TY - JOUR
T1 - Phosphodiesterase-5 inhibition potentiates cerebrovascular reactivity in chronic traumatic brain injury
AU - Kenney, Kimbra
AU - Amyot, Franck
AU - Moore, Carol
AU - Haber, Margalit
AU - Turtzo, L. Christine
AU - Shenouda, Christian
AU - Silverman, Erika
AU - Gong, Yunhua
AU - Qu, Bao Xi
AU - Harburg, Leah
AU - Wassermann, Eric M.
AU - Lu, Hanzhang
AU - Diaz-Arrastia, Ramon
N1 - Funding Information:
1Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 2Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 3Radiology and Imaging Sciences, National Institutes of Health, Bethesda, Maryland 4Department of Physical Medicine and Rehabilitation, National Institutes of Health Clinical Center, Bethesda, Maryland 5Behavioral Neurology Unit, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland 6Johns Hopkins University, Baltimore, Maryland
Funding Information:
Work in the authors’ laboratory was supported by the Center for Neuroscience and Regenerative Medicine (CNRM), Uniformed Services University of the Health Sciences (USUHS), Bethesda, MD, by the Military Clinical Neuroscience Center of Excellence (MCNCoE), Department of Neurology, USUHS, and by the Intramural Research Program of the National Institutes of Health.
PY - 2018/4
Y1 - 2018/4
N2 - Background: Traumatic cerebrovascular injury (TCVI), a common consequence of traumatic brain injury (TBI), presents an attractive therapeutic target. Because phosphodiesterase-5 (PDE5) inhibitors potentiate the action of nitric oxide (NO) produced by endothelial cells, they are candidate therapies for TCVI. This study aims to: (1) measure cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and change in CVR after a single dose of sildenafil (ΔCVR) in chronic TBI compared to uninjured controls; (2) examine the safety and tolerability of 8-week sildenafil administration in chronic symptomatic moderate/severe TBI patients; and as an exploratory aim, (3) assess the effect of an 8-week course of sildenafil on chronic TBI symptoms. Methods: Forty-six subjects (31 chronic TBI, 15 matched healthy volunteers) were enrolled. Baseline CBF and CVR before and after administration of sildenafil were measured. Symptomatic TBI subjects then completed an 8-week double-blind, placebo-controlled, crossover trial of sildenafil. A neuropsychological battery and neurobehavioral symptom questionnaires were administered at each study visit. Results: After a single dose of sildenafil, TBI subjects showed a significant increase in global CVR compared to healthy controls (P < 0.001, d = 0.9). Post-sildenafil CVR maps showed near-normalization of CVR in many regions where baseline CVR was low, predominantly within areas without structural abnormalities. Sildenafil was well tolerated. Clinical Global Impression (CGI) scale showed a trend toward clinical improvement while on sildenafil treatment. Findings: Single-dose sildenafil improves regional CVR deficits in chronic TBI patients. CVR and ΔCVR are potential predictive and pharmacodynamic biomarkers of PDE5 inhibitor therapy for TCVI. Sildenafil is a potential therapy for TCVI.
AB - Background: Traumatic cerebrovascular injury (TCVI), a common consequence of traumatic brain injury (TBI), presents an attractive therapeutic target. Because phosphodiesterase-5 (PDE5) inhibitors potentiate the action of nitric oxide (NO) produced by endothelial cells, they are candidate therapies for TCVI. This study aims to: (1) measure cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and change in CVR after a single dose of sildenafil (ΔCVR) in chronic TBI compared to uninjured controls; (2) examine the safety and tolerability of 8-week sildenafil administration in chronic symptomatic moderate/severe TBI patients; and as an exploratory aim, (3) assess the effect of an 8-week course of sildenafil on chronic TBI symptoms. Methods: Forty-six subjects (31 chronic TBI, 15 matched healthy volunteers) were enrolled. Baseline CBF and CVR before and after administration of sildenafil were measured. Symptomatic TBI subjects then completed an 8-week double-blind, placebo-controlled, crossover trial of sildenafil. A neuropsychological battery and neurobehavioral symptom questionnaires were administered at each study visit. Results: After a single dose of sildenafil, TBI subjects showed a significant increase in global CVR compared to healthy controls (P < 0.001, d = 0.9). Post-sildenafil CVR maps showed near-normalization of CVR in many regions where baseline CVR was low, predominantly within areas without structural abnormalities. Sildenafil was well tolerated. Clinical Global Impression (CGI) scale showed a trend toward clinical improvement while on sildenafil treatment. Findings: Single-dose sildenafil improves regional CVR deficits in chronic TBI patients. CVR and ΔCVR are potential predictive and pharmacodynamic biomarkers of PDE5 inhibitor therapy for TCVI. Sildenafil is a potential therapy for TCVI.
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U2 - 10.1002/acn3.541
DO - 10.1002/acn3.541
M3 - Article
C2 - 29687019
AN - SCOPUS:85043235282
VL - 5
SP - 418
EP - 428
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
SN - 2328-9503
IS - 4
ER -