Journal of Neuroscience Research 92:1091–1099 (2014)

Mini-Review Role of Vasopressin and Its Antagonism in Stroke Related Edema Pouya A. Ameli,1 Neema J. Ameli,1 David M. Gubernick,2 Saeed Ansari,2,3 Shekher Mohan,4 Irawan Satriotomo,2 Alexis K. Buckley,2 Christopher W. Maxwell Jr.,2 Vignesh H. Nayak,2 and Vishnumurthy Shushrutha Hedna2* 1

University of Central Florida College of Medicine, Orlando, Florida Department of Neurology, University of Florida College of Medicine, Gainesville, Florida 3 Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 4 Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida 2

Although many approaches have been tried in the attempt to reduce the devastating impact of stroke, tissue plasminogen activator for thromboembolic stroke is the only proved, effective acute stroke treatment to date. Vasopressin, an acute-phase reactant, is released after brain injury and is partially responsible for the subsequent inflammatory response via activation of divergent pathways. Recently there has been increasing interest in vasopressin because it is implicated in inflammation, cerebral edema, increased intracerebral pressure, and cerebral ion and neurotransmitter dysfunctions after cerebral ischemia. Additionally, copeptin, a byproduct of vasopressin production, may serve as a promising independent marker of tissue damage and prognosis after stroke, thereby corroborating the role of vasopressin in acute brain injury. Thus, vasopressin antagonists have a potential role in early stroke intervention, an effect thought to be mediated via interactions with aquaporin receptors, specifically aquaporin-4. Despite some ambiguity, vasopressin V1a receptor antagonism has been consistently associated with attenuated secondary brain injury and edema in experimental stroke models. The role of the vasopressin V2 receptor remains unclear, but perhaps it is involved in a positive feedback loop for vasopressin expression. Despite the encouraging initial findings we report here, future research is required to characterize further the utility of vasopressin antagonists in treatment of stroke. VC 2014 Wiley Periodicals, Inc. Key words: vasopressin; vasopressin antagonism; stroke; aquaporin; cerebral edema; brain injury

Brain edema and herniation after stroke contribute to the majority of stroke-related deaths. Numerous treatment modalities targeting specific components of the poststroke injury response have been attempted, the majority of which target downstream mechanisms in the progression of brain damage with variable results (O’Collins et al., 2006). IntraveC 2014 Wiley Periodicals, Inc. V

nous immunoglobulin administration after ischemic stroke in mice has been shown to decrease infarct size by half and significantly improve functional status. This is thought to be mediated by a complement-impeding mechanism (Arumugam et al., 2007). Some have suggested using inhibitors of cerebral nitric oxide synthase after ischemic stroke in an attempt to reduce cerebral edema and infarct volume (Hara et al., 1996). Nimodipine, although shown to be efficacious in the prevention of vasospasm after subarachnoid hemorrhage (Pickard et al., 1989; Tomassoni et al., 2008), has not proved effective for treatment of ischemic stroke (Horn et al., 2001). Other novel modalities that have failed include glutamate antagonists, ion channel blockers, free radical scavengers, neural stem cells, neurotrophic factors, and anti-inflammatory agents (Cheng et al., 2004). The difficulty in finding efficacious stroke interventions is better understood when one considers the multifaceted etiology of cerebrovascular injury. Therefore, we can target and block a “bottleneck” molecule that proves to be initially responsible for the sequence of damage after stroke. For example, recently arginine-vasopressin (AVP) has garnered attention as a promising drug target in the management of cerebrovascular accident (CVA) and cerebral edema after stroke. With a rat model of ischemic stroke, Chang et al. (2006) showed a time-dependent increase in serum AVP levels after brain injury in addition to attenuation of AVP levels after administration of 7.5% hypertonic saline compared with mannitol, 3% hypertonic saline, or normal saline. Furthermore, a meta-analysis of randomized clinical trials found that hypertonic saline may be superior to equimolar *Correspondence to: Vishnumurthy Shushrutha Hedna, MD, Assistant Professor, Department of Neurology, Room L3-100, McKnight Brain Institute, 1149 Newell Drive, Gainesville, FL 32611. E-mail: [email protected] Received 31 December 2013; Revised 11 March 2014; Accepted 3 April 2014 Published online 14 May 2014 in Wiley Online (wileyonlinelibrary.com). DOI: 10.1002/jnr.23407

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mannitol in the reduction of quantitative intracranial pressure (ICP) measurements (Kamel et al., 2011). Together, these studies suggest that high-osmolarity solutions are superior to low-osmolarity solutions in reducing cerebral edema, potentially identifying AVP as a common pathway through which osmotherapy reduces cerebral edema. This article focuses on the role of AVP in the progression of cerebral edema after stroke, the promising benefit of AVP-receptor antagonists, and the prognostic value of copeptin, a surrogate marker for endogenous AVP release. For this review, systematic literature searches were compiled in PubMed (1966–2013) and Google Scholar with key words “vasopressin antagonism” AND “ischemic stroke” AND “edema” in the subject heading without language restrictions. Therefore, this review discusses the various facets of vasopressin and its antagonism in treating cerebral edema in the setting of acute ischemic stroke.

ARGININE-VASOPRESSIN AND BRAIN INJURY AVP, also known as vasopressin or antidiuretic hormone (ADH), is a small, nine-amino-acid peptide hormone synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. It is stored in the posterior pituitary (neurohypophysis; de Wied et al., 1993) and secreted in response to various stimuli, most notably high effective plasma osmotic pressure and hypovolemia. Once released, AVP most recognizably interacts with endogenous V2 receptors in the principal cells of the renal collecting duct, leading to upregulation of aquaporin-2 channels and allowing for increased plasma retention of free water. This mechanism, a rapid pituitary secretion time, and a short half-life explain why AVP is considered the most prominent regulator of renal water excretion and a major determinant of serum osmolarity and ion homeostasis (Salvucci and Armstead, 2000). Brain injury of any etiology, including ischemia, causes release of stress hormones such as AVP and corticotropin-releasing hormone (CRH), both of which initiate the stress response through subsequent release of cortisol (Fassbender et al., 1994; Barreca et al., 2001; Stevens et al., 2003; Chang et al., 2006). Cortisol performs a central role in stroke injury along with glutamate, oxygen free radicals, and energy failure by playing a part in the cascade of reactions leading to acute cytotoxic edema, subsequent vasogenic edema, and eventually necrosis (Ankarcrona et al., 1995; Wood and Youle, 1995; Sternberg, 1997; Crochemore et al., 2005). Indeed, activation of the hypothalamo-pituitary-adrenal axis is among the earliest detectable physiological responses to cerebral ischemia (Fassbender et al., 1994; Johansson et al., 1997, 2000; Slowik et al., 2002). Furthermore, AVP gene expression has been shown to be upregulated in the supraoptic and paraventricular nuclei of the hypothalamus after cerebral ischemia and reperfusion, providing strong evidence of AVP’s role in acute brain injury (Liu et al., 2000). In addition to increasing cortisol release, elevated levels of AVP after stroke are thought to be responsible

for the development of water permeability in both capillaries and glial cells (Niermann et al., 2001; Bhardwaj, 2006; Chang et al., 2006), regulation of CSF production (Raichle and Grubb, 1978; Faraci et al., 1988), and cerebral ion homeostasis (DePasquale et al., 1989; Cserr and Latzkovits, 1992). Additionally, both vasopressin upregulation and inflammation have been implicated in the etiology of cerebral vasospasm after subarachnoid hemorrhage (Trandafir et al., 2004). Thus, AVP is probably an early player in the propagation of the inflammatory response after brain injury. Furthermore, AVPCRH-cortisol signaling may be a hyperacute initiator of secondary injury after stroke and therefore a valuable target in stroke management.

COPEPTIN, A SURROGATE MARKER FOR AVP AVP is difficult to measure directly because of its pulsatile secretion pattern, short half-life of 5–15 min, and significant association with platelets. However, copeptin, a cleavage product of the AVP precursor protein pre-and provasopressin, is significantly more stable than vasopressin while being secreted in equimolar concentrations and has been shown to serve as a suitable surrogate marker for AVP release (Struck et al., 2005; Katan and Christ-Crain, 2010). Recent studies on copeptin corroborate data characterizing AVP as a consistent, major player in secondary brain damage after injury and also uncover the prognostic potential of copeptin in the clinical setting. These studies suggest that copeptin may be a more subtle marker of the acute stress response than cortisol and a seemingly simultaneous reflection of acute illness, comorbidities, genetic factors, and epigenetic factors (Bhandari et al., 2009). As such, copeptin levels may provide a prediction of a patient’s ability to recover from acute injury, particularly transient ischemic attack and ischemic/hemorrhagic stroke (Zhang et al., 2013) Numerous biomarkers have been evaluated for their prognostic value in stroke, including C-reactive protein (CRP), matrix metallopeptidase 9 (MMP-9), and brain natriuretic peptide (BNP). Despite their associations with stroke outcome, no biomarkers to date have been shown to provide additional value beyond clinical appraisals already in use, such as the National Institutes of Health Stroke Scale (NIHSS; Katan and Christ-Crain, 2010). The NIHSS is a systematic assessment tool that provides a quantitative measure of stroke-related neurological deficit. From a prospective cohort study of 362 patients with acute CVA on CT/MRI, Katan and Christ-Crain (2010) concluded that copeptin is an excellent indicator of functional outcome in stroke, with potential to add to the prognostic accuracy of the NIHSS. In a continuation study, it was also shown that copeptin is an independent predictor of functional outcome and all-cause mortality 1 year after stroke, significantly improving the prognostic accuracy of the NIHSS (Urwyler et al., 2010). A prospective observational cohort study of 125 ischemic stroke patients with 90-day Journal of Neuroscience Research

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followup showed that copeptin levels correlate with the NIHSS score and remain an independent predictor of poor functional outcome and mortality after adjusting for other predictors, including NIHSS, lesion size, and CRP (Dong et al., 2013). Additionally, Tu et al. (2013) conducted a prospective cohort study of stroke patients looking into various neuroendocrine prognostic markers, including CRP, BNP, copeptin, and cortisol. They found that copeptin was the best single biomarker for predicting short-term (90 day) outcomes, with odds ratios (OR) of 2.34 for functional outcome and 4.44 for mortality if copeptin levels were elevated (>12.0 pM). Even the NIHSS was not as strong of a predictor, having OR of 1.30 and 1.62 (Tu et al., 2013). Furthermore, copeptin has been shown to be a better prognostic tool than age, presence of comorbidities, glucose level, family history of stroke, and gender (Urwyler et al., 2010). Limitations to the use of copeptin as a prognostic biomarker in brain injury patients include suppression resulting from prednisone treatment (de Kruif et al., 2008), increased levels in renal insufficiency (Marmarou, 2007; Bhandari et al., 2009), and potential for drug interactions. Nonetheless, further studies regarding the prognostic value of copeptin may be valuable in enhancing our ability to predict patient recovery after brain injury. CEREBRAL EDEMA AND AVP Cerebral edema is a leading cause of death after stroke, probably resulting from increased ICP and cerebral hypoxia (de Kruif et al., 2008). Despite its frequency, there is no definitive gold standard to treat, prevent, or slow cerebral edema (Bhandari et al., 2009). AVP can result in astroglia cell volume modulation while playing a critical role in the formation of both vasogenic and cytotoxic cerebral edema (Marmarou, 2007). Possible contributing mechanisms of AVP neuroprotection include decreases in the water permeability of CSF-producing ependymal cells, reduced CSF production via a decrease in chloride-dependent CSF secretion, changes in the water permeability of astrocytes, and conformational changes in the glial lattice upon which sit the AVPregulating neurons of the glia limitans (the outmost layer of neuronal tissue), neural pituitary, and circumventricular organs (Hertz et al., 2000). These studies indicate that AVP provides significant promise as a target in the treatment of cerebral edema. The role of AVP in brain edema after ischemic stroke is supported by in vitro and in vivo experiments, which show that AVP exacerbates cellular swelling and brain edema (Del Bigio and Fedoroff, 1990; Vajda et al., 2001). In support, edema was mitigated by a similar injection of AVP antiserum (Liu et al., 1991) and AVP release inhibitor (Ikeda et al., 1997a,b). To our knowledge, there is no report of AVP knockout mice; however, there is extensive literature about the Brattleboro rat that contains a single nucleotide mutation in the second exon of the vasopressin gene leading to neurohypophysical diabetes insipidus in homozygous mutants. Brain edema formation in Brattleboro rats, after ischemic Journal of Neuroscience Research

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stroke, was less compared with control Long-Evans strain rats (Dickinson and Betz, 1992). AQUAPORIN PROTEINS AND VASOPRESSIN RECEPTORS Today, there are 13 known mammalian aquaporin (AQP) isoforms (Papadopoulos and Verkman, 2007), each with varying structures that affect their water permeability (Yang and Verkman, 1997; Tsukaguchi et al., 1998). Aquaporin-4 (AQP-4), the major brain aquaporin, is thought to facilitate fluid flow both into and out of the brain via its expression in circumventricular organs and the hippocampus and astrocytes, where it is involved in water exchange, neuroexcitation, and cell migration (Papadopoulos and Verkman, 2013). Overexpression of AQP-4 in mice has been associated with worsened cerebral edema and brain injury after ischemic stroke (Yeung et al., 2009). Furthermore, astrocytes in mice lacking in AQP-4 display a sevenfold decrease in water permeability of plasma membranes (Solenov et al., 2004), whereas AQP-4 deletion leads to a tenfold decrease in water permeability of the overall brain (Papadopoulos and Verkman, 2005). In one study, mice deficient in AQP-4 displayed 35% less cerebral edema at 24 hr and had improved neurological outcomes after focal ischemic stroke from middle cerebral artery occlusion (MCAO; Manley et al., 2000). There is also evidence that AQP-4 downregulation in Xenopus species reduces water permeability in the brain (Papadopoulos and Verkman, 2005). Furthermore, direct inhibition of AQP-4 has been described as beneficial in stroke (Yang and Verkman, 1997), with one study indicating that pretreatment of mice with a novel AQP-4 inhibitor significantly reduces cerebral edema and infarction size after ischemia (Igarashi et al., 2011). One mechanism by which AVP has been theorized to contribute to cerebral edema is via changes in expression of AQPs secondary to modulation of three vasopressin G-protein-coupled receptors, V1a, V2, and V1b (also called V3), which are differentially expressed in numerous organs across the body (Oh, 2008). The V1a receptor appears to be the most abundant AVP receptor in the brain, with expression in various areas including the cerebral vasculature, cerebral cortex, bed nucleus of the stria terminalis, nucleus accumbens, central nucleus of amygdala, sigmoid hypothalamic nucleus, suprachiasmatic nucleus, hippocampus, choroid plexuses, and pituitary gland (Gerstberger and Fahrenholz, 1989). V1a receptors have been postulated to contribute to brain edema as a modulator of cerebral water homeostasis and stress response (Decaux et al., 2008). However, there are notable instances in which studies conflict regarding the actions of AVP receptors. In one study, it was shown that V1a agonism decreased water permeability of cells via downregulation of AQP-4 (Moeller et al., 2009), whereas another study implicated increased expression of AQP-4 channels after V1a agonism resulted in an increase influx of water (Niermann et al., 2001). Despite these

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inconsistencies, V1a receptors are generally considered to play a role in the mechanisms of secondary brain injuries. This finding has spawned a great deal of research into the potential use of AVP receptor modulators in acute stroke treatment. CURRENT NONSURGICAL MANAGEMENT OF BRAIN INJURY A staple of today’s stroke management is the evaluation of ICP and maintenance of cerebral perfusion pressure. Early studies on cerebral edema regarded swelling of the brain as a relatively benign process in isolation and instead focused on reduction in blood flow after development of edema as the primary cause of cellular dysfunction (Marshall et al., 1976; O’Brien, 1979). We have since discovered that the pathogenesis of cerebral edema is inextricable from many of the damaging responses to stroke, including inflammation (Taya et al., 2008), dysregulation of electrolytes (Yang et al., 1992), and neurotransmitter homeostasis, all of which are known to worsen patient outcomes after stroke (Gotoh et al., 1985; Minamisawa et al., 1988; Kochanek and Hallenbeck, 1992; Rane et al., 2005; Castellanos et al., 2008). For example, stroke patients have increased levels of endothelin-1 (ET-1), which is a strong vasoconstrictor, in their plasma or CSF (Sapira et al., 2010). In relationship to AVP, when centrally administered, ET-1 induced a tenfold increase in AVP secretion (Rossi et al., 1997). In support, a clinical study showed high levels of ET-1 in the serum after stroke, and these levels of ET-1 were associated with severe brain edema (Moldes et al., 2008). Experimental studies suggest that astrocytic ET-1 has deleterious effects on water homeostasis, cerebral edema, and blood–brain barrier (BBB) integrity. The BBB also consists of AQPs (i.e., AQP-4) that play a pivotal role in the brain edema. Additional support for the role of ET-1 in edema comes from a study that showed increased neurological deficits, infarct, and AQP-4 expression in mice overexpressing ET-1 (Lo et al., 2005). In support, a key experimental study showed that inhibition of the AVP V1a receptor with SR49059 reduced the expression of AQP-4 and reduced cerebral edema after intracerebral hemorrhagic brain injury (Manaenko et al., 2011a). Altogether, the evidence supports cerebral edema as a marker of cerebral injury in addition to being a causative factor for deterioration poststroke. For these reasons, there is significant emphasis on the management of cerebral edema after brain injury. Therefore, various strategies have been applied to minimize cerebral edema secondary to CVA. For example, mannitol and hypertonic saline are the agents most commonly used, but the value of both strategies remains uncertain. Mannitol, both as an osmotic agent and a free radical scavenger, has been theorized to decrease cerebral edema and act in a neuroprotective manner (Bereczki et al., 2003). Several studies from 2000 to 2008 by Bereczki et al. (2000, 2003, 2007) on mannitol in stroke, including meta-analyses, confirmed that mannitol admin-

istration reduces cerebral edema but failed to reach conclusions regarding long-term benefit. Nonetheless, several potential adverse effects of mannitol administration were identified, including electrolyte imbalances, cardiopulmonary edema, and rebound cerebral edema. In no instance did these studies confirm or deny the overall utility of mannitol in acute stroke treatment. The evidence from hypertonic saline administration in acute stroke is also unclear. In one study by Hauer et al. (2011), 3% hypertonic saline was administered to patients with target serum sodium levels of 145–155 mEq/liter in patients with cerebral edema and cerebrovascular disease. This resulted in fewer episodes of elevated ICP in patients and significantly decreased hospital mortality without increasing rates of adverse events. However, a second study by Strandvik (2009) showed that hypertonic saline administration was useful in reducing ICP but did not confer any benefit in terms of survival or other outcomes. With regard to AVP, an experimental study by Chang et al. (2006) showed that high AVP levels after MCAO were significantly attenuated with 7.5% hypertonic saline compared with 0.9% saline, 3% saline, or mannitol. In addition to attenuated serum AVP levels, 7.5% hypertonic saline also decreased brain water content (Chang et al., 2006). ANTAGONISM OF VASOPRESSIN RECEPTORS Vasopressin V1a receptor antagonism has largely been shown to improve outcomes after stroke. In one study, high doses of a V1a antagonist, SR49059, decreased rates of brain water accumulation at 48 and 72 hr after induction of intrarcranial hemorrhage (ICH; Manaenko et al., 2011b). A second study showed that a high dose of SR49059 also reduced AQP-4 expression, in addition to cerebral edema, at both 24 and 72 hr after ICH (Manaenko et al., 2011a). A third study showed that SR49059 also reduced cytotoxic brain edema via AQP-4 attenuation in rats after MCAO, with subsequent reperfusion (Kleindienst et al., 2013). In a similar, separate study of rats with MCAO, SR49059 administration showed significant benefit only when given within 1 hr of MCAO, with no advantage of higher doses over smaller doses (Shuaib et al., 2002). Further studies of SR49059 infusion in rats showed that V1a antagonism also reduced AQP-4 levels and cerebral edema in rats after trauma-induced brain injury (Taya et al., 2008). These findings demonstrate that AQP-4 levels after brain injury may in fact be regulated via activation of the V1a receptor, strongly suggesting that V1a receptor inhibition should be a future target to address cerebral edema secondary to brain injury. Another V1 antagonist, OPC-21268, was administered in rats with cold-induced edema. At higher doses, this antagonism reduced postinjury brain water content in both injured and noninjured hemispheres while also reducing brain sodium content at a higher dose and causing a dose-dependent decrease in BBB permeability (Bemana and Nagao, 1999). V1a antagonism-mediated neuroprotection is postulated to occur via dampening of Journal of Neuroscience Research

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cerebrovasodilation caused by ATP-sensitive and calcium-sensitive potassium channels, potentially leading to decreased reperfusion injury and vasogenic edema (Salvucci and Armstead, 2000). V1a antagonism also has been illustrated to decrease cerebral vasospasm after subarachnoid hemorrhage (Trandafir et al., 2004). Several studies have compared antagonism of V1a and V2 receptors for stroke treatment. Vakili, et al. (2005) determined that V1 antagonism after transient focal ischemia resulted in a dose-dependent attenuation of infarct volume, decrease in brain edema, reduced BBB disruption, and less functional deficit at 24 hr, whereas V2 inhibition had no effect. Similarly, other experiments showed that cerebral edema after stroke is decreased in AVPdeficient mice and after administration of a V1 antagonist (Shuaib et al., 2002; Kleindienst et al., 2006) via a decrease in AQP-4, which was upregulated at ischemic sites. Here as well, V2 antagonism was shown to have no

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effect on outcome (Liu et al., 2010). Similar results were obtained with V1a receptor antagonism after traumatic brain injury in mice, leading to a 29% decrease in ICP, a 45% reduction in brain water content, a 37% decrease in secondary contusion size, and significantly improved motor function 1 week after trauma. Again, V2 antagonism had no effect (Trabold et al., 2008). Cerebral V2 receptor expression occurs at much lower levels than expression of V1a receptors (Croiset and De Wied, 1997). Nonetheless, some studies have postulated that vasopressin V2 receptor antagonism may have some clinical utility, although these claims have not always proved reproducible, according to the literature. In one study, the V2 receptor was found to mediate a positive feedback loop for AVP release (Landgraf et al., 1991), suggesting clinical value of V2 antagonism in ceasing AVP-mediated brain damage after brain injury. However, the opposite V2-mediated negative feedback was

TABLE I. Brief Summary of Studies Addressing the Role of Vasopressin Antagonism (V1a and/or V2) in Brain Edema in Both In Vivo and In Vitro Studies* Reference

Receptor targeted

Kleindienst et al., 2013

V1a antagonism (SR49059)

Manaenko et al., 2011a

V1a antagonism (SR49059)

Liu et al., 2010

V1a antagonism

Taya et al., 2008

V1a antagonism (SR49059)

Ferris et al., 2006 Vakili et al., 2005

V1a antagonism (SRX251) V1 antagonism

Shuaib et al., 2002

V1a antagonism (SR49059)

Bemana and Nagao, 1999

V1a antagonism (OPC-21268)

Yeung et al., 2009

V2 receptor antagonism (OPC-31260)

Molnar et al., 2008

V2 receptor antagonism (OPC-31260)

Laszlo et al., 1999

V2 receptor antagonism (OPC-31260)

Rosenberg et al., 1990

V1 1 V1/V2–antagonism

Human et al., 2012

Mixed V1a/V2 receptor antagonism (Conivaptan) Mixed V1a/V2 receptor antagonism (Conivaptan) Mixed V1a/V2 receptor antagonism (Conivaptan) Mixed V1a/V2 receptor antagonism (Conivaptan)

Dhar and Murphy-Human, 2011 Potts et al., 2011; Murphy et al., 2009 Unpublished data by authors Ansari et al., 2013

Results Downregulation of AQP expression and decreased cerebral edema following middle cerebral artery occlusion with subsequent reperfusion in rats Reduced cerebral edema at 24 and 72 hr following intracranial hemorrhage and improved neurobehavioral deficits at 72 hr in rats Decreased infarct volume, water accumulation, and upregulation of AQP expression in mice following middle cerebral artery occlusion with reperfusion Downregulation of AQP expression and decreased cerebral edema following traumatic brain injury Reduced aggressive behavior in hamsters Dose-dependent attenuation of infarct size, cerebral edema, blood–brain barrier compromise, and functional deficits in mice Decreased infarct size, neurologic deficits, and cerebral edema when given to mice immediately or 1 hr following focal embolic middle cerebral artery occlusion Reduced brain water accumulation and sodium content in rats using cold-induced brain injury model Reduced cerebral water accumulation in the end-feet of hippocampal astrocytes in mice model with overexpression of astrocyte endothelin-1 Improved survival, reduced brain water, and prevented sodium accumulation in rat brains following global cerebral hypoxia in a model of bilateral common carotid ligation Reduced brain water and prevented sodium accumulation while increasing vasopressin plasma levels in rats following subarachnoid hemorrhage Both V1 antagonism and V1/V2 antagonism blocked water accumulation in cats after intracerebral AVP infusion Ameliorated hyponatremia in large cohort of brain-injured patients Corrected serum sodium, intracranial pressure, and cerebral perfusion pressure in 22 year old patient after traumatic brain injury Reduction of euvolemic or hypervolemic hyponatremia secondary to SIADH in the setting of subarachnoid hemorrhage via aquaresis Reduced hemispheric enlargement secondary to stroke related edema in mice at both 12 and 24 hr

*AQP, aquaporin; SIADH, syndrome of inappropriate antidiuretic hormone secretion. Journal of Neuroscience Research

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suggested in several studies, showing that V2 antagonism with OPC-31260 after subarachnoid hemorrhage or cerebral ischemia led to an enhancement in AVP levels (Laszlo et al., 1999; Molnar et al., 2008). These studies also opposed the notion described above that V2 antagonism provides no benefit after brain injury by indicating that V2 antagonism attenuates the accumulation of cerebral water content and cerebral sodium (Manaenko et al., 2011b; Kleindienst et al., 2013). In another study, ET-1 was overexpressed in astrocytes, resulting in more severe injury after ischemic stroke associated with increased cerebral water content and increased AQP-4 expression. Subsequent V2 antagonism with OPC-31260 led to a significant decrease in AQP-4 expression in the endfeet of hippocampal astrocytes and an overall decrease in cerebral water accumulation (Yeung et al., 2009). MIXED VASOPRESSIN RECEPTOR ANTAGONISM When targeting vasopressin receptors for brain injury, V1a antagonism is crucial, inasmuch as the literature indicates a strong role of the V1a receptor in the pathogenesis of secondary brain damage after initial injury. However, mixed vasopressin antagonists may be of value in additionally targeting any potential V2-mediated positive feedback to increase AVP expression after stroke (Landgraf et al., 1991; Laszlo et al., 1999; Molnar et al., 2008). Although the studies on mixed vasopressin receptor antagonists are limited, they reveal significant potential in vasopressin modulation for the future treatment of brain injuries and brain fluid disorders. Perhaps the most well-known use of mixed vasopressin antagonists is in the context of syndrome of inappropriate antidiuretic hormone secretion (SIADH) and euvolemic hyponatremia, a condition for which the FDA approved treatment with the nonpeptide vasopressin V1a and V2 antagonist conivaptan in 2005 (Walter, 2007). In one study, 13 patients had mean pretreatment serum sodium of 125.8 6 3.5 mEq/liter. After 12 hr of conivaptan treatment, average serum sodium rose to 132 6 5.6 mEq/liter and 134.1 6 4.7 mEq/liter at 24 hr (Potts et al., 2011). Similar results were obtained in patients developing hyponatremia in the neurological intensive care unit (Murphy et al., 2009) and after severe traumatic brain injury (Galton et al., 2011), showing that mixed vasopressin antagonists are safe for use in acute brain conditions and may actually help reduce ICP (Galton et al., 2011). In a case report of a 22-year-old patient with hyponatremia after traumatic brain injury, a single dose of conivaptan led to simultaneous increase in serum sodium, with a concomitant drop in ICP and subsequent augmentation of cerebral perfusion pressure (Dhar and MurphyHuman, 2011). Mixed vasopressin antagonists are currently approved to treat euvolemic hyponatremia while also being studied in other conditions, including decompensated heart failure and chronic heart failure (Walter, 2007). They have shown promise in the treatment of traumatic brain injury and increased ICP. The studies

Fig. 1. Conivaptan’s effect on brain edema. Experimental murine stroke model shows more than 50% improvement in brain edema after administration of a mixed vasopressin antagonism (unpublished data). At 12 hr, brain edema had a significant decrease (P 5 0.0003) in the conivaptan animals (n 5 16) vs. control animals (n 5 16). Moreover, at 24 hr, brain edema was reduced significantly (P 5 0.002) in the conivaptan group (n 5 12) compared with the control group (n 5 12).

reviewed here indicate that mixed vasopressin antagonists may have valuable treatment implications in a number of overlapping brain conditions, including cerebral edema and increased ICP after stroke, ICH, and traumatic brain injury. A summary of the aforementioned studies are presented in Table I. We have successfully demonstrated the beneficial effect of mixed vasopressin antagonism in ameliorating brain edema in an experimental stroke model (Ansari et al., 2013). Mice were randomized to receive conivaptan or 5% dextrose (control group) after middle cerebral artery reperfusion at 12 hr and 24 hr time points. At 12 hr, ipsilateral average hemispheric edema (HE%) in the conivaptan-treated group (n 5 16) was 6.64% 6 1.62% vs. 16.55% 6 1.76% in controls (n 5 16, P 5 0.0003). This was reproduced at 24 hr, when HE% in the conivaptantreated group (n 5 12) was 6.81% 6 1.33% in comparison with 13.93% 6 1.57% in the control group (n 5 12, P 5 0.002). Average percentage of hemispheric enlargement at both early time points (12 and 24 hr) was reduced by administration of CV (Fig. 1). This study will answer some questions about the role of mixed vasopressin antagonist (conivaptan) in reducing brain edema and also its mechanism of action in attenuation of brain edema by concentrating specifically on AQP channels and its ligands (unpublished data). CONCLUSIONS Little doubt exists about vasopressin’s role in stroke injury. Antagonism of vasopressin receptors by using novel ligands has shown great promise in experimental stroke and may very well serve as the basis for Journal of Neuroscience Research

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