Global cerebral ischemia due to cardiocirculatory arrest in mice causes neuronal degeneration and early induction of transcription factor genes in the hippocampus

To analyze the role of specific genes and proteins in neuronal signaling ca scades following global cerebral ischemia, it would be useful to have a rep roducible model of global cerebral ischemia in mice that potentially allows the investigation of mice with specific genomic mutations. We first report on the development of a model of reversible cardiocirculatory arrest in mi ce and the consequences of such an insult to neuronal degeneration and expr ession of immediate early genes (IEG) in the hippocampus. Cardiocirculatory arrest of 5 min duration was induced via ventricular fibrillation in mecha nically ventilated NMRI mice. After successful cardiopulmonary resuscitatio n (CPR), animals were allowed to reperfuse spontaneously for 3 h (n = 7) an d 7 days (n = 7). TUNEL staining revealed a selective degeneration of a sub set of neurons in the hippocampal CA1 sector at 7 days. About 30% of all TU NEL-positive nuclei showed condensed chromatin and apoptotic bodies. Immuno histochemical studies of IEG expression performed at 3 h exhibited a marked induction of c-Fos, c-Jun, and Krox-24 protein in all sectors of the hippo campus, peaking in vulnerable CA1 pyramidal neurons and in dentate gyrus. I n contrast, sham-operated animals (n = 3) did not reveal neuronal degenerat ion or increased IEG expression in the hippocampus when compared with untre ated control animals (n = 3). In conclusion, we present a new model of glob al cerebral ischemia and reperfusion in mice with the use of complete cardi ocirculatory arrest and subsequent CPR. Following 5 min of ischemia, a subs et of CAI pyramidal neurons was TUNEL-positive at 7 days. The expression of IEG was observed in all sectors of the hippocampus, including selectively vulnerable CA1 pyramidal neurons. This appears to be a good model which sho uld be useful in evaluating the role of various genes in transgenic and kno ckout mice following global ischemia. (C) 1999 Elsevier Science B.V. All ri ghts reserved.