Cyclosporine A as a potential neuroprotective agent: a study of prolonged hypothermic circulatory arrest in a chronic porcine model

Objective: To assess whether Cyclosporine A (CsA) or cycloheximide (CHX) ca n reduce ischemia-induced neurological damage by blocking apoptotic pathway s, we assessed their effects on cerebral recovery in a chronic animal model of hypothermic circulatory arrest (HCA). Methods: Twenty-eight pigs (28-33 kg) underwent 90 min of HCA at 20 degreesC. In this blinded study, animals were randomized to placebo (n = 12), 5 mg/kg CsA (n = 8), given intravenou sly before and subcutaneously for 7 days after HCA, or a single dose of 1 m g/kg CHX (n = 8), given after weaning from cardiopulmonary bypass. Hemodyna mics, intracranial pressure (ICP) and neurophysiological data (EEG, SSEP) w ere assessed for 3 h after HCA; early behavioral recovery was scored, and n eurological/behavioral evaluation (9 = normal) was carried out daily until elective sacrifice on postoperative day (POD) 7. Brains were selectively pe rfused and evaluated histopathologically fur apoptosis. Results: Basic hemo dynamic data revealed no differences between CsA or CHX and control groups. ICP was significantly lower throughout rewarming (P = 0.009) and reperfusi on (P = 0.05) in the CsA group. EEG recovery 3 h after NCA was observed in four of eight CsA animals but in only 1 of 12 controls (P = 0.11) and one o f eight CHX animals; cortical SSEP recovery also seemed faster in CsA anima ls, but failed to reach significance. Some early recovery scores were signi ficantly better in the CsA group, and daily behavioral scores were consiste ntly and significantly higher in the CsA-treated animals from POD 1 through POD4. Conclusions: The data indicate that treatment with Cyclosporine A bu t not cycloheximide has a positive effect on cerebral recovery following HC A. Whether CsA results in inhibition of neuronal apoptosis. and/or inhibits release of cytokines and thereby reduces postischemic cerebral edema remai ns to be elucidated. The neuroprotective effect of CsA, if confirmed in fur ther studies, would make its clinical application conceivable. (C) 2001 Els evier Science B.V. All rights reserved.