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Acta Neurochirurgica
Published in: Acta Neurochirurgica 1/2013

01-01-2013 | Experimental research - Brain Injury

The role of vasopressin V1A receptors in cytotoxic brain edema formation following brain injury

Authors: Andrea Kleindienst, Jana G. Dunbar, Renee Glisson, Anthony Marmarou

Published in: Acta Neurochirurgica | Issue 1/2013

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Abstract

Background

The hormone and neuropeptide arginine-vasopressin is designated to the maintenance of osmotic homoeostasis and blood pressure regulation. While experimental data show vasopressin V1A receptors to regulate aquaporin (AQP)4 water channel dependent brain water movement, the specific role in vasogenic and cytotoxic edema formation remains unclear. The present study was designed to quantify the V1A receptor mediated regional brain edema formation in two clinically relevant experimental models, brain injury combined with secondary insult and focal ischemia.

Methods

Male Sprague–Dawley rats were randomly assigned to a continuous infusion of vehicle (1 % DMSO) or the selective non-peptide V1A antagonist SR49059 (83nM = 1 mg/kg) starting before controlled cortical impact (CCI) injury plus hypoxia and hypotension (HH, 30 min), or middle cerebral artery (MCA) occlusion (2 h + 2 h reperfusion).

Results

A global analysis of brain water content by the wet/dry weight method allowed optimizing the SR49059 dosage, and demonstrated the down-regulation of brain AQP4 expression by immunoblotting. Microgravimetrical quantification in 64 one mm3 samples per animal (n = 6 per group) from bregma +2.7 to −6.3 mm analysis demonstrated brain edema to be reduced at 4 h by SR49059 treatment in the injured and contralateral cortex following CCI + HH (p = 0.007, p < 0.001) and in the infarct area following MCA occlusion (p = 0.013, p = 0.002, p = 0.004).

Conclusions

Our findings demonstrate that an early cytotoxic brain edema component following brain injury plus secondary insult or focal ischemia results from a vasopressin V1A receptor mediated response, and occurs most likely through AQP4 up-regulation. The V1A antagonist SR49059 offers a new avenue in brain edema treatment and prompts further study into the role of vasopressin following brain injury.
Literature
1.
Amedee T, Robert A, Coles JA (1997) Potassium homeostasis and glial energy metabolism. Glia 21:46–55PubMedCrossRef
2.
Amiry-Moghaddam M, Williamson A, Palomba M, Eid T, de Lanerolle NC, Nagelhus EA, Adams ME, Froehner SC, Agre P, Ottersen OP (2003) Delayed K + clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophin-null mice. Proc Natl Acad Sci USA 100:13615–13620PubMedCrossRef
3.
Ancellin N, Preisser L, Corman B, Morel A (1997) Role of protein kinase C and carboxyl-terminal region in acute desensitization of vasopressin V1a receptor. FEBS Lett 413:323–326PubMedCrossRef
4.
Badaut J, Lasbennes F, Magistretti PJ, Regli L (2002) Aquaporins in brain: distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab 22:367–378PubMedCrossRef
5.
Badaut J, Nehlig A, Verbavatz J, Stoeckel M, Freund-Mercier MJ, Lasbennes F (2000) Hypervascularization in the magnocellular nuclei of the rat hypothalamus: relationship with the distribution of aquaporin-4 and markers of energy metabolism. J Neuroendocrinol 12:960–969PubMedCrossRef
6.
Badaut J, Verbavatz JM, Freund-Mercier MJ, Lasbennes F (2000) Presence of aquaporin-4 and muscarinic receptors in astrocytes and ependymal cells in rat brain: a clue to a common function? Neurosci Lett 292:75–78PubMedCrossRef
7.
Baldwin SA, Fugaccia I, Brown DR, Brown LV, Scheff SW (1996) Blood–brain barrier breach following cortical contusion in the rat. J Neurosurg 85:476–481PubMedCrossRef
8.
Barzo P, Marmarou A, Fatouros P, Corwin F, Dunbar J (1996) Magnetic resonance imaging-monitored acute blood–brain barrier changes in experimental traumatic brain injury. J Neurosurg 85:1113–1121PubMedCrossRef
9.
Baskaya MK, Rao AM, Dogan A, Donaldson D, Dempsey RJ (1997) The biphasic opening of the blood–brain barrier in the cortex and hippocampus after traumatic brain injury in rats. Neurosci Lett 226:33–36PubMedCrossRef
10.
Belayev L, Alonso OF, Busto R, Zhao W, Ginsberg MD (1996) Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke 27:1616–1622, discussion 1623PubMedCrossRef
11.
Bemana I, Nagao S (1999) Treatment of brain edema with a nonpeptide arginine vasopressin V1 receptor antagonist OPC-21268 in rats. Neurosurgery 44:148–154, discussion 154-145PubMedCrossRef
12.
Betz AL, Iannotti F, Hoff JT (1989) Brain edema: a classification based on blood–brain barrier integrity. Cerebrovasc Brain Metab Rev 1:133–154PubMed
13.
de Vries GJ, Miller MA (1998) Anatomy and function of extrahypothalamic vasopressin systems in the brain. Prog Brain Res 119:3–20PubMedCrossRef
14.
Dhillon HS, Donaldson D, Dempsey RJ, Prasad MR (1994) Regional levels of free fatty acids and Evans blue extravasation after experimental brain injury. J Neurotrauma 11:405–415PubMedCrossRef
15.
Dijkhuizen RM, de Graaf RA, Tulleken KA, Nicolay K (1999) Changes in the diffusion of water and intracellular metabolites after excitotoxic injury and global ischemia in neonatal rat brain. J Cereb Blood Flow Metab 19:341–349PubMedCrossRef
16.
Dixon CE, Clifton GL, Lighthall JW, Yaghmai AA, Hayes RL (1991) A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Methods 39:253–262PubMedCrossRef
17.
Fazzina G, Amorini AM, Marmarou C, Fukui S, Okuno K, Glisson R, Marmarou A, Kleindienst A (2009) The PKC Activator Phorbol Myristate Acetate Decreases Brain Edema by AQP4 Down-Regulation Following Middle Cerebral Artery Occlusion in the Rat. J Neurotrauma
18.
19.
Frydenlund DS, Bhardwaj A, Otsuka T, Mylonakou MN, Yasumura T, Davidson KG, Zeynalov E, Skare O, Laake P, Haug FM, Rash JE, Agre P, Ottersen OP, Amiry-Moghaddam M (2006) Temporary loss of perivascular aquaporin-4 in neocortex after transient middle cerebral artery occlusion in mice. Proc Natl Acad Sci U S A 103:13532–13536PubMedCrossRef
20.
Groeger U, Marmarou A (1989) The importance of protein content in the oedema fluid for the resolution of brain oedema. Acta Neurochir (Wien) 101:134–140CrossRef
21.
Hawtin SR (2006) Pharmacological chaperone activity of SR49059 to functionally recover misfolded mutations of the vasopressin V1a receptor. J Biol Chem 281:14604–14614PubMedCrossRef
22.
Innamorati G, Sadeghi H, Birnbaumer M (1998) Transient phosphorylation of the V1a vasopressin receptor. J Biol Chem 273:7155–7161PubMedCrossRef
23.
Ito J, Marmarou A, Barzo P, Fatouros P, Corwin F (1996) Characterization of edema by diffusion-weighted imaging in experimental traumatic brain injury. J Neurosurg 84:97–103PubMedCrossRef
24.
Katan M, Fluri F, Morgenthaler NG, Schuetz P, Zweifel C, Bingisser R, Muller K, Meckel S, Gass A, Kappos L, Steck AJ, Engelter ST, Muller B, Christ-Crain M (2009) Copeptin: a novel, independent prognostic marker in patients with ischemic stroke. Ann Neurol 66:799–808PubMedCrossRef
25.
Ke C, Poon WS, Ng HK, Pang JC, Chan Y (2001) Heterogeneous responses of aquaporin-4 in oedema formation in a replicated severe traumatic brain injury model in rats. Neurosci Lett 301:21–24PubMedCrossRef
26.
27.
Kiening KL, van Landeghem FK, Schreiber S, Thomale UW, von Deimling A, Unterberg AW, Stover JF (2002) Decreased hemispheric Aquaporin-4 is linked to evolving brain edema following controlled cortical impact injury in rats. Neurosci Lett 324:105–108PubMedCrossRef
28.
Kimelberg HK, Rutledge E, Goderie S, Charniga C (1995) Astrocytic swelling due to hypotonic or high K + medium causes inhibition of glutamate and aspartate uptake and increases their release. J Cereb Blood Flow Metab 15:409–416PubMedCrossRef
29.
Klatzo I (1987) Pathophysiological aspects of brain edema. Acta Neuropathol (Berl) 72:236–239CrossRef
30.
Kleindienst A, Brabant G, Morgenthaler NG, Dixit KC, Parsch H, Buchfelder M (2010) Following brain trauma, copeptin, a stable peptide derived from the AVP precusor, does not reflect osmoregulation but correlates with injury severity. Acta Neurochir Suppl 106:221–224PubMedCrossRef
31.
Kleindienst A, Fazzina G, Amorini AM, Dunbar JG, Glisson R, Marmarou A (2006) Modulation of AQP4 expression by the protein kinase C activator, phorbol myristate acetate, decreases ischemia-induced brain edema. Acta Neurochir Suppl 96:393–397PubMedCrossRef
32.
Kleindienst A, Fazzina G, Dunbar JG, Glisson R, Marmarou A (2006) Protective effect of the V1a receptor antagonist SR49059 on brain edema formation following middle cerebral artery occlusion in the rat. Acta Neurochir Suppl 96:303–306PubMedCrossRef
33.
Landgraf R (1992) Central release of vasopressin: stimuli, dynamics, consequences. Prog Brain Res 91:29–39PubMedCrossRef
34.
Lindner KH, Prengel AW, Pfenninger EG, Lindner IM, Strohmenger HU, Georgieff M, Lurie KG (1995) Vasopressin improves vital organ blood flow during closed-chest cardiopulmonary resuscitation in pigs. Circulation 91:215–221PubMedCrossRef
35.
Liu X, Nakayama S, Amiry-Moghaddam M, Ottersen OP, Bhardwaj A (2009) Arginine-Vasopressin V(1) but not V (2) Receptor Antagonism Modulates Infarct Volume, Brain Water Content, and Aquaporin-4 Expression Following Experimental Stroke. Neurocrit Care
36.
Loubinoux I, Volk A, Borredon J, Guirimand S, Tiffon B, Seylaz J, Meric P (1997) Spreading of vasogenic edema and cytotoxic edema assessed by quantitative diffusion and T2 magnetic resonance imaging. Stroke 28:419–426, discussion 426-417PubMedCrossRef
37.
Lu H, Sun SQ (2003) A correlative study between AQP4 expression and the manifestation of DWI after the acute ischemic brain edema in rats. Chin Med J (Engl) 116:1063–1069
38.
Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6:159–163PubMedCrossRef
39.
Marmarou A, Fatouros P, Ward J, Appley A, Young H (1990) In vivo measurement of brain water by MRI. Acta Neurochir Suppl (Wien) 51:123–124
40.
Meinild AK, Klaerke DA, Zeuthen T (1998) Bidirectional water fluxes and specificity for small hydrophilic molecules in aquaporins 0 –5. J Biol Chem 273:32446–32451PubMedCrossRef
41.
Meng S, Qiao M, Lin L, Del Bigio MR, Tomanek B, Tuor UI (2004) Correspondence of AQP4 expression and hypoxic-ischaemic brain oedema monitored by magnetic resonance imaging in the immature and juvenile rat. Eur J Neurosci 19:2261–2269PubMedCrossRef
42.
Nagelhus EA, Horio Y, Inanobe A, Fujita A, Haug FM, Nielsen S, Kurachi Y, Ottersen OP (1999) Immunogold evidence suggests that coupling of K + siphoning and water transport in rat retinal Muller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia 26:47–54PubMedCrossRef
43.
Nakahama K, Nagano M, Fujioka A, Shinoda K, Sasaki H (1999) Effect of TPA on aquaporin 4 mRNA expression in cultured rat astrocytes. Glia 25:240–246PubMedCrossRef
44.
Neely JD, Christensen BM, Nielsen S, Agre P (1999) Heterotetrameric composition of aquaporin-4 water channels. Biochemistry 38:11156–11163PubMedCrossRef
45.
Neumann-Haefelin T, Kastrup A, de Crespigny A, Yenari MA, Ringer T, Sun GH, Moseley ME (2000) Serial MRI after transient focal cerebral ischemia in rats: dynamics of tissue injury, blood–brain barrier damage, and edema formation. Stroke 31:1965–1972, discussion 1972-1963PubMedCrossRef
46.
Newman EA (1995) Glial cell regulation of extracellular potassium. In: Randsom B (ed) Kettenmann H. Neuroglia. Oxford University Press, New York, pp 717–731
47.
Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP (1997) Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17:171–180PubMed
48.
Niermann H, Amiry-Moghaddam M, Holthoff K, Witte OW, Ottersen OP (2001) A novel role of vasopressin in the brain: modulation of activity-dependent water flux in the neocortex. J Neurosci 21:3045–3051PubMed
49.
Okuno K, Taya K, Marmarou CR, Ozisik P, Fazzina G, Kleindienst A, Gulsen S, Marmarou A (2008) The modulation of aquaporin-4 by using PKC-activator (phorbol myristate acetate) and V1a receptor antagonist (SR49059) following middle cerebral artery occlusion/reperfusion in the rat. Acta Neurochir Suppl 102:431–436PubMedCrossRef
50.
Orkand RK, Nicholls JG, Kuffler SW (1966) Effect of nerve impulses on the membrane potential of glial cells in the central nervous system of amphibia. J Neurophysiol 29:788–806PubMed
51.
Papadopoulos MC, Verkman AS (2008) Potential utility of aquaporin modulators for therapy of brain disorders. Prog Brain Res 170:589–601PubMedCrossRef
52.
Pascale CL, Szmydynger-Chodobska J, Sarri JE, Chodobski A (2006) Traumatic brain injury results in a concomitant increase in neocortical expression of vasopressin and its V1a receptor. J Physiol Pharmacol 57(Suppl 11):161–167PubMed
53.
Perez-Pinzon MA, Tao L, Nicholson C (1995) Extracellular potassium, volume fraction, and tortuosity in rat hippocampal CA1, CA3, and cortical slices during ischemia. J Neurophysiol 74:565–573PubMed
54.
Reiber H (2001) Dynamics of brain-derived proteins in cerebrospinal fluid. Clinica Chimica Acta; International Journal of Clinical Chemistry 310:173–186PubMedCrossRef
55.
Saadoun S, Papadopoulos MC (2010) Aquaporin-4 in brain and spinal cord oedema. Neuroscience 168:1036–1046PubMedCrossRef
56.
Schrier RW (2007) The sea within us: disorders of body water homeostasis. Curr Opin Investig Drugs 8:304–311PubMed
57.
Schrier RW, Chen YC, Cadnapaphornchai MA (2004) From finch to fish to man: role of aquaporins in body fluid and brain water regulation. Neuroscience 129:897–904PubMedCrossRef
58.
Serradeil-Le Gal C, Wagnon J, Garcia C, Lacour C, Guiraudou P, Christophe B, Villanova G, Nisato D, Maffrand JP, Le Fur G et al (1993) Biochemical and pharmacological properties of SR 49059, a new, potent, nonpeptide antagonist of rat and human vasopressin V1a receptors. J Clin Invest 92:224–231PubMedCrossRef
59.
Smith SL, Andrus PK, Zhang JR, Hall ED (1994) Direct measurement of hydroxyl radicals, lipid peroxidation, and blood–brain barrier disruption following unilateral cortical impact head injury in the rat. J Neurotrauma 11:393–404PubMedCrossRef
60.
Somjen GG (2002) Ion regulation in the brain: implications for pathophysiology. Neuroscientist 8:254–267PubMed
61.
Stroop R, Thomale UW, Pauser S, Bernarding J, Vollmann W, Wolf KJ, Lanksch WR, Unterberg AW (1998) Magnetic resonance imaging studies with cluster algorithm for characterization of brain edema after controlled cortical impact injury (CCII). Acta Neurochir Suppl 71:303–305PubMed
62.
Taniguchi M, Yamashita T, Kumura E, Tamatani M, Kobayashi A, Yokawa T, Maruno M, Kato A, Ohnishi T, Kohmura E, Tohyama M, Yoshimine T (2000) Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Brain Res Mol Brain Res 78:131–137PubMedCrossRef
63.
Taya K, Marmarou CR, Okuno K, Prieto R, Marmarou A (2010) Effect of secondary insults upon aquaporin-4 water channels following experimental cortical contusion in rats. J Neurotrauma 27:229–239PubMedCrossRef
64.
Thibonnier M, Kilani A, Rahman M, DiBlasi TP, Warner K, Smith MC, Leenhardt AF, Brouard R (1999) Effects of the nonpeptide V(1) vasopressin receptor antagonist SR49059 in hypertensive patients. Hypertension 34:1293–1300PubMedCrossRef
65.
Trabold R, Krieg S, Scholler K, Plesnila N (2008) Role of vasopressin V(1a) and V2 receptors for the development of secondary brain damage after traumatic brain injury in mice. J Neurotrauma 25:1459–1465PubMedCrossRef
66.
Tribollet E, Raufaste D, Maffrand J, Serradeil-Le Gal C (1999) Binding of the non-peptide vasopressin V1a receptor antagonist SR-49059 in the rat brain: an in vitro and in vivo autoradiographic study. Neuroendocrinology 69:113–120PubMedCrossRef
67.
Unterberg AW, Stroop R, Thomale UW, Kiening KL, Pauser S, Vollmann W (1997) Characterisation of brain edema following “controlled cortical impact injury” in rats. Acta Neurochir Suppl 70:106–108PubMed
68.
Vakili A, Kataoka H, Plesnila N (2005) Role of arginine vasopressin V1 and V2 receptors for brain damage after transient focal cerebral ischemia. J Cereb Blood Flow Metab 25:1012–1019PubMedCrossRef
69.
van Balkom BW, Savelkoul PJ, Markovich D, Hofman E, Nielsen S, van der Sluijs P, Deen PM (2002) The role of putative phosphorylation sites in the targeting and shuttling of the aquaporin-2 water channel. J Biol Chem 277:41473–41479PubMedCrossRef
70.
Venero JL, Vizuete ML, Ilundain AA, Machado A, Echevarria M, Cano J (1999) Detailed localization of aquaporin-4 messenger RNA in the CNS: preferential expression in periventricular organs. Neuroscience 94:239–250PubMedCrossRef
71.
Venero JL, Vizuete ML, Machado A, Cano J (2001) Aquaporins in the central nervous system. Prog Neurobiol 63:321–336PubMedCrossRef
72.
Vizuete ML, Venero JL, Vargas C, Ilundain AA, Echevarria M, Machado A, Cano J (1999) Differential upregulation of aquaporin-4 mRNA expression in reactive astrocytes after brain injury: potential role in brain edema. Neurobiol Dis 6:245–258PubMedCrossRef
73.
Yang GY, Betz AL (1994) Reperfusion-induced injury to the blood–brain barrier after middle cerebral artery occlusion in rats. Stroke 25:1658–1664, discussion 1664-1655PubMedCrossRef
Metadata
Title
The role of vasopressin V1A receptors in cytotoxic brain edema formation following brain injury
Authors
Andrea Kleindienst
Jana G. Dunbar
Renee Glisson
Anthony Marmarou
Publication date
01-01-2013
Publisher
Springer Vienna
Published in
Acta Neurochirurgica / Issue 1/2013
Print ISSN: 0001-6268
Electronic ISSN: 0942-0940
DOI
https://doi.org/10.1007/s00701-012-1558-z

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