VULNERABILITY TO GLUCOSE DEPRIVATION INJURY CORRELATES WITH GLUTATHIONE LEVELS IN ASTROCYTES

Astrocyte death from glucose deprivation appears to be mediated by fre e radicals. Reduced glutathione (GSH) was used as a measure of antioxi dant defenses in primary cultures of cortical astrocytes. Glucose depr ivation caused progressive, near complete loss of reduced glutathione (GSH). Astrocytes were protected by increasing endogenous GSH levels. Depletion of GSH to 21.4 +/- 3.3% of controls by the glutathione synth etase inhibitor buthionine sulfoximine resulted in more rapid injury b y glucose deprivation, yet depletion of glutathione alone did not kill astrocytes. Both enhanced lipid peroxidation and membrane rigidificat ion were caused by glucose deprivation, both indicators of oxidative d amage. Membrane peroxidation was detected as a 24 +/- 2% decrease in c is-parinaric acid fluorescence, membrane rigidification as a 6.3 +/- 0 .8% increase in fluorescence anisotropy using diphenylhexatriene. Gluc ose deprivation under normoxic conditions may occur clinically in pati ents such as diabetics. In addition, oxidative damage in the setting o f energy depletion occurs with other insults, including ischemic brain injury. Glucose deprivation may thus be a clinically relevant model o f hypoglycemic astrocyte injury, and may be useful to investigate the effects of glutathione and redox modulation on second messenger system s and gene regulation.