Cyclic nucleotide phosphodiesterases (PDEs) and endothelial function in ischaemic stroke. A review.
3',5'-Cyclic-AMP Phosphodiesterases
/ antagonists & inhibitors
Animals
Brain Ischemia
/ drug therapy
Cyclic AMP
/ metabolism
Cyclic GMP
/ metabolism
Endothelial Cells
/ drug effects
Humans
Neovascularization, Physiologic
/ drug effects
Neuroprotection
/ drug effects
Phosphodiesterase Inhibitors
/ pharmacology
Recovery of Function
/ drug effects
Stroke
/ drug therapy
Cyclic nucleotide
Endothelial function
PDE
Stroke
cAMP
cGMP
Journal
Cellular signalling
ISSN: 1873-3913
Titre abrégé: Cell Signal
Pays: England
ID NLM: 8904683
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
13
08
2018
revised:
21
05
2019
accepted:
22
05
2019
pubmed:
28
5
2019
medline:
22
8
2020
entrez:
28
5
2019
Statut:
ppublish
Résumé
Endothelial dysfunction is a hallmark of cerebrovascular disease, including ischemic stroke. Modulating endothelial signalling by cyclic nucleotides, cAMP and cGMP, is a potential therapeutic target in stroke. Inhibitors of the cyclic nucleotide degrading phosphodiesterase (PDE) enzymes may restore cerebral endothelial function. Current knowledge on PDE distribution and function in cerebral endothelial cells is sparse. This review explores data on PDE distribution and effects of PDEi in cerebral endothelial cells and identifies which PDEs are potential treatment targets in stroke. We performed a systematic search of electronic databases (Medline and Embase). Our search terms were cerebral ischaemia, cerebral endothelial cells, cyclic nucleotide, phosphodiesterase and phosphodiesterase inhibitors. We found 23 publications which described effects of selective inhibitors of only three PDE families on endothelial function in ischemic stroke. PDE3 inhibitors (PDE3i) (11 publications) and PDE4 inhibitors (PDE4i) (3 publications) showed anti-inflammatory, anti-apoptotic or pro-angiogenic effects. PDE3i also reduced leucocyte infiltration and MMP-9 expression. Both PDE3i and PDE4i increased expression of tight junction proteins and protected the blood-brain barrier. PDE5 inhibitors (PDE5i) (6 publications) reduced inflammation and apoptosis. In preclinical models, PDE5i enhanced cGMP/NO signalling associated with microvascular angiogenesis, increased cerebral blood flow and improved functional recovery. Non-specific PDEi (3 publications) had mainly anti-inflammatory effects. This review demonstrates that non-selective and selective PDEi of PDE3, PDE4 and PDE5 modulated endothelial function in cerebral ischemic stroke by regulating processes involved in vascular repair and neuroprotection and thus reduced cell death and inflammation. Of note, they promoted angiogenesis, microcirculation and improved functional recovery; all are important in stroke prevention and recovery, and effects should be further evaluated in humans.
Sections du résumé
BACKGROUND
Endothelial dysfunction is a hallmark of cerebrovascular disease, including ischemic stroke. Modulating endothelial signalling by cyclic nucleotides, cAMP and cGMP, is a potential therapeutic target in stroke. Inhibitors of the cyclic nucleotide degrading phosphodiesterase (PDE) enzymes may restore cerebral endothelial function. Current knowledge on PDE distribution and function in cerebral endothelial cells is sparse. This review explores data on PDE distribution and effects of PDEi in cerebral endothelial cells and identifies which PDEs are potential treatment targets in stroke.
METHOD
We performed a systematic search of electronic databases (Medline and Embase). Our search terms were cerebral ischaemia, cerebral endothelial cells, cyclic nucleotide, phosphodiesterase and phosphodiesterase inhibitors.
RESULTS
We found 23 publications which described effects of selective inhibitors of only three PDE families on endothelial function in ischemic stroke. PDE3 inhibitors (PDE3i) (11 publications) and PDE4 inhibitors (PDE4i) (3 publications) showed anti-inflammatory, anti-apoptotic or pro-angiogenic effects. PDE3i also reduced leucocyte infiltration and MMP-9 expression. Both PDE3i and PDE4i increased expression of tight junction proteins and protected the blood-brain barrier. PDE5 inhibitors (PDE5i) (6 publications) reduced inflammation and apoptosis. In preclinical models, PDE5i enhanced cGMP/NO signalling associated with microvascular angiogenesis, increased cerebral blood flow and improved functional recovery. Non-specific PDEi (3 publications) had mainly anti-inflammatory effects.
CONCLUSION
This review demonstrates that non-selective and selective PDEi of PDE3, PDE4 and PDE5 modulated endothelial function in cerebral ischemic stroke by regulating processes involved in vascular repair and neuroprotection and thus reduced cell death and inflammation. Of note, they promoted angiogenesis, microcirculation and improved functional recovery; all are important in stroke prevention and recovery, and effects should be further evaluated in humans.
Identifiants
pubmed: 31132399
pii: S0898-6568(19)30116-0
doi: 10.1016/j.cellsig.2019.05.011
pii:
doi:
Substances chimiques
Phosphodiesterase Inhibitors
0
Cyclic AMP
E0399OZS9N
3',5'-Cyclic-AMP Phosphodiesterases
EC 3.1.4.17
Cyclic GMP
H2D2X058MU
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
108-119Subventions
Organisme : Alzheimer's Society
ID : 151
Pays : United Kingdom
Organisme : National Centre for the Replacement, Refinement and Reduction of Animals in Research
ID : G0800701/1
Pays : United Kingdom
Informations de copyright
Copyright © 2019. Published by Elsevier Inc.