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The Journal of Neuroscience, May 15, 1998, 18(10):3554-3562

Effects of Glucose Deprivation, Chemical Hypoxia, and Simulated Ischemia on Na⁺ Homeostasis in Rat Spinal Cord Astrocytes

Christine R. Rose^{1, 2}, Stephen G. Waxman^{1, 2}, and Bruce R. Ransom³

¹ Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520, ² Neuroscience Research Center, VA Hospital, West Haven, Connecticut 06516, and ³ Department of Neurology, University of Washington School of Medicine, Seattle, Washington 98195-6465

A steep inwardly directed Na⁺ gradient is essential for glial functions such as glutamate reuptake and regulation of intracellular ion concentrations. We investigated the effects of glucose deprivation, chemical hypoxia, and simulated ischemia on intracellular Na⁺ concentration ([Na⁺]_i) in cultured spinal cord astrocytes using fluorescence ratio imaging with sodium-binding benzofuran isophthalate (SBFI) AM. Glucose removal or chemical hypoxia (induced by 10 mM NaN₃) for 60 min increased [Na⁺]_i from a baseline of 8.3 to 11 mM. Combined glycolytic and respiratory blockage by NaN₃ and 0 glucose saline caused [Na⁺]_i to increase by 20 mM, similar to the [Na⁺]_i increases elicited by blocking the Na⁺/K⁺-ATPase with ouabain. Recovery from large [Na⁺]_i increases (>15 mM) induced by the glutamatergic agonist kainate was attenuated during glucose deprivation or NaN₃ application and was blocked in NaN₃ and 0 glucose. To mimic in vivo ischemia, we exposed astrocytes to NaN₃ and 0 glucose saline containing L-lactate and glutamate with increased [K⁺] and decreased [Na⁺], [Ca²⁺], and pH. This induced an [Na⁺]_i decrease followed by an [Na⁺]_i rise and a further [Na⁺]_i increase after reperfusion with standard saline. Similar multiphasic [Na⁺]_i changes were observed after NaN₃ and 0 glucose saline with only reduced [Na⁺]_e. Our results suggest that the ability to maintain a low [Na⁺]_i enables spinal cord astrocytes to continue uptake of K⁺ and/or glutamate at the onset of energy failure. With prolonged energy failure, however, astrocytic [Na⁺]_i rises; with loss of their steep transmembrane Na⁺ gradient, astrocytes may aggravate metabolic insults by carrier reversal and release of acid, K⁺, and/or glutamate into the extracellular space.

Key words: glia; hypoglycemia; anoxia; sodium-binding benzofuran isophthalate; Na⁺/K⁺-ATPase; kainate; excitotoxicity

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18103554-09$05.00/0

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