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.

Divergent pathways mediate 5-HT1A receptor agonist effects on close social interaction, grooming and aggressive behaviour in mice: Exploring the involvement of the oxytocin and vasopressin systems

Background: 5-HT1A receptor (5-HT1AR) abnormalities are implicated in aggression, and there has been considerable interest in developing 5-HT1AR agonists for treating aggression. Endogenous oxytocin (OXT) released upon stimulation of 5-HT1ARs in the hypothalamus mediates at least some of the effects of 5-HT1AR agonists on social behaviour. Aims: Given 5-HT1AR, OXT receptor (OXTR) and vasopressin V1a receptor (V1aR) agonists can all reduce aggression, the current study aimed to determine whether the anti-aggressive effects of 5-HT1AR stimulation can also be explained by downstream actions at OXTRs and/or V1aRs in a mouse model of non-territorial, hyper-aggressive behaviour. Methods: Male Swiss mice ( N=80) were socially isolated or group housed for six weeks prior to the start of testing. Testing involved placing two unfamiliar weight- and condition-matched mice together in a neutral context for 10 minutes. Results: Social isolation led to a pronounced increase in aggressive behaviour, which was dose-dependently inhibited by the 5-HT1AR agonist 8-OH-DPAT (0.1, 0.3 and 1 mg/kg intraperitoneally (i.p.)), with accompanying increases in close social contact (huddling) and grooming. The effects of 8-OH-DPAT on aggression, huddling and grooming were blocked by pretreatment with a selective 5-HT1AR antagonist (WAY-100635; 0.1 mg/kg i.p.). The anti-aggressive effects of 8-OH-DPAT were unaffected by an OXTR antagonist (L-368,899; 10 mg/kg i.p.), whereas the effects on huddling and grooming were inhibited. Pretreatment with a V1aR antagonist (SR49059; 20 mg/kg i.p.) had no effect. Conclusions: Our study suggests that stimulation of endogenous oxytocin is involved in the effects of 5-HT1AR activation on close social contact and grooming but not aggression.

Exogenous vasopressin dose-dependently modulates gastric microcirculatory oxygenation in dogs via V1A receptor

Background Hypercapnia improves gastric microcirculatory oxygenation (μHbO2) and increases vasopressin plasma levels, whereas V1A receptor blockade abolishes the increase of μHbO2. The aim of this study was to evaluate the effect of exogenous vasopressin (AVP) in increasing doses on microcirculatory perfusion and oxygenation and systemic hemodynamic variables. Furthermore, we evaluated the role of the vasopressin V1A receptor in mediating the effects. Methods In repetitive experiments, six anesthetized dogs received a selective vasopressin V1A receptor inhibitor ([Pmp1, Tyr (Me)2]-Arg8-Vasopressin) or sodium chloride (control groups). Thereafter, a continuous infusion of AVP was started with dose escalation every 30 min (0.001 ng/kg/min–1 ng/kg/min). Microcirculatory variables of the oral and gastric mucosa were measured with reflectance spectrometry, laser Doppler flowmetry, and incident dark field imaging. Transpulmonary thermodilution was used to measure systemic hemodynamic variables. AVP plasma concentrations were measured during baseline conditions and 30 min after each dose escalation. Results During control conditions, gastric μHbO2 did not change during the course of experiments. Infusion of 0.001 ng/kg/min and 0.01 ng/kg/min AVP increased gastric μHbO2 to 87 ± 4% and 87 ± 6%, respectively, compared to baseline values (80 ± 7%), whereas application of 1 ng/kg/min AVP strongly reduced gastric μHbO2 (59 ± 16%). V1A receptor blockade prior to AVP treatment abolished these effects on μHbO2. AVP dose-dependently enhanced systemic vascular resistance (SVR) and decreased cardiac output (CO). After prior V1A receptor blockade, SVR was reduced and CO increased (0.1 ng/kg/min + 1 ng/kg/min AVP). Conclusions Exogenous AVP dose-dependently modulates gastric μHbO2, with an increased μHbO2 with ultra-low dose AVP. The effects of AVP on μHbO2 are abolished by V1A receptor inhibition. These effects are independent of a modulation of systemic hemodynamic variables.

A phase 2 clinical trial of a vasopressin V1a receptor antagonist shows improved adaptive behaviors in men with autism spectrum disorder

There are no approved pharmacological therapies to address the core symptoms of autism spectrum disorder (ASD), namely, persistent deficits in social communication and social interaction and the presence of restricted, repetitive patterns of behaviors, interests, or activities. The neuropeptide vasopressin has been implicated in the regulation of social behaviors, and its modulation has emerged as a therapeutic target for ASD. The phase 2 VANILLA clinical trial reported here evaluated balovaptan, an orally administered selective vasopressin V1a receptor antagonist, in 223 men with ASD and intelligence quotient ≥70. The drug was administered daily for 12 weeks and was compared with placebo. Participants were randomized to placebo (n = 75) or one of three balovaptan dose arms (1.5 mg, n = 32; 4 mg, n = 77; 10 mg, n = 39). Balovaptan treatment was not associated with a change from baseline compared with placebo at 12 weeks in the primary efficacy endpoint (Social Responsiveness Scale, 2nd Edition). However, dose-dependent and clinically meaningful improvements on the Vineland-II Adaptive Behavior Scales composite score were observed for participants treated with balovaptan 4 or 10 mg compared with placebo. This was driven principally by improvements in the Vineland-II socialization and communication scores. Balovaptan was well tolerated across all doses, and no drug-related safety concerns were identified. These results support further study of balovaptan as a potential treatment for the socialization and communication deficits in ASD.