TY - JOUR

T1 - Phosphodiesterase 5 inhibition as a therapeutic target for ischemic stroke

T2 - A systematic review of preclinical studies

AU - Ölmestig, Joakim N E

AU - Marlet, Ida R

AU - Hainsworth, Atticus H

AU - Kruuse, Christina

N1 - Copyright © 2017. Published by Elsevier Inc.

PY - 2017/10

Y1 - 2017/10

N2 - Phosphodiesterase 5 inhibitors (PDE5i), such as sildenafil (Viagra®) are widely used for erectile dysfunction and pulmonary hypertension. Preclinical studies suggest that PDE5i may improve functional outcome following ischemic stroke. In this systematic review we aimed to evaluate the effects of selective PDE5i in animal models of brain ischaemia. A systematic search in Medline, Embase, and The Cochrane Library was performed including studies in English assessing the effects of selective PDE5i. 32 publications were included describing outcome in 3646 animals. Neuroprotective effects of PDE5i were dependent on the NO-cGMP-PKG-pathway. These included reduced neuronal apoptosis (n=3 studies), oxidative stress (n=5), and neuroinflammation (n=2). PDE5i increased angiogenesis and elevated regional cerebral blood flow in the ischemic penumbra, and improved functional recovery. Some studies found that PDE5i treatment reduced lesion volume (n=9), others found no effect (n=9). Treatment was effective when administered within 24h post-ischemia, though treatment delayed to seven days improved outcome in one study. This review demonstrates both neuroprotective and neurorestorative effects of PDE5i in animal models of stroke, though the specific underlying signaling pathways relating to PDE5 inhibition and cGMP may remain serendipitous in some studies. There is currently limited evidence on the effects of selective PDE5i in human stroke patients, hence translation of preclinical results into clinical trials may be warranted.

AB - Phosphodiesterase 5 inhibitors (PDE5i), such as sildenafil (Viagra®) are widely used for erectile dysfunction and pulmonary hypertension. Preclinical studies suggest that PDE5i may improve functional outcome following ischemic stroke. In this systematic review we aimed to evaluate the effects of selective PDE5i in animal models of brain ischaemia. A systematic search in Medline, Embase, and The Cochrane Library was performed including studies in English assessing the effects of selective PDE5i. 32 publications were included describing outcome in 3646 animals. Neuroprotective effects of PDE5i were dependent on the NO-cGMP-PKG-pathway. These included reduced neuronal apoptosis (n=3 studies), oxidative stress (n=5), and neuroinflammation (n=2). PDE5i increased angiogenesis and elevated regional cerebral blood flow in the ischemic penumbra, and improved functional recovery. Some studies found that PDE5i treatment reduced lesion volume (n=9), others found no effect (n=9). Treatment was effective when administered within 24h post-ischemia, though treatment delayed to seven days improved outcome in one study. This review demonstrates both neuroprotective and neurorestorative effects of PDE5i in animal models of stroke, though the specific underlying signaling pathways relating to PDE5 inhibition and cGMP may remain serendipitous in some studies. There is currently limited evidence on the effects of selective PDE5i in human stroke patients, hence translation of preclinical results into clinical trials may be warranted.

U2 - 10.1016/j.cellsig.2017.06.015

DO - 10.1016/j.cellsig.2017.06.015

M3 - Review

C2 - 28648945

VL - 38

SP - 39

EP - 48

JO - Cellular Signalling

JF - Cellular Signalling

SN - 0898-6568

ER -