A New Drug for the Treatment of Traumatic Brain Injury - Project Summary/Abstract
Traumatic Brain Injury (TBI) contributes to a third of injury-related deaths in the US and is among the
leading causes of death and disability in people under 35 and over 65. Recent statistics show that TBI annually
causes 50,000 deaths, 275,000 hospital admissions, carries an average lifetime expense of $550,000/patient,
and an annual economic burden conservatively estimated at $86 billion. The lack of any approved drugs that
prevent, minimize, or reverse the brain damage and deficits caused by moderate to severe TBI is a critical
unmet need. We propose to test a novel class of vasopressin 1a (V1a) receptor antagonists as a new treatment to
meet this need.
There is a strong scientific rationale for V1a receptor antagonism as a disease-modifying
pharmacotherapy for moderate to severe TBI. Brain edema following TBI is associated with poor prognosis.
Following TBI, increased vasopressin (AVP) expression, acting through the V1a receptor, is a major driver of
cerebral edema. We recently found that 5 days of treatment with one of Azevan's novel, blood-brain barrier
(BBB) penetrating V1a antagonists beginning 24 hr after moderate TBI was induced using the momentum
exchange model significantly reduced cerebral edema and eliminated cognitive deficits in concussed animals.
The proposed studies will confirm and build on these encouraging preliminary findings.
Using the momentum exchange model to induce moderate TBI in female and male rats with a single
head strike, four candidate compounds will be screened in physiological, imaging, behavioral, and
pharmacokinetic experiments. The compounds will be tested to characterize their effects on 1) edema and
resting state functional connectivity using MRI; 2) plasma biomarkers (S100b, GFAP, UCH-l1) in the first 24
hours post-injury that are known to reflect injury severity in rats and humans; and 3) cognitive function based
on performance on the Novel Object Recognition task and Barnes Maze test. Finally, we will measure plasma
levels of the 4 candidate compounds after intravenous, intraperitoneal, and oral gavage administration. Serial
sampling of blood will allow calculation of pharmacokinetic (PK) parameters. These data will help inform
planning for studies to help optimize route of administration and formulations for use in treating moderate to
severe TBI.
The two compounds that most effectively reduce edema, improve rsFC, eliminate cognitive deficits on
both tests, and exhibit the best PK profiles (e.g., IV and oral availability, t1/2, AUC) will be designated for
continued development in Phase 2, where further IND-enabling work (mechanistic studies, formulation, safety
& toxicology) will be undertaken.
