Functional and cytoarchitectural spinal cord protection by ATL-146e after ischemia/reperfusion is mediated by adenosine receptor agonism

Background: ATL-146e protects the spinal cord from ischemia/reperfusion injury, presumably via adenosine A_2A receptor activation, but this relationship remains unproven. We hypothesized that spinal cord functional and cytoarchitectural preservation from ATL-146e would be lost with simultaneous administration of the specific adenosine A_2A antagonist ZM241385 (ZM), thus proving that adenosine A_2A receptor activation is responsible for the protective effects of this compound. Methods: New Zealand White rabbits underwent 45 minutes of infrarenal aortic cross-clamping. Groups (n = 10) included sham, ischemia, ischemia plus ATL-146e (ATL-146E), ischemia plus ZM, or ischemia with both compounds (agonist-antagonist). Tarlov scores were recorded every 12 hours. After 48 hours, the spinal cord was fixed for histology and microtubule-associated protein 2 immunohistochemistry. Results: Tarlov scores at 48 hours were significantly better in the sham and ATL-146E groups (5.0 and 3.9, respectively) compared with the other three groups (all ≤1.3; P < .001). On hematoxylin and eosin, neuronal viability was higher in the sham, ATL-146E, and agonist-antagonist groups compared with the control and ZM groups (P < .05). Microtubule-associated protein 2 expression was preserved in the sham and ATL-146E groups but was lost in the ATL + ZM, ZM241385, and control groups. Conclusions: ATL-146e preserves the spinal cord in terms of both cytoarchitecture and function after reperfusion of the ischemic spinal cord, but this preservation is not completely blocked by competitive adenosine A_2A receptor antagonism. Although ATL-146e does seem to partially function through activation of the adenosine A_2A receptor, the neuroprotective mechanism may not be limited to this particular receptor.