Novel Treatment Targets for Cerebral Edema

Brian P. Walcott Kristopher T. Kahle J. Marc Simard 0 ) Department of Neurosurgery, University of Maryland School of Medicine , Baltimore, MD 21201, USA Cerebral edema is a common finding in a variety of neurological conditions, including ischemic stroke, traumatic brain injury, ruptured cerebral aneurysm, and neoplasia. With the possible exception of neoplasia, most pathological processes leading to edema seem to share similar molecular mechanisms of edema formation. Challenges to brain-cell volume homeostasis can have dramatic consequences, given the fixed volume of the rigid skull and the effect of swelling on secondary neuronal injury. With even small changes in cellular and extracellular volume, cerebral edema can compromise regional or global cerebral blood flow and metabolism or result in compression of vital brain structures. Osmotherapy has been the mainstay of pharmacologic therapy and is typically administered as part of an escalating medical treatment algorithm that can include corticosteroids, diuretics, and pharmacological cerebral metabolic suppression. Novel treatment targets for cerebral edema include the Na(+)-K(+)-2Cl() co-transporter (NKCC1) and the SUR1-regulated NCCa-ATP (SUR1/TRPM4) channel. These two ion channels have been demonstrated to be critical mediators of edema formation in brain-injured states. Their specific inhibitors, bumetanide and glibenclamide, respectively, are well-characterized Food and Drug Administration-approved drugs with excellent safety profiles. Directed inhibition of these ion transporters has the potential to reduce the development of cerebral edema and is currently being investigated in human clinical trials. Another class of treatment agents for cerebral edema is vasopressin receptor antagonists. Euvolemic hyponatremia is present in a myriad of neurological conditions resulting in cerebral edema. A specific antagonist of the vasopressin V1A- and V2-receptor, conivaptan, promotes water excretion while sparing electrolytes through a process known as aquaresis. - Cerebral edema in the neurointensive care setting can occur with a heterogenous group of neurological diseases, which typically fall under the categories of metabolic [1, 2], infectious [3], neoplastic [4], cerebrovascular [57], and traumatic [8, 9] brain injury. Irrespective of the inciting process, cerebral edema results in the pathological accumulation of fluid in the brains intracellular and extracellular spaces. This occurs secondary to alterations in the complex interplay between 4 distinct fluid compartments within the cranium; fluid is present within: 1) the blood in the cerebral blood vessels, 2) the cerebrospinal fluid in the ventricular system and subarachnoid space, 3) the interstitial fluid of the brain parenchyma, and 4) the intracellular fluid of the neurons and glia. These fluid compartments are not isolated, and specific movements of solutes and water from one compartment to another occur under normal conditions. When dysregulation of this normally tightly controlled fluid balance occurs, in either the cerebral endothelial cells or the glia and neurons, volume and solute compositions are pathologically altered. From a fluid mechanics perspective, cerebral edema can result in increased intracranial pressure and death secondary to cerebral compression, due to the confined space within the fixed-volume cranium. Additionally, alterations in the precisely regulated ion gradients that typically exist across neuronal plasma membranes interfere with action potential generation, propagation, and metabolism, leading to dysfunction or death at the cellular level (Table 1). Historical conventions that dichotomize edematous states into cytotoxic or vasogenic categories are fading, as a better understanding of the pathophysiological processes that underlie edema formation in brain-injured states is elucidated. Although it is not optimal to use historical terms to describe new paradigms, conventional terms remain useful for differentiating the sequential events in edema development. After brain injury, alterations in ionic gradients lead to a step-wise temporal progression from what is known as cytotoxic (cellular) edema to ionic edema, and finally to vasogenic edema [10]. Ischemia leads to the cessation of primary active transport via Na+-K+-adenosinetriphosphatase (ATPase). Resultant to this, co-transporters (secondary active transport) and passive transporters (via ion channels) attempt to maintain cellular processes. By doing so, neurons and neuroglia accumulate osmotically active solutes intracellularly that cause cellular swelling and eventually passage of fluid into the extracellular space [11]. Although aquaporin-4 (AQP4), the most abundant water channel in the brain [12], has been implicated in the pathogenesis of post-stroke cerebral edema [1316], the primary driver behind the formation of cytotoxic edema is truly the intracellular accumulation of sodium. Eventually, endothelial and neuroglial dysfunction impairs the ability to maindtain the integrity of the bloodbrain barrier and vasogenic edema ensues. Intracellular accumulation of sodium during the cytotoxic (cellular) edema phase derives from a multitude of Table 1 Novel targets to treat cerebral edema transporters, including ion channels [10]. These ion transport proteins located in the cell membrane are activated or upregulated by factors associated with ischemia, such as elevated levels of extracellular potassium, alterations in pH, inflammatory mediators (such as cytokines), and excitatory neurotransmitters (such as glutamate). An example of this is the NKCC1 transporter, which normally mediates sodium entry into cells [1719]. Another example is an ion channel that has been shown to be transcriptionally upregulated after ischemic injury and trauma (i.e., the SUR1- regulated NCCa-ATP) [SUR1/ TRPM4] channel). Activation of this channel results in the net influx of cations, driving the osmotic influx of water, thereby causing cellular swelling. In this review, we highlight the mainstay of pharmacological treatment for cerebral edema (osmotherapy), and then we focus on emerging treatment targets (i.e., the molecular processes that are actually responsible for edema formation, including the ion transporters, NKCC1 and SUR1/TRPM4, and vasopressin receptors). Cerebral edema (and its effect, elevated intracranial pressure) occurs in a heterogeneous group of conditions treated in the neurointensive care unit. A profound and morbid example can be seen in the development of malignant edema in patients after large vascular territory ischemic stroke [20]. A multi-organ system treatment algorithm is the standard of care, with hyperosmotic therapy, in the form of mannitol and hypertonic saline, being the mainstays of traditional pharmacologic treatment. These powerful medications, which draw fluid into the intravascular space via an osmotic gradient, are effective and their use is widespread. Among (...truncated)