Adenosine A2A agonist reduces paralysis after spinal cord ischemia: correlation with A2A receptor expression on motor neurons.
BACKGROUND
The adenosine A2A agonist ATL-146e ameliorates reperfusion inflammation, reducing subsequent paralysis and neuronal apoptosis after spinal cord ischemia. We hypothesized that neuroprotection with ATL-146e involves inducible neuronal adenosine A2A receptors (A2A-R) that are upregulated after ischemia.


METHODS
Eighteen rabbits underwent laparotomy, and 14 sustained spinal cord ischemia from cross-clamping the infrarenal aorta for 45 minutes. One group (ischemia-reperfusion [I/R] + ATL) received ATL-146e intravenously for 3 hours during spinal cord reperfusion. A second group (I/R) received equivolume intravenous saline solution for 3 hours and served as an ischemic control, and a third group (Sham) underwent sham laparotomy. At 48 hours, all subjects were assessed for motor impairment using the Tarlov scoring system (0 to 5). Lumbar spinal cord sections were immunolabeled for A2A-R and graded in a blinded fashion using light microscopy.


RESULTS
There was a significant improvement in Tarlov scores in I/R + ATL animals compared with the I/R group. Sham-operated animals demonstrated no A2A-R immunoreactivity. There was a dramatic increase in A2A-R immunoreactivity in neurons of lumbar spinal cord sections from I/R compared with I/R + ATL and sham-operated animals.


CONCLUSIONS
Reduction in paralysis in animals receiving ATL-146e correlates with the new finding of A2A-R expression on lumbar spinal cord motor neurons after ischemia. Adenosine A2A agonists may exert neuroprotective effects by binding to inducible neuronal A2A-R that are upregulated during spinal cord reperfusion, and reduced in response to administration of an A2A-R-specific agonist.
Cassada
David C
DC
Division of Vascular and Endovascular Surgery, University of Tennessee Medical Center, Knoxville, USA.
Tribble
Curtis G
CG
Long
Stewart M
SM
Kaza
Aditya K
AK
Linden
Joel
J
Rieger
Jayson M
JM
Rosin
Diane
D
Kron
Irving L
IL
Kern
John A
JA
D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010243:Paralysis / Q000473:pathology / Q000503:physiopathology*; D058906:Purinergic P1 Receptor Agonists; D011687:Purines / Q000494:pharmacology*; D011817:Rabbits; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020760:Spinal Cord Ischemia / Q000473:pathology / Q000503:physiopathology*; D015854:Up-Regulation / Q000187:drug effects
C431129:ATL 146e; D003509:Cyclohexanecarboxylic Acids; D018696:Neuroprotective Agents; D058906:Purinergic P1 Receptor Agonists; D011687:Purines; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1