Background and Goal of study: Several clinical studies have indicated that serotonin re-uptake inhibitor (SSRI) administration after acute ischemic stroke can improve clinical recovery. Fluoxetine (FLX: one of the SSRIs) has several mechanisms which contribute to relieve the ischemic brain damage. We have previously reported that FLX had neuroprotective effects on day3 after cardiac arrest and cardiopulmonary resuscitation (CA/CPR) in mice. However, the neuronal loss after global ischemia is suspected to continue up to 14 days after insults. The goal of this study is to evaluate the neuroprotective effect of FLX for a longer observation period. 
Material and methods: 
PROTOCOL 1: Global cerebral ischemia was induced in male C57BL/6 mice for 7 minutes of CA. Thirty minutes after recovery of spontaneous circulation, the mice were randomly assigned to 2 groups and administered either FLX 10 mg/kg (Group F: n = 12) or 0 mg/kg (Group C: n = 12). Six and seven days after CA/CPR, behavioral tests (passive avoidance test) were conducted and brains were removed for histological evaluation. 
PROTOCOL 2: Methods of global ischemia and behavioral test were same as protocol 1. Fourteen days after CA/CPR, behavioral tests and histological evaluations were similarly conducted. (Group F: n=24, Group C: n=24) Data are presented as mean±SEM, and the groups were compared by unpaired t test or Mann-Whitney U test. The χ2 test was used for survival analysis. 
Results and discussion: Seven days after CA/CPR, there was a significant difference in number of surviving neurons (Neu-N positive cell) between the groups. On day14, the difference disappeared. However, Group F showed a significantly greater number of immature neurons (Doublecortin positive cell) than Group C. No differences were found in number of microglia (IBA-1 positive cell). At this time point, memory function significantly improved in Group F. The previous study has shown that the neurogenesis in hippocampus modulates the hippocampus-dependent period of memory, without loss of memory. The functional recovery in this study may have been induced by neurogenesis in hippocampus.
Conclusion: Fluoxetine improved memory function after cardiac arrest. This recovery may be due to neurogenesis in hippocampus, but not due to surviving neurons. Further investigation is needed to clarify the interaction of memory function and neurogenesis after fluoxetine administration.

Single administration of fluoxetine improves memory function without neuroprotection after cardiac arrest/cardiopulmonary resuscitation in mice