabolism are important features in Alzheimer's disease. These metabolic abnormalities may induce functional disturbances and are associated with significant cognitive impairment.. To determine whether mitochondrial function is altered by Alzheimer's disease, a quantitative analysis of substrates that enter the tricarboxylic acid cycle was carried out in cerebrospinal fluid (CSF) from Alzheimer patients.. Organic acid levels related to carbohydrate oxidation were measured in CSF from patients affected by dementia of Alzheimer type (n = 17) and from nondemented elderly controls (n = 17) using a gas chromatography/mass spectrometry system. CSF glucose and glutamine concentrations were determined by a quantitative enzymatic method and by ion exchange chromatography, respectively.. Compared to age-matched controls, patients had a higher CSF level of lactate (p = 0.002) and a lower mean level of succinate (p = 0.002), fumarate (p = 0.003) and glutamine (p = 0.0005). The CSF glucose level was not modified.. Our results suggest an impairment of mitochondrial oxidative metabolism in brain cells of patients with Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cerebrospinal Fluid; Citric Acid Cycle; Female; Fumarates; Glutamine; Humans; Lactic Acid; Male; Mitochondria; Reference Values; Substrate Specificity; Succinic Acid