Evidence of early vasogenic edema following minor head impact that can be reduced with a vasopressin V1a receptor antagonist

Abstract

Background: Does minor head impact without signs of structural brain damage cause short-term changes in vasogenic edema as measured by an increase 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 impact.

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 impact and again 7-8 hrs later. At 2 h, 6 h, and 24 h 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 scanned at 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 parsed into 11 major brain regions.

Results: Untreated rats with brain injury showed a significant increase in global brain vasogenic edema as compared to sham and SRX251 treated rats. Edema peaked at 6 h in injured, untreated rats in three brain regions where changes in ADC were observed, but returned to sham levels by 24 h. 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 response to treatment.

Conclusion: A single minor impact to the forehead causes regional increases in vasogenic edema that peak at 6 h 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.

Keywords: Apparent diffusion coefficient; Cerebellum; Diffusion weighted imaging; Magnetic resonance imaging; Traumatic brain injury.

Figure 1. Edema in whole brain

Shown are scatter plots of average ADC values taken from whole brain (150 areas) for sham (black), vehicle (blue) and SRX251 (red) treatments 2, 6 and 24 hrs post head injury. The analysis from a two-way ANOVA is shown below. ns – not significant, *** p<0.001, * p<0.05

Figure 2. Mild head impact without evidence of brain damage

Shown are serial coronal sections of T2-weighted anatomical images taken at 2, 6 and 24 hrs post mild head impact. The site of impact is shown by the arrow. The bright area above the skull is fluid from swelling under the skin. These images are from a single rat representative of each experimental treatment.

Figure 3. Edema in cerebellum

Shown are scatter plots of average ADC values taken from the cerebellum (20 areas shown below) for sham (black), vehicle (blue) and SRX251 (red) treatments 2, 6 and 24 hrs post head injury. ns – not significant, *** p<0.001, ** p<0.01

Figure 4. Edema in thalamus

Shown are scatter plots of average ADC values taken from thalamus (20 areas shown below) for sham (black), vehicle (blue) and SRX251 (red) treatments 2, 6 and 24 hrs post head injury. ns – not significant, *** p<0.001, ** p<0.01

Figure 5. Edema in the basal ganglia

Shown are scatter plots of average ADC values taken from the basal ganglia (10 areas shown below) for sham (black), vehicle (blue) and SRX251 (red) treatments 2, 6 and 24 hrs post head injury. ns – not significant, * p<0.05

Figure 6. 3D reconstruction of affected brain areas

Shown is a color-coded reconstruction of brain areas showing significant increases in edema following a single mild hit to the forehead (black ball and circle)