PJ34 Enhanced Spinal Cord Tissue Viability and Differential Gene Expression In A Murine Model Of Thoracic Aortic Ischemia Reperfusion Injury

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Introduction and Objectives:
The inflammatory response associated with thoracic aortic ischemia reperfusion(TAR) has been implicated as a likely source of morbidity and mortality. Spinal cord ischemia(SCI), remains among the most dreaded complications of complex aortic reconstruction. These experiments were designed to determine whether PJ34, a Poly-ADP Ribose Polymerase Inhibitor, could ameliorate the sequelae of TAR by evaluating spinal cord tissue viability using a murine model of TAA. In addition, experiments were performed to determine transcriptional differences in PJ34 treated and untreated spinal cord tissue exposed to TAR to identify potential mediators of injury vs. tissue protection.
Methods:
Twenty-seven 129S1/SvImj mice were subjected to TAR followed by 48 hours of reperfusion. The thoracic aorta was clamped at the left subclavian artery for 11 minutes. Animals were treated with normal saline Control(UC),(n=11) 0.5 ml NS IP) or PJ34 (PJ)(n=11) 10 mg/kg IP both 1 hour before and after TAR. Sham(SH) mice(n=5) underwent median sternotomy without TAR. After 48 hours, mice were euthanized and spinal cord mitochondrial activity(MTT assay) was measured. Expression differences among sham, untreated control, and PJ34 treated mice were determined using microarray technology. COX-2 expression differences were measured using Real time RT-PCR.
Results:
PJ34 improved spinal cord mitochondrial activity following TAR(UC: 53.1 ± 6.3, P: 73.5 ± 4.1^*, ^*p<0.01). Transcriptional interrogation revealed numerous genes, which were differentially expressed following TAR. COX-2 was induced by TAR but was unaffected by PJ34 administration(UC: 1.72 ± 0.29, PJ: 1.66 ± 0.13 p=NS). Data is depicted as fold change versus sham.
Conclusions:
PJ34 administration enhances spinal cord mitochondrial activity following TAR. COX-2 expression is induced by TAR, however was not ameliorated by PJ34 administration. These findings suggest that PJ34 enhances spinal cord viability via COX-2 independent mechanisms. This data also identifies COX-2 inhibition as a potential alternative novel therapeutic adjunct for thoracoabdominal aortic reconstruction.