Abstract
SummarySwelling of the brain or spinal cord (CNS edema) affects millions of people every year. All potential pharmacological interventions have failed in clinical trials, meaning that symptom management is the only treatment option. The water channel protein aquaporin-4 (AQP4) is expressed in astrocytes and mediates water flux across the blood-brain and blood-spinal cord barriers. Here we show that AQP4 cell-surface abundance increases in response to hypoxia-induced cell swelling in a calmodulin-dependent manner. Calmodulin directly binds the AQP4 carboxyl terminus, causing a specific conformational change and driving AQP4 cell-surface localization. Inhibition of calmodulin in a rat spinal cord injury model with the licensed drug trifluoperazine inhibited AQP4 localization to the blood-spinal cord barrier, ablated CNS edema, and led to accelerated functional recovery compared with untreated animals. We propose that targeting the mechanism of calmodulin-mediated cell-surface localization of AQP4 is a viable strategy for development of CNS edema therapies.
Highlights
Swelling of the brain or spinal cord is a result of increased CNS water content and can occur after trauma, infection, tumor growth, or obstruction of blood supply (Jha et al, 2019; Liang et al, 2007)
When normoxic primary cortical astrocytes were treated with 5% oxygen, AQP4 cell-surface abundance increased over 6 h of hypoxia compared with untreated normoxic astrocytes (Figure 1B)
The increase in shrinkage rate constant for human primary cortical astrocytes treated with 5% oxygen for 6 h compared with controls mirrored the increase seen in AQP4 surface localization in the same cells (Figure 1A)
Summary
Swelling of the brain or spinal cord (known as central nervous system [CNS] edema) is a result of increased CNS water content and can occur after trauma, infection, tumor growth, or obstruction of blood supply (Jha et al, 2019; Liang et al, 2007). Traumatic injury and stroke are major causes; according to World Health Organization (WHO) data, worldwide each year, 60 million people sustain a traumatic brain or spinal cord injury (TBI or SCI), and 15 million people suffer a stroke (5 million die, another 5 million are permanently disabled). These injuries can be fatal or lead to long-term disability, psychiatric disorders, substance abuse, or self-harm (Fazel et al, 2014). Cytotoxic edema is the accumulation of water in intact cells It is rapidly triggered when a state of hypoxia causes loss of energy-dependent solute homeostasis (Bordone et al, 2019). Cytotoxic and vasogenic edema are key interdependent contributors to the development of CNS edema, with extended periods of cytotoxic edema inducing vasogenic edema and vice versa (Jha et al, 2019)
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