title: Novel treatment targets for cerebral edema.
abstract: 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 NC(Ca-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.
authors: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Brian P
authors: BP
authors: Walcott
authors: Kristopher T
authors: KT
authors: Kahle
authors: J Marc
authors: JM
authors: Simard
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000627:therapeutic use; D001929:Brain Edema / Q000209:etiology / Q000473:pathology / Q000628:therapy; D002034:Bumetanide; D002540:Cerebral Cortex / Q000503:physiopathology*; D006801:Humans; D009422:Nervous System Diseases / Q000150:complications*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D064233:Sulfonylurea Receptors
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; C578877:SLC12A2 protein, human; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D064233:Sulfonylurea Receptors; C106389:conivaptan; D002034:Bumetanide