Role of Vasopressin V_1a and V₂ Receptors for the Development of Secondary Brain Damage after Traumatic Brain Injury in Mice

Abstract

Brain edema is still one of the most deleterious sequels of traumatic brain injury (TBI), and its pathophysiology is not sufficiently understood. The goal of the current study was to investigate the role of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), an important regulator of tissue water homeostasis, for the formation of post-traumatic brain edema, intracranial pressure (ICP), brain damage, and functional deficits following brain trauma. C57/B16 mice (n=112) were subjected to controlled cortical impact (CCI; 8m/s, 1 mm). At 3 min after trauma, animals received 500 ng of the AVP V(1a)-receptor antogonist (deamino-Pen(1), O-Me-Tyr(2), Arg(8)]-Vasopressin) or 500 ng of the AVP V2-receptor antagonist (adamantaneacetyl(1), O-Et-D-Tyr(2),Val(4), Abu(6),Arg(8,9)]-Vasopressin) by intracerebroventricular injection. After trauma, cerebral water content (24 h), ICP (24 h), contusion volume (24 h and 7 days), and functional outcome (1-7 days) were assessed (n=8 per experimental group). Post-traumatic inhibition of AVP V(1A) receptors reduced ICP by 29% (p < 0.05), brain water content by 45% (p < 0.05), and secondary contusion expansion by 37% (p < 0.05), and it significantly improved motor function 6 and 7 days after trauma (p < 0.05). Inhibition of AVP V2 receptors had no significant effect. The current results demonstrate that vasopressin V(1A) receptors are involved in the pathogenesis of brain edema formation and the subsequent development of secondary brain damage after traumatic brain injury. Accordingly, our study suggests that vasopressin V(1A) receptors may represent a novel therapeutic target for the treatment of post-traumatic brain edema and secondary brain damage.

Use of Oral Vasopressin V₂ Receptor Antagonist for Hyponatremia in Acute Brain Injury

“…This ICP-lowering effect has been hypothesized to be mediated through the V 1A receptor and aquaporin-4 channel expressed by astrocytes in the brain [10,22,23,24,25,26]. Although V 2 receptors are also expressed in the brain, animal studies are inconclusive regarding the role of V 2 receptor antagonists in the reduction of cerebral edema [3,24,26,27]. V 2 receptor antagonists' ability to reduce cerebral edema in humans has not been studied.…”

Vasopressin V 1a Receptors Mediate Posthemorrhagic Systemic Hypertension Thereby Determining Rebleeding Rate and Outcome After Experimental Subarachnoid Hemorrhage

“…Previously, we and others suggested that inhibition of the V 1 receptor may reduce brain edema formation after cerebral ischemia and traumatic brain injury directly through inhibition central V 1 receptors. 11,12,24,25 Although we cannot fully exclude that this mechanism may also be responsible for part of the neuroprotective effect of V 1 receptor inhibition observed in the current study, our findings suggest that AVP has a very specific, so far unrecognized, role in the pathophysiology of SAH, in which systemic blood pressure has an immediate and direct effect on the primary insult and the frequency of rebleedings, both strong predictors of outcome after SAH. 26 Therefore, the direct effect of V 1 receptor inhibition on brain edema formation seems to be of only subordinate significance in SAH.…”

“…11,12 Forty micrograms of the drug dissolved in 400 L saline (vehicle) was applied as a bolus (100 L) given immediately before SAH followed by a 3-hour continuous infusion (100 L/hour). Control animals received only vehicle.…”

“…10 Pharmacological blockage of V 1 receptors resulted in a significantly improved functional outcome and reduced brain damage in animal models of cerebral ischemia and traumatic brain injury. 11,12 It remains to be elucidated whether AVP V 1 receptors also have a pathophysiological role after SAH. Therefore, the aim of the current study was to investigate the therapeutic potential of AVP V 1 receptors in an experimental model of SAH.…”

Non-Peptide Arginine-Vasopressin Antagonists (Vaptans) for the Treatment of Hyponatremia in Neurocritical Care: A New Alternative?

“…Perhaps most intriguingly, the V1a receptor has recently been implicated in the formation of brain edema via the perivascular pool of aquaporin-4 (AQP-4) [14]. In animal models, decreasing the expression of AQP-4 either by inhibition of the V1a receptor or knock-out of the AQP-4 gene itself leads to the reduction of edema and intracranial pressure following neurotrauma [13] and stroke [15,16]. Experimental studies in animal models of neuro-injury suggest the anti-edema effects following treatment with nonpeptide AVP antagonists are related to inhibition of AVP at the V1a receptor [17,18].…”