Purpose: Phosphodiesterase 5A (PDE5A) inhibitors improve functional recovery in experimental models of stroke in rats when treatment is delayed and without effect on infarct volume. PDE5A is expressed to only a very limited extent in forebrain tissues, raising the possibility that the locus of effect for the inhibitors is outside the brain. To start to address this question, we determined whether PDE5A inhibitors must have the ability to cross the blood brain barrier to improve recovery.
Method: After permanent middle cerebral artery occlusion in rats, PF-5 and UK-489,791, PDE5A inhibitors that do or do not pass the blood brain barrier, were administered starting 24 h after occlusion and continued for 1 week. Motor function was assessed at intervals to 28 days using body swing and limb placement measures.
Results: Both PF-5 and UK-489,791 produced improvement in motor scores over 28 days that were significantly greater than in vehicle treated animals. There was no difference in efficacy between the two PDE5A inhibitors.
Conclusions: Brain penetrability appears not to be critical to the ability of a PDE5A inhibitor to improve functional recovery after experimental stroke in rats. This finding is discussed with regard to the cellular target(s) for PDE5A inhibitors mediating this effect.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.3233/RNN-2012-110187 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Exploring the Therapeutic Potential of 8-Prenyldaidzein: A Comprehensive Study of its Multi-Target Efficacy in Alzheimer's Disease.
Curr Alzheimer Res
December 2024
Silicon Script Sciences Private Limited, Bharatpur, Gorahi-22400, Dang, Nepal.
Background: Alzheimer's disease (AD) is marked by cognitive decline, amyloid plaques, neurofibrillary tangles, and cholinergic loss. Due to the limited success of amyloid-targeted therapies, attention has shifted to new non-amyloid targets like phosphodiesterases (PDE). This study investigates the potential of Flemingia vestita (FV) phytomolecules and derivatives, particularly 8-Prenyldaidzein, in AD treatment.
View Article and Find Full Text PDFExploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia.
Transl Psychiatry
December 2024
Department of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Basal ganglia is proposed to mediate symptoms underlying bipolar disorder (BD). To understand the cell type-specific gene expression and network changes of BD basal ganglia, we performed single-nucleus RNA sequencing of 30,752 nuclei from caudate, putamen, globus pallidus, and substantia nigra of control human postmortem brain and 24,672 nuclei from BD brain. Differential expression analysis revealed major difference lying in caudate, with BD medium spiny neurons (MSNs) expressing significantly higher PDE5A, a cGMP-specific phosphodiesterase.
View Article and Find Full Text PDFDiscovery and Optimization of Dihydroquinolin-2(1)-ones as Novel Highly Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension.
J Med Chem
December 2024
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, P. R. China.
Article Synopsis
- A newly optimized compound showed potent inhibition of PDE5A with an impressive selectivity over other PDE enzymes, indicating strong potential as a treatment option.
- In animal studies, the compound outperformed sildenafil in reducing mean pulmonary artery pressure and right ventricle hypertrophy, suggesting it could be a promising new therapy for PAH.
Downregulation of miR-214 promotes dilated Cardiomyopathy Progression through PDE5A-Mediated cGMP regulation.
Sci Rep
November 2024
Second Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, 450002, China.
Dilated cardiomyopathy (DCM) is a myocardial disorder resulting in a substantial decline in cardiac function and potentially leading to heart failure. This research combines bioinformatics analysis with empirical validation to explore the roles and mechanisms of miR-214 in DCM. Using the DEseq2 R package, a total of 125 differentially expressed circulating miRNAs (DE c-miRNAs) and 784 DE genes (DEGs) were identified.
View Article and Find Full Text PDFPhosphodiesterase 5 and its inhibitors with ischemic heart disease: a Mendelian randomization analysis and a real-world study.
Eur Heart J Cardiovasc Pharmacother
October 2024
Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China.
Background: Accumulating studies reported that several phosphodiesterases (PDEs) inhibitors might have cardiovascular benefits.
Objectives: This study aimed to explore the relationship between genetically-predicted PDEs and ischemia heart disease via drug target Mendelian randomization (MR) approach, and then examine the effect of inhibitors of identified target on the outcomes by using real-world data.
Methods: In the two-sample MR study, the expression of genes encoding PDEs was used to proxy the level of PDEs and available expression quantitative trait loci (eQTLs) for each target gene were identified as the genetic instruments.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!