Molecular mechanisms of ischemic cerebral edema: role of electroneutral ion transport.
The brain achieves homeostasis of its intracellular and extracellular fluids by precisely regulating the transport of solute and water across its major cellular barriers: endothelia of the blood-brain barrier (BBB), choroid plexus epithelia, and neuroglial cell membranes. Cerebral edema, the pathological accumulation of fluid in the brain's intracellular and extracellular spaces, is a major cause of morbidity and mortality following stroke and other forms of ischemic brain injury. Until recently, mechanisms of cerebral edema formation have been obscure; consequently, its treatment has been empiric and suboptimal. Here, we provide a paradigm for understanding ischemic cerebral edema, showing that its molecular pathogenesis is a complex yet step-wise process that results largely from impaired astrocytic cell volume regulation and permeability alterations in the cerebral microvasculature, both of which arise from pathological changes in the activities of specific ion channels and transporters. Recent data has implicated the bumetanide-sensitive NKCC1, an electroneutral cotransporter expressed in astrocytes and the BBB, in cerebral edema formation in several different rodent models of stroke. Pharmacological inhibition or genetic deficiency of NKCC1 decreases ischemia-induced cell swelling, BBB breakdown, cerebral edema, and neurotoxicity. Combination pharmacological strategies that include NKCC1 as a target might thus prove beneficial for the treatment of ischemic, and potentially other types of, cerebral edema.
Kahle
Kristopher T
KT
Departments of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. kkahle@partners.org
Simard
J Marc
JM
Staley
Kevin J
KJ
Nahed
Brian V
BV
Jones
Pamela S
PS
Sun
Dandan
D
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001929:Brain Edema / Q000209:etiology / Q000503:physiopathology*; D002545:Brain Ischemia / Q000150:complications / Q000503:physiopathology*; D002463:Cell Membrane Permeability / Q000502:physiology; D004727:Endothelium / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D017136:Ion Transport / Q000502:physiology*; D028021:Sodium-Potassium-Chloride Symporters / Q000502:physiology; D064506:Solute Carrier Family 12, Member 2
C578877:SLC12A2 protein, human; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2