Suppression of aquaporin-4 by antisense oligonucleotides reduces brain edema in experimental traumatic brain injury

Abstract

AIM: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. MATERIAL and METHODS: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. RESULTS: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. CONCLUSION:This study demonstrated that AQP4-ASO therapy, when administered early after diffuse traumatic brain injury, leads to a significant reduction in brain edema.

Aquaporins: Gatekeepers of Fluid Dynamics in Traumatic Brain Injury

“…It is plausible that intervening early, prior to the onset of cytotoxic edema within hours of trauma, could yield more promising results. Hence, adjusting the dosage of the antisense or altering the timing of administration might warrant consideration [ 145 ].…”

“…Antisense oligonucleotides Bind to mRINA, prevent AQP4 functional protein formation, reduce edema if administered early [145] Minocycline Suppresses AQP4 expression post-TBI, protects BBB integrity, modulates astrocyte characteristics [146] Acetazolamide Inhibits CA, prevents AQP4 redistribution post-TBI, mitigates cytotoxic edema [147] miR-211-5p Regulates MMP9/AQP4 axis, therapeutic potential for TBI treatment by targeting this pathway [148] Trifluoperazine Reduces AQP4 accumulation, mitigates brain edema, reduces neurological severity post-TBI [149][150][151] Adenine dinucleotide phosphate oxidase 2 NOX2 inhibition reduces AQP4 levels, enhances cognitive function, reduces brain edema post-TBI [152] Hypertonic saline Reduces AQP4, TNFa, IL-1B levels, and brain water contact, suppresses apoptosis post-TBI [153] Monocyte locomotion inhibitor factor Reduces brain water content, suppresses AQP4 suppression, provides protection against TBI [154,155] Lentivirus-mediated AQP4 gene silencing Reduces AQP4 expression, mitigates brain edema, reduces neurological deficits and neuronal apoptosis post-TBI [156] Omega-3 polyunsaturated fatty acids Improve glymphatic clearance, reduce AB42 accumulation, protect BBB integrity post-TBI [162] Angiotensin II type 1 receptor Deficiency preserves BBB integrity, reduces AQP4 polarization, improves glymphatic function, and AB clearance post-TBI [158] Melatonin receptors Interaction with estrogen may reduce BBB permeability, influence AQP4 expression [160] Arginin and laminin Regulate BBB integrity and AQP4 polarization, important for astrocyte migration and plasticity [161] Future research should focus on developing specific inhibitors and modulators of AQP channels, particularly AQP4, to directly intervene in the edema formation process. Additionally, the exploration of gene silencing techniques, such as the use of antisense oligonucleotides, and the modulation of aquaporin expression through pharmacological agents or dietary supplements like Omega-3 PUFAs could provide new therapeutic avenues.…”