Delayed transient ischemic attacks kill some CA1 neurons previously salvaged with postischemic hypothermia: neuroprotection undone.

Delayed hypothermia reduces ischemic hippocampal CA1 injury. However, there are residual structural and functional abnormalities. Therefore, we studied whether these apparently vulnerable rescued neurons are susceptible to secondary insults. All gerbils were subjected to normothermic forebrain ischemia (ISC, 5 min) or SHAM operation. Gerbils were treated with mild hypothermia (HYPO; 33 degrees C for 24 h+35 degrees C for 24 h) beginning 12 h after surgery, or they remained normothermic (NORMO). Then 5 and 6 days following ISC/SHAM operation gerbils received sublethal transient ischemic attacks (TIA, 1.5 min) or sham (SH) surgeries. Behavioral testing was done and animals survived for 30 days for quantification of medial, middle and lateral CA1 sector cell death. The SHAM groups were not significantly different. The ISC+NORMO+SH group lost 87.3% (of SHAM) of medial CA1 neurons, which was not significantly exacerbated in the ISC+NORMO+TIA group (91.1%, P=0.633). However, the ISC+HYPO+TIA group (58.8% loss) had significantly more cell death than the ISC+HYPO+SH group (42.8%; P=0.035), although CA1 protection was still better than in ISC+NORMO groups (P<0.001). Trends were similar in middle and lateral CA1, but the deleterious effects of TIAs were not statistically significant. Behavioral testing did not distinguish groups with or without TIA, but did reveal deficits in ISC+NORMO groups and protection in ISC+HYPO groups. These data, like previous ultrastructural findings, show that while most hypothermia-rescued CA1 neurons are healthy, some are susceptible. Perhaps other neuroprotectants, especially weaker ones, might be undone by delayed insults (e.g. TIA, fever).