TY - JOUR
T1 - Pharmacologically induced preconditioning with diazoxide
T2 - A novel approach to brain protection
AU - Shake, Jay G.
AU - Peck, Eric A.
AU - Marban, Eduardo
AU - Gott, Vincent L
AU - Johnston, Michael V
AU - Troncoso, Juan C.
AU - Redmond, J. Mark
AU - Baumgartner, William A.
N1 - Funding Information:
This study was supported by the Dana and Albert Broccoli Center for Aortic Diseases, the Mildred and Carmont Blitz Cardiac Research Fund, and the National Institutes of Health (2R01NS31238-05 to William A. Baumgartner). Doctors Jay G. Shake and Eric A. Peck have been the Irene Piccinini Investigators in Cardiac Surgery, established to recognize outstanding research trainees in Cardiac Surgery at The Johns Hopkins Medical Institutions. The authors wish to thank Mr Jeffrey Brawn, Ms Melissa Haggerty, and Ms Molly Brown for their contribution of outstanding technical assistance. This project could not have been completed without their participation.
PY - 2001
Y1 - 2001
N2 - Background. Ischemic preconditioning is an endogenous mechanism whereby brief periods of ischemia render neurons resistant to subsequent lethal insults. This protection appears to alter cellular apoptosis and can be induced by potassium channel openers acting on the inner membrane of the mitochondria (mitoKATP). To test the hypothesis that pharmacologic preconditioning could provide neuroprotection, the mitoKATP opener diazoxide was used in a canine model of brain injury induced by hypothermic circulatory arrest (HCA). Methods. Seventeen dogs were placed on cardiopulmonary bypass (CPB) and cooled to 18°C. After 2 hours of HCA, animals were rewarmed and weaned from CPB. Six dogs received intravenous diazoxide (2.5 mg/kg bolus 15 minutes prior to CPB, then 0.5 mg/min until circulatory arrest, then restarted for the first hour of rewarming). Six animals received vehicle only. Five received diazoxide and the mitoKATP blocker 5-hydroxydecanoate (5-HD). Using a modified Pittsburgh Canine Neurological Scoring System (0 = normal, 500 = brain death), animals were evaluated every 24 hours for 3 days. The brains were removed and histologic sections of four regions characteristically injured in this model were scored (0 = no injury, 4 = infarction) by a neuropathologist in a blinded fashion. Results. Clinical scoring showed marked improvement in the diazoxide group at 48 hours (101 ± 10.5 vs 165 ± 14.8, p < 0.01) and 72 hours (54 ± 9.3 vs 137 ± 12.1, p < 0.01). This neuroprotection was attenuated when 5-HD was concomitantly administered. Three of four brain regions typically injured in this model (cortex, hippocampus, and entorhinal cortex) had significant neuron preservation in the diazoxide group. Likewise, combined region scores were significantly improved in the treatment group (1.18 ± 0.2 vs 2.46 ± 0.2, p < 0.01). Conclusions. Pretreatment with diazoxide resulted in significant improvement in both clinical neurologic scores and histopathology in our model of HCA. This suggests that pharmacologic preconditioning with the mitoKATP channel opener diazoxide may offer effective neuroprotection during HCA.
AB - Background. Ischemic preconditioning is an endogenous mechanism whereby brief periods of ischemia render neurons resistant to subsequent lethal insults. This protection appears to alter cellular apoptosis and can be induced by potassium channel openers acting on the inner membrane of the mitochondria (mitoKATP). To test the hypothesis that pharmacologic preconditioning could provide neuroprotection, the mitoKATP opener diazoxide was used in a canine model of brain injury induced by hypothermic circulatory arrest (HCA). Methods. Seventeen dogs were placed on cardiopulmonary bypass (CPB) and cooled to 18°C. After 2 hours of HCA, animals were rewarmed and weaned from CPB. Six dogs received intravenous diazoxide (2.5 mg/kg bolus 15 minutes prior to CPB, then 0.5 mg/min until circulatory arrest, then restarted for the first hour of rewarming). Six animals received vehicle only. Five received diazoxide and the mitoKATP blocker 5-hydroxydecanoate (5-HD). Using a modified Pittsburgh Canine Neurological Scoring System (0 = normal, 500 = brain death), animals were evaluated every 24 hours for 3 days. The brains were removed and histologic sections of four regions characteristically injured in this model were scored (0 = no injury, 4 = infarction) by a neuropathologist in a blinded fashion. Results. Clinical scoring showed marked improvement in the diazoxide group at 48 hours (101 ± 10.5 vs 165 ± 14.8, p < 0.01) and 72 hours (54 ± 9.3 vs 137 ± 12.1, p < 0.01). This neuroprotection was attenuated when 5-HD was concomitantly administered. Three of four brain regions typically injured in this model (cortex, hippocampus, and entorhinal cortex) had significant neuron preservation in the diazoxide group. Likewise, combined region scores were significantly improved in the treatment group (1.18 ± 0.2 vs 2.46 ± 0.2, p < 0.01). Conclusions. Pretreatment with diazoxide resulted in significant improvement in both clinical neurologic scores and histopathology in our model of HCA. This suggests that pharmacologic preconditioning with the mitoKATP channel opener diazoxide may offer effective neuroprotection during HCA.
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U2 - 10.1016/S0003-4975(01)03192-7
DO - 10.1016/S0003-4975(01)03192-7
M3 - Article
C2 - 11789759
AN - SCOPUS:0035662096
SN - 0003-4975
VL - 72
SP - 1849
EP - 1854
JO - Annals of Thoracic Surgery
JF - Annals of Thoracic Surgery
IS - 6
ER -