Sulfonylurea receptor 1 in central nervous system injury: a focused review.
The sulfonylurea receptor 1 (Sur1)-regulated NC(Ca-ATP) channel is a nonselective cation channel that is regulated by intracellular calcium and adenosine triphosphate. The channel is not constitutively expressed, but is transcriptionally upregulated de novo in all cells of the neurovascular unit, in many forms of central nervous system (CNS) injury, including cerebral ischemia, traumatic brain injury (TBI), spinal cord injury (SCI), and subarachnoid hemorrhage (SAH). The channel is linked to microvascular dysfunction that manifests as edema formation and delayed secondary hemorrhage. Also implicated in oncotic cell swelling and oncotic (necrotic) cell death, the channel is a major molecular mechanism of 'accidental necrotic cell death' in the CNS. In animal models of SCI, pharmacological inhibition of Sur1 by glibenclamide, as well as gene suppression of Abcc8, prevents delayed capillary fragmentation and tissue necrosis. In models of stroke and TBI, glibenclamide ameliorates edema, secondary hemorrhage, and tissue damage. In a model of SAH, glibenclamide attenuates the inflammatory response due to extravasated blood. Clinical trials of an intravenous formulation of glibenclamide in TBI and stroke underscore the importance of recent advances in understanding the role of the Sur1-regulated NC(Ca-ATP) channel in acute ischemic, traumatic, and inflammatory injury to the CNS.
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA. msimard@smail.umaryland.edu
J Marc
JM
Simard
S Kyoon
SK
Woo
Gary T
GT
Schwartzbauer
Volodymyr
V
Gerzanich
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001812:Blood-Brain Barrier; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D002490:Central Nervous System / Q000293:injuries* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D009336:Necrosis; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011955:Receptors, Drug / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism; D064233:Sulfonylurea Receptors; D013489:Suppression, Genetic; D015854:Up-Regulation
C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors