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The Journal of Neuroscience, June 15, 2003, 23(12):5061-5068
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Na-K-Cl Cotransporter Contributes to Glutamate-Mediated Excitotoxicity
Joe Beck,1,3 Brett Lenart,1 Douglas B. Kintner,1 andDandan Sun1,2 Department of 1Neurological Surgery, 2Physiology, and 3Pathology, University of Wisconsin Medical School, Madison, Wisconsin 53792
We hypothesized that cation-dependent Cl- transport protein Na-K-Cl cotransporter isoform 1 (NKCC1) plays a role in the disruption of ion homeostasis in cerebral ischemia. In the current study, a role for NKCC1 in neuronal death was elucidated in neurotoxicity induced by glutamate and oxygen and glucose deprivation (OGD). Incubation of cortical neurons cultured for 14–15 d in vitro (DIV) with 100 µM glutamate for 24 hr resulted in 50% cell death. Three hours of OGD followed by 21 hr of reoxygenation led to 70% cell death. Inhibition of NMDA receptors with dizocilpine hydrogen maleate (1 µM) prevented both OGD- and glutamate-mediated cell death. Moreover, blocking of NKCC1 activity with bumetanide (5–10 µM) abolished glutamate- or OGD-induced neurotoxicity. Bumetanide was ineffective if added after 10–120 min of glutamate incubation or 3–6 hr of OGD treatment. Accumulation of intracellular Na+ and 36Cl content after NMDA receptor activation was inhibited by bumetanide. Blockage of NKCC1 significantly attenuated cell swelling after OGD or NMDA receptor activation. This neuroprotection was age dependent. Inhibition of NKCC1 did not protect DIV 7–8 neurons against OGD-mediated cell death. In contrast, cell death in DIV 7–8 neurons was prevented by the protein-synthesis inhibitor, cycloheximide. Taken together, the results suggest that NKCC1 activity is involved in the acute excitotoxicity as a result of excessive Na+ and Cl- entry and disruption of ion homeostasis.
Key words: excitotoxicity; active Cl- transport; Na+ entry; cell volume; necrosis; bumetanide
Received Dec. 17, 2002; revised Apr. 4, 2003; accepted Apr. 7, 2003.
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