amyloid-beta-peptides and icariin

Phosphodiesterase-5 (PDE5) inhibitors are predominantly used in the treatment of erectile dysfunction, and have been recently shown to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD) through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signalling by elevating cGMP, which is a secondary messenger involved in processes of neuroplasticity. In the present study, the effects of a PDE5 inhibitor, icarrin (ICA), on learning and memory as well as the pathological features in APP/PS1 transgenic AD mice were investigated. Ten-month-old APP/PS1 transgenic mice overexpressing human amyloid precursor protein (APP695swe) and presenilin 1 (PS1-dE9) were given ICA (30 and 60 mg/kg) or sildenafil (SIL) (2 mg/kg), age-matched wild-type (WT) mice were given ICA (60 mg/kg), and APP/PS1 and WT control groups were given an isovolumic vehicle orally twice a day for four months. Results demonstrated that ICA treatments significantly improved learning and memory of APP/PS1 transgenic mice in Y-maze tasks. The amyloid precursor protein (APP), amyloid-beta (Aβ1-40/42) and PDE5 mRNA and/or protein levels were increased in the hippocampus and cortex of APP/PS1 mice, and ICA treatments decreased these physiopathological changes. Furthermore, ICA-treated mice showed an increased expression of three nitric oxide synthase (NOS) isoforms at both mRNA and protein levels, together with increased NO and cGMP levels in the hippocampus and cortex of mice. These findings demonstrate that ICA improves learning and memory functions in APP/PS1 transgenic mice possibly through the stimulation of NO/cGMP signalling and co-ordinated induction of NOS isoforms.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cerebral Cortex; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Flavonoids; Hippocampus; Humans; Male; Maze Learning; Mice, Transgenic; Nitric Oxide; Nitric Oxide Synthase; Nootropic Agents; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Presenilin-1; Random Allocation

The present study was undertaken to investigate the protective effects of icariin on the learning and memory abilities in Alzheimer's disease model rats and explore its protection mechanisms. Beta-amyloid peptide (Abeta) is a key etiology in Alzheimer's disease and targeting on Abeta production and assembly is a new therapeutic strategy. Six-month (400-600 g) Wistar rats were unilaterally injected with amyloid beta-protein fragment 25-35 (Abeta(25-35)) 10 microg (5 g/l, 2 microl) into the right hippocampus. The day following Abeta injection, icariin 30, 60 or 120 mg/kg was administered by gavage for 14 days. The ability of spatial learning and memory of the animals was tested by the Morris water maze. In place navigation test, icariin significantly decreased the mean escape latency and searching distance. In the space probing test, icariin increased remarkably the searching time and searching distance in the quadrant where the platform was originally located. All tests indicated icariin improved the ability of spatial learning and memory in Alzheimer's disease model rats. Furthermore, immunohistochemistry and real time RT-PCR analysis showed that icariin significantly reduced the contents of Abeta(1-40) and the mRNA levels of beta-secretase in the hippocampus and increased the mRNA level of superoxide dismutase-2, but it had no apparent effects on the immunostain and mRNA level of amyloid protein precursor. These results demonstrate that icariin can improve the learning and memory abilities in Abeta(25-35)-induced Alzheimer's disease rats. The mechanisms appear to be due to the decreased production of insoluble fragments of Abeta through suppression of beta-secretase expression.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Flavonoids; Gene Expression Regulation, Enzymologic; Hippocampus; Learning; Male; Memory Disorders; Peptide Fragments; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Solubility

1. The present study examined the protective effects of icariin against the learning and memory deficits in aluminium-treated rats and its potential mechanisms of action. 2. Qualified rats were treated with 1600 p.p.m. AlCl(3) in drinking water for 8 months and the ability of spatial learning and memory was tested by the Morris water maze. In the place navigation test, aluminium administration significantly increased the mean escape latency and searching distance. In space probing test, aluminium markedly decreased the searching time and searching distance in the quadrant where the platform was originally located. All tests indicated deficits in rat spatial learning and memory induced by aluminium. Icariin treatment (60 and 120 mg/kg, by gavage for 3 months) dose-dependently protected against the development of aluminium-induced spatial learning and memory deficits. 3. To examine the mechanisms responsible for the protection afforded by icariin, the superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in the hippocampus were assayed biochemically and the level of Abeta(1-40) in the hippocampus was determined immunohistochemically. Icariin treatment significantly increased SOD activity and decreased MDA and Abeta(1-40) content in the hippocampus of aluminium-intoxicated rats. 4. In conclusion, the present study demonstrates that icariin is effective in improving the spatial learning and memory of aluminium-intoxicated rats. The mechanisms responsible appear to be due, at least in part, to an increased anti-oxidant capacity and decreased lipid peroxidation and Abeta(1-40) levels in the rat hippocampus.

Topics: Aluminum Chloride; Aluminum Compounds; Amyloid beta-Peptides; Animals; Antioxidants; Behavior, Animal; Chlorides; Dose-Response Relationship, Drug; Flavonoids; Hippocampus; Learning; Lipid Peroxidation; Male; Malondialdehyde; Memory; Peptide Fragments; Rats; Rats, Wistar; Reaction Time; Spatial Behavior; Superoxide Dismutase; Time Factors