Print this pageAdenosine A2A Receptor Activation Is a Critical Pathway For Spinal Cord Preservation Following Ischemia-Reperfusion
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T. Brett Reece, MD, David O. Okonkwo, MD PhD, Joel Linden, PhD, Irving L. Kron, MD, Curtis G. Tribble, MD, John A. Kern, MD.
University of Virginia, Charlottesville, VA, USA.
Background: ATL-146e, an adenosine A2A receptor agonist, treatment at reperfusion has effectively ameliorated neurological injury in animal studies of spinal cord ischemia-reperfusion. The mechanism of protection has been assumed to be specific activation of the adenosine A2A receptor in the spinal cord and circulating leukocytes. The agent ZM241385, a specific competitive adenosine A2A antagonist, is used pharmacologically to identify specific action at this receptor in drug development. This study hypothesized that the amelioration of functional and cytoarchitectural spinal cord injury with ATL-146e given at reperfusion would be negated by the simultaneous administration of ZM241385.
Methods: New Zealand White Rabbits underwent 45 minutes infrarenal aortic cross-clamping. Groups (each n=10) included Sham, Ischemia (control), ischemia plus ATL-146e (ATL, 0.06 mg/kg/min for 3 hours), ischemia plus ZM241385 (ZM, 0.42 mg/kg/min for 3 hours or 10 times the dose of agonist), or ischemia with both compounds (Both). Drug infusion began 10 minutes following reperfusion. The animals were observed for 48 hours. Hind limb function was assessed every 12 hours using Tarlov scale. Tarlov scores are defined as: 0=paralysis, 1=hind limb movement, 2=sit with assistance, 3=sit alone, 4=weak hop, 5=normal hop. After 48 hours of reperfusion, animals were euthanized. The spinal cord was fixed for assessment of neuronal viability (viable neurons/high powered field on H&E) and MAP-2 immunohistochemistry (percent of gray matter stained for the protein). The groups were compared using ANOVA.
Results: Hemodynamics during the procedure and recovery periods were similar among groups. Tarlov scores at 48 hours were significantly better in sham and ATL (5.0 and 3.9, respectively) compared to the other three groups (all ≤ 1.3, p < 0.001). On H&E, neuronal viability was significantly higher in Sham and ATL 25.1±0.6 and 13.5±3.3) compared to control and ZM (10 2.6 and 10.6 2.8, both p<0.01). Sham and ATL demonstrated a trend towards higher neuronal viability compared to Both (13.5 2.6, p =0.1 vs ATL). MAP-2 expression in gray matter was significantly better in Sham and in ATL (42±8% and 32.5±9.3%) than Both, ZM, and Control (24.5±5.9, 20.4±4.9, and 21.2±5.0%, all p≤0.01).
Conclusion: ATL-146e preserves spinal cord function and cytoarchitecture when given at reperfusion after temporary aortic cross clamping in rabbit. The competitive adenosine A2A receptor antagonist significantly impairs this protection in terms of function and of MAP-2 expression with a trend towards worse neuronal viability. In conclusion, Adenosine A2A receptor activation appears to be an important mechanism of protection against spinal cord injury following temporary aortic occlusion and ischemia-reperfusion.
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