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Acute regional neuronal injury following hypothermic circulatory arrest in a porcine model

^a Department of Cardiac Surgery, Panepistimiou Avenue, Ioannina, 45500 Greece
^b Department of Anatomy-Histology-Embryology, University of Ioannina, School of Medicine, Ioannina, Greece
^c Department of Cardiac Surgery, Onassis Cardiac Center, Athens, Greece

*Corresponding author. Tel.: +30-2651099680; fax: +30-2651099676.

E-mail address: drogevan{at}otenet.gr (G.E. Drossos).

Objective: Although deep hypothermic circulatory arrest (HCA) is routinely used to interrupt normal perfusion of the brain and prevent subsequent cerebral ischemic injury during cardiac surgery, it is associated with various forms of neurologic disturbances. Neurologic sequelae after prolonged HCA include motor, memory and cognitive deficits. The present study was designed to assess acute regional neuronal injury after HCA in an animal model. Methods: Six piglets underwent 75 min of HCA at 18 °C. Four piglets served as normal controls. After gradual rewarming and reperfusion, treatment animals were killed and their brains were perfusion-fixed and cryopreserved. Regional patterns of neuronal apoptosis after HCA was characterized by in situ DNA fragmentation using terminal deoxyneucleotidyl-transferase-mediated biotin-dUTP nick end-labeling (TUNEL) histochemistry. Hematoxylin and eosin histology was used to characterize cell damage morphologically. TUNEL-positive cells were scored on a scale of 0 to 5. Grade 0: no TUNEL-positive cells; Grade 1: <10%, Grade 2: 10–25%, Grade 3: 25–50%, Grade 4: 50–75%; and Grade 5: >75%. Results: TUNEL-positive cells indicating DNA-fragmentation were scored in the precentral gyrus (motor neocortex), postcentral gyrus (sensory neocortex), hippocampus, cerebellum, thalamus and ventral medulla of HCA treated animals and were significantly greater than in normal controls (P0.05). Significantly higher concentrations of TUNEL-positive cells were observed in the sensory and motor neocortex and hippocampus, compared to the cerebellum, thalamus and medulla, indicating an increased selective vulnerability of these brain subregions (P0.05). Despite significant DNA fragmentation indicated by high-concentrations TUNEL-positive cells, no morphologic evidence of apoptosis or necrosis was observed in this acute model. Conclusion: The data indicate that sensory and motor neocortex and hippocampal neurons are selectively vulnerable to neurologic injury after HCA as indicated by elevated levels of TUNEL-positive cells in these brain regions. It is noteworthy that evidence of significant neuronal injury is observed in the acute state. The absence of morphological evidence of apoptosis or necrosis with high levels of TUNEL-positive cells, strongly suggests activation of the apoptotic mechanisms at this early stage. These findings are compatible with data showing morphological evidence of apoptosis in these regions after a more prolonged period in a chronic animal model. The mechanisms underlying neuronal injury, and potential neuroprotective strategies remain to be elucidated.

Key Words: Apoptosis; Neurologic injury; HCA; Hypothermia; TUNEL; Porcine model

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				O. G. Ananiadou, K. Bibou, G. E. Drossos, A. Charchanti, M. Bai, S. Haj-Yahia, C. E. Anagnostopoulos, and E. O. Johnson Effect of profound hypothermia during circulatory arrest on neurologic injury and apoptotic repressor protein Bcl-2 expression in an acute porcine model J. Thorac. Cardiovasc. Surg., April 1, 2007; 133(4): 919 - 926. [Abstract] [Full Text] [PDF]