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

Abstract

BackgroundTraumatic 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.MethodsForty‐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.ResultsAfter 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.FindingsSingle‐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.

Impairment of cerebrovascular reactivity in response to hypercapnic challenge in a mouse model of repetitive mild traumatic brain injury

“…Although CVR deficit is a symptom of many neurodegenerative diseases, 23,54,55 recent work by Diaz-Arrastia et al 7,17,56,57 has demonstrated global, Figure 7. ELISA measurement of aSMA concentration in cortical vascular-enriched fractions at three months and nine months post-injury.…”

Traumatic microbleeds suggest vascular injury and predict disability in traumatic brain injury

“…Our data suggest that acute TMBs are associated with acute MRI diffusion-weighted changes like those well-described from acute stroke studies. Thus, we postulate that TMBs may be useful biomarkers for identifying TBI patients that may benefit in the acute phase from therapies aimed at minimizing acute ischaemic damage, or in the chronic phase, at improving microvascular cerebral blood flow (Zhang et al, 2006;Kenney et al, 2018). The persistence of inflammatory cells triggered by these TMBs in the perivascular spaces may also impede fluid movement, which, if in humans is analogous to the glymphatic system critical for removing substrates from the brain as described in rodents (Glushakova et al, 2014), may affect the build-up of substrates and lead to secondary injury in humans as well.…”

“…TMBs may also serve as biomarkers for patients more likely to have these glymphatic flow system disruptions, facilitating the identification of appropriate patients for therapeutic clinical trials. For example, pharmacological agents suggested by other TBI investigators to act on the microvasculature to increase cerebral perfusion include sildenafil (Kenney et al, 2018) and beta blockers such as propranolol (Loftus et al, 2016). In contrast, minocycline has the potential to reduce acute ischaemic injury through its effects on inflammation, blood-brain barrier, and oedema (Mizuma and Yenari, 2017).…”

Vascular Abnormalities within Normal Appearing Tissue in Chronic Traumatic Brain Injury

“…Sildenafil has been shown to increase CVR specifically within regions with decreased CVR in chronic TBI subjects. 33,59 This suggests CVR may be a useful biomarker to monitor response to therapy as well. These findings highlight the need for further study of traumatic vascular injury as distinct endophenotype of TBI.…”