Time-Dependent Effects of Arginine-Vasopressin V1 Receptor Inhibition on Secondary Brain Damage after Traumatic Brain Injury.

Arginine-vasopressin (AVP) V ₁ receptors are known to mediate brain edema formation after traumatic brain injury (TBI). So far, however, AVP V ₁ receptors were only inhibited by genetic deletion or prior to trauma. Therefore, the current study aimed to determine the therapeutic window of AVP V ₁ receptor antagonization after TBI. Male C57BL/6 mice (n = 7 per group) were subjected to controlled cortical impact (CCI), and 500 ng of a selective peptide V ₁ receptor antagonist (V1880) were applied by intracerebroventricular injection 5 min, and 1, 3, and 6 h thereafter. After 24 h, brain water content (BWC), intracranial pressure (ICP), and secondary contusion expansion volume were assessed. Neurological function was assessed daily for 7 days after trauma. Inhibition of AVP V ₁ receptors within 1 h after TBI significantly reduced BWC from 81.6 ± 0.7 to 80.6 ± 0.7% (mean ± SD; p < 0.05). Reduction of brain edema resulted in a significant decrease in ICP from 25.9 ± 1.8 mm Hg to 21.0 ± 1.5 mm Hg (p < 0.05) and a reduction in contusion volume (26.1 ± 2.5 mm ³ vs. 30.1 ± 2.0 mm ³ in controls; p < 0.05). This reduction of brain injury resulted in a significantly improved neurological function 7 days after trauma. Treatments initiated 6 h after TBI had no effect. The results of the current study demonstrate that inhibition of AVP V ₁ receptors improve outcome after experimental TBI when given within a clinically relevant time window. Therefore, AVP V ₁ receptors may represent a therapeutic target with clinical potential.