Pharmacologically induced preconditioning with diazoxide: a novel approach to brain protection.
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 (mitoK(ATP)). To test the hypothesis that pharmacologic preconditioning could provide neuroprotection, the mitoK(ATP) 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 degrees 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 mitoK(ATP) 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 mitoK(ATP) channel opener diazoxide may offer effective neuroprotection during HCA.
Shake
J G
JG
Division of Cardiac Surgery, The Johns Hopkins Medical Institutions, and Kennedy-Krieger Research Institute, Baltimore, Maryland, USA.
Peck
E A
EA
Marban
E
E
Gott
V L
VL
Johnston
M V
MV
Troncoso
J C
JC
Redmond
J M
JM
Baumgartner
W A
WA
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000473:pathology; D001925:Brain Damage, Chronic / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D002544:Cerebral Infarction / Q000473:pathology*; D003981:Diazoxide / Q000494:pharmacology*; D004285:Dogs; D006324:Heart Arrest, Induced; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D018696:Neuroprotective Agents; D014665:Vasodilator Agents; D003981:Diazoxide