Cerebral edema is normally a common finding in a number of neurological conditions including ischemic stroke distressing brain injury ruptured cerebral aneurysm and neoplasia. 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 crucial mediators of edema formation in brain-injured says. Their specific inhibitors bumetanide and glibenclamide respectively are well-characterized Food and Drug Administration-approved drugs with excellent security 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 brokers for cerebral edema is usually vasopressin receptor antagonists. Euvolemic hyponatremia is present in a myriad of neurological conditions resulting in cerebral edema. A specific antagonist of the vasopressin V1A- CENPA and V2-receptor conivaptan promotes water excretion while sparing electrolytes through a process known as aquaresis. Electronic supplementary material The online version of this article (doi:10.1007/s13311-011-0087-4) contains supplementary material which is available to authorized users. Keywords: Cerebral edema Hyponatraemia Osmotherapy NKCC1 SUR1/TRPM4 Vaptan Glyburide Overview of Perturbations in Brain Fluid Homeostasis 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  neoplastic  cerebrovascular [5-7] and traumatic [8 9 brain injury. Irrespective of the inciting process cerebral edema results in the pathological accumulation of fluid in the brain’s intracellular and extracellular spaces. This occurs secondary to alterations in the complex interplay between 4 unique 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 HA-1077 2HCl 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). Table 1 Novel targets to treat cerebral edema HA-1077 2HCl Cerebral Edema Historical conventions that dichotomize edematous says into “cytotoxic” or “vasogenic” groups are fading as a better understanding of the pathophysiological processes that underlie edema formation in brain-injured says is elucidated. Although it is not optimal to use historical terms to describe new paradigms standard 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 . Ischemia prospects to the cessation of main 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 HA-1077 2HCl solutes intracellularly that cause cellular swelling and eventually passage of fluid HA-1077 2HCl into the extracellular space . Although aquaporin-4 (AQP4) the most abundant water channel in the brain  has been implicated in the pathogenesis of post-stroke cerebral edema [13-16] the primary driver behind the formation of cytotoxic edema is truly the.