Activation of NF-κB mediates astrocyte swelling and brain edema in traumatic brain injury.
Brain edema and associated increased intracranial pressure are major consequences of traumatic brain injury (TBI). While astrocyte swelling (cytotoxic edema) represents a major component of the brain edema in the early phase of TBI, its mechanisms are unclear. One factor known to be activated by trauma is nuclear factor-κB (NF-κB). Because this factor has been implicated in the mechanism of cell swelling/brain edema in other neurological conditions, we examined whether NF-κB might also be involved in the mediation of post-traumatic astrocyte swelling/brain edema. Here we show an increase in NF-κB activation in cultured astrocytes at 1 and 3 h after trauma (fluid percussion injury, FPI), and that BAY 11-7082, an inhibitor of NF-κB, significantly blocked the trauma-induced astrocyte swelling. Increased activities of nicotinamide adenine dinucleotide phosphate-oxidase and the Na(+), K(+), 2Cl(-) cotransporter were also observed in cultured astrocytes after trauma, and BAY 11-7082 reduced these effects. We also examined the role of NF-κB in the mechanism of cell swelling by using astrocyte cultures derived from transgenic (Tg) mice with a functional inactivation of astrocytic NF-κB. Exposure of cultured astrocytes from wild-type mice to in vitro trauma (3 h) caused a significant increase in cell swelling. By contrast, traumatized astrocyte cultures derived from NF-κB Tg mice showed no swelling. We also found increased astrocytic NF-κB activation and brain water content in rats after FPI, while BAY 11-7082 significantly reduced such effects. Our findings strongly suggest that activation of astrocytic NF-κB represents a key element in the process by which cytotoxic brain edema occurs after TBI.
1 Department of Pathology, University of Miami School of Medicine and Veterans Affairs Medical Center , Miami, Florida.
Arumugam R
AR
Jayakumar
Xiao Y
XY
Tong
Roberto
R
Ruiz-Cordero
Amade
A
Bregy
John R
JR
Bethea
Helen M
HM
Bramlett
Michael D
MD
Norenberg
D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D015153:Blotting, Western; D001929:Brain Edema / Q000473:pathology*; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats
D016328:NF-kappa B
NF-κB, traumatic brain injury; astrocyte swelling; transgenic mice