Modulation of AQP4 expression by the selective V1a receptor antagonist, SR49059, decreases trauma-induced brain edema.
BACKGROUND
Currently, there are no pharmacological treatments available for traumatically induced brain edema and the subsequent rise of ICP. Evidence indicates that Aquaporin-4 (AQP4) plays a significant role in the pathophysiology of brain edema. Previously we have reported that SR49059 reduced brain edema secondary to ischemia. We, therefore, examined whether the selective V1a receptor antagonist, SR49059, reduces brain edema by modulating AQP4 expression following cortical contusion injury (CCI).


METHODS
Traumatic brain injury (TBI) was produced in thirty-two adult male Sprague-Dawley rats by lateral CCI (6.0 m/sec, 3 mm depth). Animals were randomly assigned to vehicle (n=16) or SR49059 treatment (n=16) groups and administered drug (960 microl/hr i.v.) immediately after injury over a 5 hr period. Animals were sacrificed for assessment of brain water content by Wet/Dry method and AQP4 protein expression by immunoblotting expressed as the ratio of AQP4 and Cyclophilin-A densitometries.


RESULTS
Elevated AQP4 expression levels and water content were observed on the right injured side in both the right anterior (RA) and right posterior (RP) section compared to the left non-injured side inclusive of the left anterior (LA) and right anterior (RA) sections. The average AQP4 expression levels in contused areas for animals receiving SR drug treatment (RA: 1.313 +/- 0.172, RP: 1.308 +/- 0.175) were significantly decreased from vehicle-treated animals (RA: 2.181 +/- 0.232, RP: 2.303 +/- 0.370, p = 0.001, p= 0.003). Water content levels on SR treatment (78.89 +/- 0.14) was also significantly decreased from vehicle levels (80.38 +/- 0.38, p < 0.01) in the traumatized hemisphere.


CONCLUSIONS
SR49059 significantly reduced trauma-induced AQP4 up-regulation in the contused hemisphere. Moreover, brain water content was also significantly reduced paralleling the AQP4 suppression. These data provide further support that vasopressin (AVP) and V1a receptors can control water flux through astrocytic plasma membranes by regulating AQP4 expression. Taken in concert, these results affirm our laboratories contention that AQP4 can be effectively modulated pharmacologically.
Taya
Keisuke
K
Department of Neurosurgery, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, P.O. Box 980508, Richmond, VA 23298-0508, USA.
Gulsen
Salih
S
Okuno
Kenji
K
Prieto
Ruth
R
Marmarou
Christina R
CR
Marmarou
Anthony
A
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism*; D001929:Brain Edema / Q000188:drug therapy* / Q000378:metabolism*; D001930:Brain Injuries / Q000150:complications; D004195:Disease Models, Animal; D007839:Functional Laterality; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D011759:Pyrrolidines / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects*
D065092:Antidiuretic Hormone Receptor Antagonists; C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D007211:Indoles; D011759:Pyrrolidines; C082134:relcovaptan