Arginine Vasopressin V_1a Receptor-Deficient Mice Have Reduced Brain Edema and Secondary Brain Damage following Traumatic Brain Injury

Abstract

The formation of brain edema and subsequent intracranial hypertension are major predictors of unfavorable outcome following traumatic brain injury (TBI). Previously, we reported that arginine vasopressin (AVP) receptor antagonists reduce post-traumatic and post-ischemic brain edema in mice. The aim of the current study was to investigate further the contribution of arginine vasopressin V1a receptors to TBI-induced secondary brain damage in V1a receptor knock-out mice. V1a receptor knock-out (V1a -/-) and wild-type mice were subjected to controlled cortical impact (CCI), and edema (brain water content measured before and 24 h after CCI), primary and secondary contusion volume (15 min and 24 h after CCI), neurological function (one day before and seven days after CCI), body weight (before and seven days after CCI) and mortality were measured. Twenty-four h after CCI, V1a receptor knock-out mice had significantly less brain water content than wild-type mice (mean±standard error of the mean: 79.8%±0.3 vs. 80.6%±0.2, respectively), and secondary contusion volume was significantly smaller (38.2±1.7 mm(3) vs. 45.1±1.5 mm(3) in wild-type mice). Furthermore, the V1a receptor knock-out mice had less neurological dysfunction (3.2±0.8 vs. 7.0±1.4 in wild-type mice) and weight loss (1.0±1.0% vs. 4.9±1.8% in wild-type mice) seven days after CCI. Our data show that mice lacking V1a receptors have less secondary brain damage following experimental traumatic brain injury. We therefore conclude that V1a receptors may represent a novel drug target for preventing post-traumatic brain edema.

Selective vasopressin-1a receptor antagonist prevents brain edema, reduces astrocytic cell swelling and GFAP, V1aR and AQP4 expression after focal traumatic brain injury

“…et al, 2006b, Kleindienst et al, 2010, Kleindienst et al, 2013, Okuno et al, 2008, Taya et al, 2008, Taya et al, 2010) as well as others (Bemana and Nagao, 1999, Doczi et al, 1982, Doczi et al, 1984, Fazzina et al, 2010, Filippidis et al, 2014, Guo et al, 2006, Liu et al, 2010, Manaenko,. et al, 2011b, Okuno et al, 2008, Rauen et al, 2013, Serradeil-Le et al, 1993, Shuaib et al, 2002, Szmydynger-Chodobska et al, 2004, Trabold et al, 2008, Vakili et al, 2005) as we continue to identify the mechanisms of post-traumatic cellular swelling and explore potential therapies to blunt post-traumatic edema. Based on the hypothesis that edema in TBI is predominately cellular in origin, the goal of this work was to elucidate injury-induced changes in astrocytes that we posit are the underlying mechanisms of cellular swelling and subsequent post-traumatic edema.…”

“…Further, OPC-21268, a non-peptide V1aR antagonist, reduced brain tissue water and electrolytes following cold lesion brain injury (Bemana and Nagao, 1999). Recent novel studies using V1aR deficient rats (Szmydynger-Chodobska et al, 2010) and mice (Rauen et al, 2013) demonstrate the importance of this receptor following CCI; in V1aR deficient animals there was no astrocytic production of inflammatory chemokines or edematous change. These findings add an additional mechanistic context to our results showing a decrease in V1aR following treatment with SR49059 (Figs.…”

Vasopressin Increases Cerebral Perfusion Pressure but not Cerebral Blood Flow in Neurosurgical Patients with Catecholamine-Refractory Hypotension: A Preliminary Evaluation Using the Non-Invasive Quantix ND in Comparison to the Literature

“…Despite the fact that vasopressin enhances cerebral edema after ischemia [16,29] and also leads to a increased rebleeding rate in an animal model of SAH [30], some recent studies demonstrated that AVP is safe to use after TBI using the increase in MAP and CPP as endpoints [19,31] or in an animal model where cerebral oxygenation was also studied [18]. But to our knowledge this preliminary study is the first to measure not only the changes in MAP and CPP but put the focus of attention to changes in cerebral blood flow (CBF) after AVP application.…”

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

“…The intracerebroventricular injection of V1a receptor antagonists e.g., SR-49059, V1880 [61] or the peptidic deamino-Pen(1), O-Me-Tyr(2), Arg(8)]-vasopressin [31,62], are also effective but only when given within the rst few hrs of injury [61].Moderate head injury is associated with elevated levels of the water channel AQP4, GFAP, and V1a receptor, and disruption in sodium/potassium balance, all of which can be corrected by continuous exposure to SR49059 [22,23,30]. The edema in the these moderate TBI models is reduced in V1a null mice [24].In a recent study, we reported that AVN576, an orally active V1a receptor antagonist,givenipbeginning 24 hrs post injury for 5 days, could effectively reduce edema following TBI with brain damage [25].…”

“…For instance, V1a receptor density increases following TBI and infusion of V1a antagonists block increased intracranial pressure after head injury or brain lesion in animal models [21][22][23]. Knockout mice lacking V1a receptors show reduced edema, secondary injuries, and behavioral impairments in the days following brain damage [24]. We recently showed that systemic treatment with a highly selective V1a receptor antagonist for 5 days starting within 24 hrs of moderate/severe brain TBI signi cantly reduced edema and prevented cognitive de cits [25].…”