Alterations in cellular membrane structure and the subsequent failure of its function after CNS ischemia were monitored by analyzing changes in the plasma membrane marker enzyme (Na+ + K+‐ATPase. The levels of two isozymes of Na+ + K+)‐ATPase, α+ and α, which have distinct cellular and anatomical distributions, were studied to determine if differential cellular damage occurs in primary and peri‐ischemic injury areas. The efficacy of monosialoganglioside (GM1) treatment was assessed, since this glycosphingolipid has been shown to reduce ischemic injury by protecting cell membrane structure/function. Using a rat model of cortical focal ischemia, levels of both ATPase isozyme activities were assayed in total membrane fractions from primary ischemic tissue (parietal cortex) and three peri‐ischemic tissue areas (frontal, occipital, and temporal cortex) at 1, 3, 5, 7, and 14 days after ischemia. No significant loss of either isozyme's activity occurred in any tissue area at 1 day after ischemia. At 5 dyas, in the primary ischemic area, both isozyme activity levels decreased by 70–75%. The α+ enzyme activity loss persisted up to 14 days, while a 17% recovery in α activity occurred. In the three peri‐ischemic tissue areas, enzyme activity losses ranged from 42%–59% at 3 days after ischemia. A complete restoration of both isozyme activities was seen at 14 days. After three days of GM1 ganglioside treatment there was no loss of total (Na+ + K+)‐ATPase activity in the three peri‐ischemic areas, and a significantly reduced loss in the primary infarct tissue. An autoradiographic analysis of brain coronal sections using 3H‐ouabain supports the enzymatic data and GM1 effects. Reductions in 3H‐ouabain binding in all cortical layers at 3 days after ischemia were visualized. GM1 treatment significantly reduced these 3H‐ouabain binding losses. In summary, time‐dependent quantitative changes in activity levels of ATPase isozymes (α+ and α) reflect the different degree of membrane damage that occurs in primary vs. peri‐ischemic tissues (e.g., irreversible vs. reversible membrane damage), and that ischemia affects cell membranes of all neural elements in a largely similar fashion. GM1 ganglioside was found to reduce plasma membrane damage in all CNS cell types. © 1992 Wiley‐Liss, Inc. Copyright © 1992 Wiley‐Liss, Inc.