Abstract
Introduction: Pharmacologic induction of metabolic tolerance to spinal cord ischemia-reperfusion injury (SCI) after thoracoabdominal aortic intervention is not well established. We previously demonstrated that nicorandil pretreatment preserved motor function in a murine SCI model via direct mitochondrial ATP-sensitive potassium (KATP) channel activation and nitric oxide (NO) donation. However, the independent role of NO-mediated neuroprotection has not been elucidated. Hypothesis: Nitroglycerin pretreatment will induce neuroprotection through NO-mediated KATP channel activation. Methods: SCI was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Pretreatment constituted intraperitoneal injection 3 consecutive days before injury. Experimental groups: sham (no pretreatment or ischemia, n=10), SCI control (normal saline, n=20), nitroglycerin 1 mg/kg (n=18), nitroglycerin 1 mg/kg + 5-hydroxydecanonate 5 mg/kg (5HD, mitochondrial KATP channel blocker, n=13), 5HD 5 mg/kg (n=10), nitroglycerin 1 mg/kg + carboxy-PTIO (cPTIO) 1 mg/kg (NO scavenger, n=16), and cPTIO 1 mg/kg (n=10). Limb motor function and the number of viable neurons within the anterior horn of the spinal cord were evaluated. Results: Compared to SCI control, motor function was significantly preserved in the nitroglycerin pretreatment group at every time point after ischemia. In the nitroglycerin+5HD and nitroglycerin+cPTIO groups, motor preservation was significantly attenuated compared to nitroglycerin pretreatment (p<0.001). Histological analysis showed significant neuron preservation in the nitroglycerin pretreatment group compared with SCI control (p=0.011). This preservation was completely attenuated with 5HD or cPTIO co-administration (p=0.001). Conclusions: Nitroglycerin pretreatment significantly preserved motor function in a murine SCI model through NO-mediated KATP channel activation.
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