Selective vulnerability and early progression of hippocampal CA1 pyramidal cell degeneration and GFAP-positive astrocyte reactivity in the rat four-vessel occlusion model of transient global ischemia

Selective, delayed-onset vulnerability of hippocampal CA1 pyramidal cells has been reported as a unique phenomenon in man and the rat four-vessel occlusion (4-VO) model of global ischemia. This has become of great interest for clarification of CA1 pathophysiology and pharmacological intervention after global ischemia. Studies of pathophysiology and pharmacotherapy appear to be impeded by variability in specific criteria and duration of 4-VO ischemia for producing selective CA1 and differential CA1-CA3 damage. The goals of this study were to: (1) develop specific criteria for 4-VO ischemia to ensure selective, bilaterally symmetrical CA1 pyramidal cell damage, (2) examine the effects of 15 min of ischemia on concomitant CA1 cell necrosis and presence of remaining and/or “viable” neurons postischemia, (3) compare 15 and 30 min of ischemia on differential vulnerability of CA1-CA3 subfields, and (4) evaluate the effects of 15 min of ischemia on CA1 pyramidal cell necrosis and glial fibrillary acidic protein (GFAP)-positive astrocyte reactivity in CA1. After 15 min of ischemia, hippocampal pyramidal cell damage was well delineated, with CA1 severely damaged, but leaving CA3 virtually intact. In contrast, 30 min of ischemia produced severe CA1 and less severe CA3 necrosis. Histological evaluations across Days 1, 3, 6, and 14 indicated a significant delayed onset of CA1-CA3 cell necrosis by Day 3. Counting of remaining cells indicated a detectable loss of some large pyramidal neurons even 1 day after ischemia. Compared to controls, there was a differential increase in GFAP-positive astrocytes in CA1-CA3 after ischemia. The results provided quantitative data on the effects of specific 4-VO criteria and durations on: (1) selective CA1 cell necrosis, (2) differential CA1-CA3 cell vulnerability, (3) presence of postischemic remaining and/or viable neurons, and (4) prospect of a “therapeutic window” for pharmacological treatment of CA1 neuronal injury.