DIFFERENTIAL IMMEDIATE-EARLY GENE-EXPRESSION IN-OVINE BRAIN AFTER CARDIOPULMONARY BYPASS AND HYPOTHERMIC CIRCULATORY ARREST

Background: This study determined the induction profiles of immediate- early genes in the ovine brain after cardiopulmonary bypass (CPB) and hypothermic circulatory arrest (HCA), and the effects of the noncompet itive N-methyl-D-aspartate antagonist, aptiganel, on immediate-early g ene expression, neuronal necrosis, and functional outcome. Methods: Ca nnulas were inserted into isoflurane-anesthetized neonatal lambs under going CPB. One group received 2.5 mg/kg intravenous aptiganel. Animals underwent 90 or 120 min of HCA at 16 degrees C, were rewarmed to 38 d egrees C, and were weaned from CPB. One hour after CPB was discontinue d, brain perfusion was fixed and removed for immunohistochemical analy sis in one half of the animals. The other half survived 2 or 3 days be fore their brains were evaluated for neuronal degeneration. Data were analyzed using analysis of variance; P < 0.05 was considered significa nt. Results: Cardiopulmonary bypass and HCA differentially induced c-J un and Fos proteins in the hippocampal formation, with c-Jun expressio n increasing with the duration of HCA, whereas Fos protein expressions were greatest after 90 min of HCA. The c-Jun protein was expressed in all neurons except the dentate gyrus. The Fos proteins were expressed in all neurons, including the dentate gyrus. Neuronal necrosis was ob served in CA1 (73%) and CA3 (29%) neurons but not in the dentate gyrus after 120 min of HCA. Aptiganel completely inhibited c-Jun expression (P < 0.001) but not Fos, improved functional outcome, and attenuated neuronal necrosis (P < 0.05). Conclusions: The c-Jun and c-Fos protein s are expressed differentially in hippocampal neurons after CPB and HC A. Expression of c-Jun is associated with neuronal necrosis, whereas F os protein expression is associated with survival Aptiganel inhibits c -Jun expression, attenuates neuronal necrosis, and improves outcome.