Pretreatment With Diazoxide Attenuates Spinal Cord Ischemia-Reperfusion Injury Through Signaling Transducer and Activator of Transcription 3 Pathway.

Abstract

Delayed paraplegia remains a feared complication of thoracoabdominal aortic intervention. Pharmacologic preconditioning with diazoxide (DZ), an adenosine 5'-triphosphate-sensitive potassium channel opener, results in neuroprotection against ischemic insult. However, the effects of DZ in spinal cord ischemia-reperfusion injury have not been fully elucidated. We hypothesized that DZ attenuates spinal cord ischemia-reperfusion injury through the signaling transducer and activator of transcription (STAT) 3 pathway. Adult male C57/BL6 mice received DZ (20 mg/kg) by oral gavage. Spinal cords were harvested at 0, 12, 24, 36, 48, and 60 hours after administration of DZ. The expression of phosphorylated STAT3 was assessed by Western blot analysis. Five groups were studied: DZ (DZ pretreatment, n = 8), ischemic control (phosphate-buffered saline pretreatment, n = 11), DZ + STAT3 inhibitor LY5 (DZ pretreatment + LY5, n = 8), LY5 (phosphate-buffered saline pretreatment + LY5, n = 8), and sham (without cross-clamping, n = 5). Spinal cord ischemia was induced by 4 minutes of thoracic aortic cross-clamp. Functional scoring (Basso Mouse Score) was done at 12-hour intervals until 48 hours, and spinal cords were harvested for the evaluation of B-cell lymphoma 2 expression and histologic changes. The expression of phosphorylated STAT3 was significantly upregulated 36 hours after the administration of DZ. The motor function in the DZ group was significantly preserved compared with all other groups. The expression of B-cell lymphoma 2 in the DZ group was significantly higher than in the ischemic control, DZ + LY5, and LY5 groups 48 hours after reperfusion. DZ preserves motor function in spinal cord ischemia-reperfusion injury by the STAT3 pathway. DZ may be beneficial clinically for use in spinal protection in aortic intervention.