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Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer's disease mouse model.

Puzzo D, Staniszewski A, Deng SX, Privitera L, Leznik E, Liu S, Zhang H, Feng Y, Palmeri A, Landry DW, Arancio O

Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York 10032, USA.

Memory loss, synaptic dysfunction, and accumulation of amyloid beta-peptides (A beta) are major hallmarks of Alzheimer's disease (AD). Downregulation of the nitric oxide/cGMP/cGMP-dependent protein kinase/c-AMP responsive element-binding protein (CREB) cascade has been linked to the synaptic deficits after A beta elevation. Here, we report that the phosphodiesterase 5 inhibitor (PDE5) sildenafil (Viagra), a molecule that enhances phosphorylation of CREB, a molecule involved in memory, through elevation of cGMP levels, is beneficial against the AD phenotype in a mouse model of amyloid deposition. We demonstrate that the inhibitor produces an immediate and long-lasting amelioration of synaptic function, CREB phosphorylation, and memory. This effect is also associated with a long-lasting reduction of A beta levels. Given that side effects of PDE5 inhibitors are widely known and do not preclude their administration to a senile population, these drugs have potential for the treatment of AD and other diseases associated with elevated A beta levels.

Published 25 June 2009 in J Neurosci, 29(25): 8075-86.
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Articles on Viagra published 23 June 2009:

Endothelial Dysfunction in the Mesenteric Artery and Disturbed Nonadrenergic Noncholinergic Relaxation of the Ileum due to Intestinal Ischemia-Reperfusion Can Be Prevented by Sildenafil.   Pharmacology, 84(2): 61-67.

The aim of the present study was to evaluate the effects of sildenafil on endothelium-dependent mesenteric artery vasorelaxation and nonadrenergic noncholinergic (NANC) ileal responses in an experimental rat intestinal ischemia-reperfusion (I/R) model. The superior mesenteric artery was occluded for 45 min of ischemia and then the clamp was removed for 60 min of reperfusion. Sildenafil (1 mg/kg, i.v.) or saline was administered prior to surgery in the I/R and sham-operated groups. ... [Abstract] [Full-text]

cGMP-hydrolytic activity and its inhibition by sildenafil in normal and failing human and mouse myocardium.   J Pharmacol Exp Ther.

In mouse models of cardiac disease, the PDE5-selective phosphodiesterase inhibitor sildenafil has anti-hypertrophic and cardioprotective effects attributable to the inhibition of cGMP hydrolysis. To investigate the relevance of these findings to humans, we quantified cGMP-hydrolytic activity and its inhibition by sildenafil in cytosolic and microsomal preparations from the left ventricular myocardium of normal and failing human hearts. The vast majority of cGMP-hydrolytic activity was ... [Abstract] [Full-text]

Articles on Viagra published 22 June 2009:

Pulmonary arterial hypertension associated with interferon beta treatment for multiple sclerosis: a case report.   Mult Scler, 15(7): 885-6.

A 23-year-old woman with multiple sclerosis developed respiratory symptoms 3 years after introduction of interferon beta-1b. The diagnosis of pulmonary arterial hypertension (PAH) was established. The patient partially responded to sildenafil and bosetan treatment. This is the first report of PAH, associated with interferon beta therapy. As shown in experimental models, interferon treatment can induce PAH by stimulation of thromboxane cascade and secretion of various inflammatory mediators. [Abstract] [Full-text]

Differential Structural and Functional Changes in Penile and Coronary Arteries from Obese Zucker Rats.   Am J Physiol Heart Circ Physiol.

Erectile dysfunction (ED) frequently coexists with coronary artery disease (CAD) and has been proposed as a potential marker for silent CAD in type 2 diabetes. In the present study we comparatively assessed the structural and functional changes of both penile arteries (PA) and coronary arteries (CA) from a prediabetic animal model. PA and CA from 17-18 weeks old Obese Zucker rats (OZR) and from their control counterpart Lean Zucker rats (LZR) were mounted in microvascular myographs to evaluate ... [Abstract] [Full-text]

Screening of Indian aphrodisiac ayurvedic/herbal healthcare products for adulteration with sildenafil, tadalafil and/or vardenafil using LC/PDA and extracted ion LC-MS/TOF.   J Pharm Biomed Anal.

Ayurvedic/herbal healthcare products are considered safe under the impression that they are derived from natural products. But recently, there have been several reports worldwide on the adulteration of synthetic PDE-5 inhibitors in aphrodisiac herbal formulations. Therefore, the objective of the present study was to explore the presence of synthetic PDE-5 inhibitors (sildenafil, tadalafil and/or vardenafil) in ayurvedic/herbal healthcare products sold in Indian market for aphrodisiac/related ... [Abstract] [Full-text]

High performance liquid chromatography-diode array and electrospray-mass spectrometry analysis of vardenafil, sildenafil, tadalafil, testosterone and local anesthetics in cosmetic creams sold on the Internet web sites.   J Pharm Biomed Anal.

A simple high-performance liquid chromatography (HPLC) method with ultraviolet diode array (UV-DAD) and electrospray ionisation mass spectrometry (ESI-MS) detection has been developed for the determination of vardenafil, sildenafil, tadalafil, testosterone, procaine, lidocaine, prilocaine, and benzocaine in cosmetic creams sold as promising remedies for male erectile dysfunction and female genitals stimulation. The presence of these substances in commercial cosmetic samples is prohibited. ... [Abstract] [Full-text]

Expression of caveolin-1 in penile cavernosal tissue in a denervated animal model after treatment with sildenafil citrate.   J Sex Med, 6(6): 1587-93.

INTRODUCTION: Radical pelvic surgery is a major cause of erectile dysfunction due to iatrogenic cavernous nerve damage. Endothelial nitric oxide synthase, which generates nitric oxide (NO) in the cavernosal tissues, localizes to specialized plasma membrane invaginations known as caveolae. Growing evidence suggests that caveolae are major components of signal trafficking and that stimuli that affect the concentration of the main structural protein of caveolae, caveolin-1 influence NO signaling. ... [Abstract] [Full-text]

Articles on Viagra published 15 June 2009:

Evaluation of a microfluidic based cell culture platform with primary human hepatocytes for the prediction of hepatic clearance in human.   Biochem Pharmacol.

Integral to the discovery of new pharmaceutical entities is the ability to predict in vivo pharmacokinetic parameters from early stage in vitro data generated prior to the onset of clinical testing. Within the pharmaceutical industry, a whole host of assay methods and mathematical models exist to predict the in vivo pharmacokinetic parameters of drug candidates. One of the most important pharmacokinetic properties of new drug candidates predicted from these methods and models is the hepatic ... [Abstract] [Full-text]

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