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Phosphodiesterase-5 inhibition potentiates cerebrovascular reactivity in chronic traumatic brain injury

Kimbra Kenney1, Franck Amyot1, Carol Moore1

  • 1Department of Neurology Uniformed Services University of the Health Sciences Bethesda Maryland.

Annals of Clinical and Translational Neurology
|April 25, 2018
PubMed
Abstract

Insights

Sildenafil treatment improved cerebrovascular reactivity (CVR) in patients with chronic traumatic brain injury (TBI). This phosphodiesterase-5 inhibitor shows promise for treating traumatic cerebrovascular injury (TCVI).

Area of Science:

  • Neuroscience
  • Vascular Biology
  • Pharmacology

Background:

  • Traumatic cerebrovascular injury (TCVI) is a significant complication of traumatic brain injury (TBI).
  • Phosphodiesterase-5 (PDE5) inhibitors, like sildenafil, enhance nitric oxide (NO) signaling and are potential treatments for TCVI.
  • Understanding the impact of PDE5 inhibitors on cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) in TBI is crucial.

Purpose of the Study:

  • To measure CBF, CVR, and the change in CVR (ΔCVR) after a single sildenafil dose in chronic TBI patients versus controls.
  • To assess the safety and tolerability of 8-week sildenafil administration in symptomatic TBI patients.
  • To explore the effect of 8-week sildenafil treatment on chronic TBI symptoms.

Main Methods:

  • Forty-six participants (31 with chronic TBI, 15 healthy controls) were enrolled.
  • Baseline CBF and CVR were measured before and after sildenafil administration.
  • A double-blind, placebo-controlled, crossover trial of 8-week sildenafil was conducted in symptomatic TBI patients, with neuropsychological and symptom assessments.

Main Results:

  • A single dose of sildenafil significantly increased global CVR in TBI subjects compared to controls (P < 0.001).
  • Post-sildenafil CVR maps indicated near-normalization in regions with previously low CVR, particularly in structurally intact areas.
  • Sildenafil was well-tolerated, and a trend toward clinical improvement was observed on the Clinical Global Impression scale.

Conclusions:

  • Single-dose sildenafil effectively improves regional CVR deficits in chronic TBI patients.
  • CVR and ΔCVR may serve as predictive and pharmacodynamic biomarkers for PDE5 inhibitor therapy in TCVI.
  • Sildenafil demonstrates potential as a therapeutic agent for TCVI.

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