Neuroinflammation is a common pathological event observed in many different brain diseases, frequently associated with blood brain barrier (BBB) dysfunction and followed by cerebral edema. Neuroinflammation is characterized with microglia activation and astrogliosis, which is a hypertrophy of the astrocytes. Astrocytes express aquaporin 4, the water channel protein, involved in water homeostasis and edema formation. Aside from its function in water homeostasis, recent studies started to show possible interrelations between aquaporin 4 and neuroinflammation. In this review the roles of aquaporin 4 in neuroinflammation associated with BBB disruption and cerebral edema will be discussed with recent studies in the field.

Neuroimaging with diffusion-weighted imaging is routinely used for clinical diagnosis/prognosis. Its quantitative parameter, the apparent diffusion coefficient (ADC), is thought to reflect water mobility in brain tissues. After injury, reduced ADC values are thought to be secondary to decreases in the extracellular space caused by cell swelling. However, the physiological mechanisms associated with such changes remain uncertain. Aquaporins (AQPs) facilitate water diffusion through the plasma membrane and provide a unique opportunity to examine the molecular mechanisms underlying water mobility. Because of this critical role and the recognition that brain AQP4 is distributed within astrocytic cell membranes, we hypothesized that AQP4 contributes to the regulation of water diffusion and variations in its expression would alter ADC values in normal brain. Using RNA interference in the rodent brain, we acutely knocked down AQP4 expression and observed that a 27% AQP4-specific silencing induced a 50% decrease in ADC values, without modification of tissue histology. Our results demonstrate that ADC values in normal brain are modulated by astrocytic AQP4. These findings have major clinical relevance as they suggest that imaging changes seen in acute neurologic disorders such as stroke and trauma are in part due to changes in tissue AQP4 levels.

In cerebrovascular disease, edema formation is frequently observed within the first 7 days and is characterized by molecular and cellular changes in the neurovascular unit. The presence of water channels, aquaporins (AQPs), within the neurovascular unit has led to intensive research in understanding the underlying roles of each of the AQPs under normal conditions and in different diseases. In this review, we summarize some of the recent knowledge on AQPs, focusing on AQP4, the most abundant AQP in the central nervous system. Several experimental models illustrate that AQPs have dual, complex regulatory roles in edema formation and resolution. To date, no specific therapeutic agents have been developed to inhibit water flux through these channels. However, experimental results strongly suggest that this is an important area for future investigation. In fact, early inhibition of water channels may have positive effects in the prevention of edema formation. At later time points during the course of disease, AQP is important for the clearance of water from the brain into blood vessels. Thus, AQPs, and in particular AQP4, have important roles in the resolution of edema after brain injury. The function of these water channel proteins makes them an excellent therapeutic target.

Traumatic brain injury (TBI) is common in young children and adolescents and is associated with long-term disability and mortality. The neuropathologic sequelae that result from juvenile TBI are a complex cascade of events that include edema formation and brain swelling. Brain aquaporin-4 (AQP4) has a key role in edema formation. Thus, development of novel treatments targeting AQP4 to reduce edema could lessen the neuropathologic sequelae. We hypothesized that inhibiting AQP4 expression by injection of small-interfering RNA (siRNA) targeting AQP4 (siAQP4) after juvenile TBI would decrease edema formation, neuroinflammation, neuronal cell death, and improve neurologic outcomes. The siAQP4 or a RNA-induced silencing complex (RISC)-free control siRNA (siGLO) was injected lateral to the trauma site after controlled cortical impact in postnatal day 17 rats. Magnetic resonance imaging, neurologic testing, and immunohistochemistry were performed to assess outcomes. Pups treated with siAQP4 showed acute (3 days after injury) improvements in motor function and in spatial memory at long term (60 days after injury) compared with siGLO-treated animals. These improvements were associated with decreased edema formation, increased microglial activation, decreased blood–brain barrier disruption, reduced astrogliosis and neuronal cell death. The effectiveness of our treatment paradigm was associated with a 30% decrease in AQP4 expression at the injection site.