Suppression of Aquaporin-4 by Antisense Oligonucleotides Reduces Brain Edema in Experimental Traumatic Brain Injury

To investigate the suppression of aquaporin-4 (AQP4) synthesis through intracerebroventricular (i.c.v.) injection of antisense oligonucleotide after focal cortical contusion injury in mice.

This study used 12-week-old female Swiss albino mice (weight, 20-25 g) to create a focal cortical contusion model by the weight-drop method (35 g blunt weight, 70 cm height) onto the parietal cortex after craniectomy. The sham group underwent craniectomy without trauma. In the control group, weight was dropped onto the parietal cortex immediately after i.c.v. injection of Dulbecco's Modified Eagle Medium after craniectomy. In addition, 1 nM of aquaporin-4 (AQP4) antisense oligonucleotide (ASO) was injected via the i.c.v. route immediately after trauma (0 hour) and 4 hours after trauma. All animals underwent magnetic resonance (MR) imaging and were sacrificed at 24 hours. The brain?water content was determined using the wet/dry weight method.

In the sham group, the average percentage of the brain?water content was 77.75% compared with the control group with 79.87%, and the difference was significant (p=0.017). The average was 78.81% and significantly reduced in the therapy group compared with the control group (p=0.026) at 0 hour. In the 4-hour treatment group, the average of 79.11% was not significant (p=0.39). MR imaging findings also showed a substantial reduction in brain edema in the 0-h treatment group. However, the 4-h treatment results, when compared with the control trauma group, did not show a significant difference.

This study demonstrated that AQP4-ASO therapy, when administered early after diffuse traumatic brain injury, leads to a significant reduction in brain edema.