Saiqa Yasmeen1, Bilal Hussain Akram1, Atticus H Hainsworth2, Christina Kruuse3. 1. Stroke Unit and Neurovascular Research Unit, Department of Neurology, Herlev Gentofte Hospital, Herlev Ringvej 75, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. 2. Clinical Neuroscience, Molecular & Clinical Sciences Research Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK. 3. Stroke Unit and Neurovascular Research Unit, Department of Neurology, Herlev Gentofte Hospital, Herlev Ringvej 75, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: ckruuse@dadlnet.dk.
Abstract
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.
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.
Authors: George Goshua; Alexander B Pine; Matthew L Meizlish; C-Hong Chang; Hanming Zhang; Parveen Bahel; Audrey Baluha; Noffar Bar; Robert D Bona; Adrienne J Burns; Charles S Dela Cruz; Anne Dumont; Stephanie Halene; John Hwa; Jonathan Koff; Hope Menninger; Natalia Neparidze; Christina Price; Jonathan M Siner; Christopher Tormey; Henry M Rinder; Hyung J Chun; Alfred I Lee Journal: Lancet Haematol Date: 2020-06-30 Impact factor: 18.959
Authors: Sean X Gu; Tarun Tyagi; Kanika Jain; Vivian W Gu; Seung Hee Lee; Jonathan M Hwa; Jennifer M Kwan; Diane S Krause; Alfred I Lee; Stephanie Halene; Kathleen A Martin; Hyung J Chun; John Hwa Journal: Nat Rev Cardiol Date: 2020-11-19 Impact factor: 32.419