Evidence of Early Vasogenic Edema Following Minor Head Injury That Can Be Reduced With a Vasopressin V1a Receptor Antagonist

Background: Does minor head injury without signs of structural brain damage cause short-term changes in vasogenic edema as measured by an increased apparent diffusion coefficient (ADC) using diffusion weighted imaging? If so, could the increase in vasogenic edema be treated with a vasopressin V1a receptor antagonist? We hypothesized that SRX251, a highly selective V1a antagonist, would reduce vasogenic edema in response to a single minor head injury.Methods: Lightly anesthetized male rats were subjected to a sham procedure or a single hit to the forehead using a closed skull, momentum exchange model. Animals recovered in five min and were injected with saline vehicle (n=8) or SRX251 (n=8) at 15 min post head injury and again 7-8 hrs later. At 2 hrs, 6 hrs, and 24 hrs post injury, rats were anesthetized and scanned for increases in ADC, a neurological measure of vasogenic edema. Sham rats (n=6) were exposed to anesthesia and scannedat all time points but were not hit or treated. Images were registered to and analyzed using a 3D MRI rat atlas providing site-specific data on 150 different brain areas. These brain areas were divided into 11 major brain regions.Results: Untreated rats with head injury showed a significant increase in global brain vasogenic edema as compared to sham and SRX251 treated rats. Edema peaked at 6 hrs in injured, untreated rats in three brain regions where changes in ADC were observed, but returned to sham levels by 24 hrs. There were regional variations in the time course of vasogenic edema and drug efficacy. Edema was significantly reduced in cerebellum and thalamus with SRX251 treatment while the basal ganglia did not show a significant response to treatment. Conclusion: A single minor impact to the forehead causes regional increases in vasogenic edema that peak at 6 hrs but return to baseline within a day in a subset of brain regions. Treatment with a selective V1a receptor antagonist can reduce much of the edema.