1. Optimizing Nicorandil for Spinal Cord Protection in a Murine Model of Complex Aortic Intervention
- Author
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Muhammad Aftab, Joseph C. Cleveland, David A. Fullerton, Michael J. Weyant, Gavriel F. Roda, Yuki Ikeno, T.B. Reece, Linling Cheng, Xianzhong Meng, and Christian V. Ghincea
- Subjects
Male ,Pulmonary and Respiratory Medicine ,ATP-sensitive potassium channel ,Ischemia ,030204 cardiovascular system & hematology ,Pharmacology ,Neuroprotection ,Nitric oxide ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,KATP Channels ,medicine ,Animals ,Humans ,Nicorandil ,Spinal cord injury ,Spinal Cord Ischemia ,business.industry ,General Medicine ,medicine.disease ,Spinal cord ,Mice, Inbred C57BL ,Disease Models, Animal ,Treatment Outcome ,medicine.anatomical_structure ,030228 respiratory system ,chemistry ,Reperfusion Injury ,cardiovascular system ,Surgery ,Neuron ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
There are currently no clinically utilized pharmacological agents for the induction of metabolic tolerance to spinal cord ischemia-reperfusion injury in the setting of complex aortic intervention. Nicorandil, a nitric oxide donor and ATP-sensitive potassium (KATP) channel opener, has shown promise in neuroprotection. However, the optimized clinical application of the drug and its mechanism of neuroprotection remains unclear. We hypothesized that 3-days pretreatment would confer the most effective neuroprotection, mediated by mitochondrial KATP channel activation. Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Time course: mice received 0.1 mg/kg nicorandil for 10 min, 4 hours, and 3 consecutive days prior to ischemia compared with control. Dose challenge: mice received 3-days nicorandil pretreatment comparing 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, and saline administration. Mitochondrial KATP channel blocker 5-hydroxy-decanoate (5HD) was co-administered to elucidate mechanism. Limb motor function was evaluated, and viable anterior horn neurons quantified. Nicorandil pretreatment at 4 hours and 3 days before ischemia demonstrated significant motor function preservation; administration 10 minutes before ischemia showed no neuroprotection. All nicorandil doses showed significant motor function preservation. Three days administration of Nicorandil 1.0 mg/kg was most potent. Neuroprotection was completely abolished by 5HD co-administration. Histological analysis showed significant neuron preservation with nicorandil pretreatment, which was attenuated by 5HD co-administration. Three days administration of Nicorandil 1.0 mg/kg showed near-total motor function preservation in a murine spinal cord ischemia-reperfusion model, mediated by the mitochondrial KATP channel.
- Published
- 2022