title: Selective vasopressin-1a receptor antagonist prevents brain edema, reduces astrocytic cell swelling and GFAP, V1aR and AQP4 expression after focal traumatic brain injury.
abstract: A secondary and often lethal consequence of traumatic brain injury is cellular edema that we posit is due to astrocytic swelling caused by transmembrane water fluxes augmented by vasopressin-regulated aquaporin-4 (AQP4). We therefore tested whether vasopressin 1a receptor (V1aR) inhibition would suppress astrocyte AQP4, reduce astrocytic edema, and thereby diminish TBI-induced edematous changes. V1aR inhibition by SR49059 significantly reduced brain edema after cortical contusion injury (CCI) in rat 5h post-injury. Injured-hemisphere brain water content (n=6 animals/group) and astrocytic area (n=3/group) were significantly higher in CCI-vehicle (80.5±0.3%; 18.0±1.4 µm(2)) versus sham groups (78.3±0.1%; 9.5±0.9 µm(2)), and SR49059 blunted CCI-induced increases in brain edema (79.0±0.2%; 9.4±0.8µm(2)). CCI significantly up-regulated GFAP, V1aR and AQP4 protein levels and SR49059 suppressed injury induced up regulation (n=6/group). In CCI-vehicle, sham and CCI-SR49059 groups, GFAP was 1.58±0.04, 0.47±0.02, and 0.81±0.03, respectively; V1aR was 1.00±0.06, 0.45±0.05, and 0.46±0.09; and AQP4 was 2.03±0.34, 0.49±0.04, and 0.92±0.22. Confocal immunohistochemistry gave analogous results. In CCI-vehicle, sham and CCI-SR49059 groups, fluorescence intensity of GFAP was 349±38, 56±5, and 244±30, respectively, V1aR was 601±71, 117.8±14, and 390±76, and AQP4 was 818±117, 158±5, and 458±55 (n=3/group). The results support that edema was predominantly cellular following CCI and documented that V1aR inhibition with SR49059 suppressed injury-induced up regulation of GFAP, V1A and AQP4, blunting edematous changes. Our findings suggest V1aR inhibitors may be potential therapeutic tools to prevent cellular swelling and provide treatment for post-traumatic brain edema.
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA; Department of Physiology and Biophysics, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA. Electronic address: crmarmar@vcu.edu.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Marmarou
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA.
authors.forename: Xiuyin
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA.
authors.forename: Naqeeb H
authors.initials: NH
authors.lastname: Abidi
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA.
authors.forename: Shanaz
authors.initials: S
authors.lastname: Parveen
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Taya
authors.affiliation: Department of Anatomy and Neurobiolog, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Henderson
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA.
authors.forename: Harold F
authors.initials: HF
authors.lastname: Young
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA.
authors.forename: Aristotelis S
authors.initials: AS
authors.lastname: Filippidis
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA.
authors.forename: Clive M
authors.initials: CM
authors.lastname: Baumgarten
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists / Q000494:pharmacology; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D001929:Brain Edema / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D018613:Microscopy, Confocal; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000378:metabolism
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D018696:Neuroprotective Agents; D011759:Pyrrolidines; D017483:Receptors, Vasopressin; C582098:V1a vasopressin receptor, rat; C082134:relcovaptan
keywords: Aquaporin 4; Astrocyte; Edema; SR49059; Traumatic brain injury; Vasopressin