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Eur J Cardiothorac Surg 2001;19:746-755
© 2001 Elsevier Science NL

Apoptotic cell death in the hippocampus due to prolonged hypothermic circulatory arrest: comparison of cyclosporine A and cycloheximide on neuron survival

Nadine A. Tattona, Christian Haglb, Sarah Nandora, Stephanie Insoliaa, David Spielvogelb, Randall B. Grieppb

a Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA
b Department of Cardiothoracic Surgery, Mount Sinai School of Medicine, New York University, New York, NY, USA

Received 15 November 2000; received in revised form 16 March 2001; accepted 16 March 2001.

Corresponding author. Tel.: +1-212-241-7067; fax: +1-212-828-4177
e-mail: nadine.tatton{at}mssm.edu

Objective: To determine whether cyclosporine A (CsA) or cycloheximide (CHX) can reduce neuronal apoptosis in the hippocampus in a chronic animal model of hypothermic circulatory arrest (HCA). Methods: Twenty-eight pigs (28–33 kg) underwent 90 min of HCA at 20°C. In a blinded study, animals were randomized to placebo (n=12), 5 mg/kg CsA (n=8), or 1 mg/kg CHX (n=8). After elective sacrifice 7 days postoperatively, brains were perfusion-fixed and the left hippocampus was examined for evidence of neuronal cell death. An in situ double-labeling method was used on cryosections to unequivocally identify apoptotic nuclei by the simultaneous visualization of DNA fragmentation and apoptotic chromatin condensation. Sections were also examined by immunocytochemistry for upregulation of the pro-apoptotic proteins Bax, activated caspase 3, and glyceraldehyde-3-phosphate dehydrogenase. Results: Apoptotic nuclear degradation was clearly present in the CA1, CA2 and CA3 subregions of the hippocampus after HCA. However, there was also morphological evidence for an accompanying necrotic-like cell death. There was no significant difference between the number of apoptotic nuclei observed in CSA-treated animals, mean value 4.4±1.63 SEM or CHX-treated animals, mean value 4.0±1.92 SEM, and age-matched control HCA pigs, mean value 4.85±1.69 SEM, (P>0.10).Conclusions: The data clearly demonstrate apoptotic cell death in pigs after HCA by simultaneously demonstrating in situ end labeling (TUNEL reaction) and apoptotic chromatin condensation using a nucleic acid-binding dye. Since CsA shows promising neuroprotective effects in behavioral studies, and since the peak of HCA-induced apoptosis occurs earlier than 7 days, further studies will be required to determine whether CsA can improve neuronal survival in the first few days after HCA. CHX was not effective in reducing apoptosis in this model.

Key Words: Apoptosis • Hippocampus • Global ischemia • Hypothermic circulatory arrest • Cyclosporine A • Pig model




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