NKCC1-mediated traumatic brain injury-induced brain edema and neuron death via Raf/MEK/MAPK cascade.
OBJECTIVE
Brain edema is one of the characteristic features of patients with severe traumatic brain injury. The aim of this study was to examine the effects of Na+-K+-2Cl- co-transporter on traumatic brain injury-induced brain edema and neuron damage and to elucidate the relationship between Na+-K+-2Cl- co-transporter and mitogen-activated protein kinase (MAPK) cascade.


METHODS
Laboratory investigation.


METHODS
University research laboratory.


METHODS
Male Wistar rats weighing 350-400 g.


METHODS
Anesthetized animals were subjected to a weight-drop device (450-g weight, 1.8-m height) to induce traumatic brain injury.


RESULTS
The expression of Na+-K+-2Cl- co-transporter and phosphorylation of MAPK cascade were determined by Western blot test. We also analyzed the degree of brain edema and neuronal damage in this study. We found that the messenger RNA and protein of Na+-K+-2Cl- co-transporter were up-regulated mainly in hippocampus neurons from 2 to 24 hrs after traumatic brain injury. After traumatic brain injury, animals displayed severe brain edema and neuron damage. The phosphorylation of extracellular signal-regulated kinase, MAPK kinase, and Raf also was significantly elevated after traumatic brain injury. Bumetanide (15.2 mg/kg), a specific Na+-K+-2Cl- co-transporter inhibitor, significantly attenuated the neuronal damage and brain edema after traumatic brain injury by decreasing the phosphorylation of Raf/MEK/ERK cascade proteins.


CONCLUSIONS
The present study suggests that Na+-K+-2Cl- co-transporter plays an important role in TBI-induced brain edema and neuronal damage via activation of MAPK cascade.
Lu
Kwok-Tung
KT
Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
Cheng
Nai-Chi
NC
Wu
Chang-Yen
CY
Yang
Yi-Ling
YL
D000818:Animals; D001929:Brain Edema / Q000209:etiology*; D001930:Brain Injuries / Q000150:complications*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D028021:Sodium-Potassium-Chloride Symporters / Q000502:physiology*; D064506:Solute Carrier Family 12, Member 2; D048490:raf Kinases / Q000502:physiology*
C578879:Slc12a2 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D048490:raf Kinases; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases