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

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 la 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 5 h 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 mu m(2)) versus sham groups (78.3 +/- 0.1%; 9.5 +/- 0.91 mu m(2)), and SR49059 blunted CCI-induced increases in brain edema (79.0 +/- 0.2%; 9.4 +/- 00.8 mu m(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 +/- 30.04, 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 VlaR inhibition with SR49059 suppressed injury-induced up regulation of GFAP, VIA 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. (C) 2014 Elsevier B.V. All rights reserved.