Delayed pharmacological pre-conditioning effect of mitochondrial ATP-sensitive potassium channel opener on neurologic injury in a rabbit model of spinal cord ischemia

Abstract

BACKGROUND: Diazoxide, pharmacological openers of mitochondrial ATP-sensitive potassium channels have been shown to induce early pre-conditioning in the spinal cord. Here, the authors investigated whether diazoxide also induce delayed pre-conditioning and thereby reduce neurologic complications using a rabbit model of spinal cord ischemia. METHODS: Infrarenal blood flow was interrupted for 20 min in 21 rabbits. Non-treated control animals received no pre-treatment. Diazoxide (5 mg/kg) were given 48 h before 20 min ischemia in the 48-h DZ group, whereas 15-min DZ group received diazoxide (5 mg/kg) 15 min before 20-min ischemia. Neurological functions were evaluated using Johnson scores for 3 days after reperfusion, after which, spinal cords were procured for hematoxylin and eosin staining for cell counting. RESULTS: Johnson scores revealed a marked improvement in both the diazoxide-treated groups vs. the non-treated control group at 3, 24, 48, and 72 h after reperfusion (P<0.01). The histologic changes were proportional to the Johnson scores, with better preservation of motor neuron numbers in the animals of the 48-h DZ and 15-min DZ group relative to the non-treated controls (81+/-12, 90+/-10, 50+/-23 motor neurons, respectively, P<0.01). No difference was found between the 48-h DZ group and 15-min DZ group with respect to the Johnson scores or neuron numbers. CONCLUSIONS: The study demonstrates that pre-treatment with diazoxide 48 h before ischemia, induce delayed pharmacological pre-conditioning, thereby significantly improving clinical neurologic scores and histologic findings in this animal model.