atl-146e and Paralysis

ATL-146e, an adenosine A2A agonist, reduces paralysis after spinal cord ischemia-reperfusion. We hypothesized that systemic ATL-146e could improve neurologic outcome after blunt spinal cord trauma.. Twenty rabbits survived a thoracic spinal cord impact of 30 g-cm. One group received 0.06 microg/kg/min ATL-146e for the first 3 hours after impact (A2A group), whereas a second group received saline carrier (T/C group). Neurologic outcome was measured using the Tarlov scale (0-5). Histologic sections from the A2A and T/C groups were compared for neuronal viability.. There was significant improvement in Tarlov scores of A2A animals compared with T/C animals at 12 hours (p = 0.007), with a trend toward improvement at 36 (p = 0.08) and 48 (p = 0.09) hours after injury. There was decreased neuronal attrition in A2A animals (p = 0.06).. Systemic ATL-146e given after spinal cord trauma results in improved neurologic outcome. Adenosine A2A agonists may hold promise as a rapidly acting alternative to steroids in the early treatment of the spinal cord injured patient.

Topics: Animals; Cyclohexanecarboxylic Acids; Hemodynamics; Neuroprotective Agents; Paralysis; Purinergic P1 Receptor Agonists; Purines; Rabbits; Receptor, Adenosine A2A; Spinal Cord Injuries; Statistics, Nonparametric; Wounds, Nonpenetrating

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.. 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.. 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.. 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.

Topics: Animals; Cyclohexanecarboxylic Acids; Motor Neurons; Neuroprotective Agents; Paralysis; Purinergic P1 Receptor Agonists; Purines; Rabbits; Receptor, Adenosine A2A; Receptors, Purinergic P1; Spinal Cord; Spinal Cord Ischemia; Up-Regulation

We hypothesized that systemic ATL-146e, an adenosine A(2A) agonist, would decrease spinal cord reperfusion inflammatory stress and inhibit apoptosis and that these effects would correlate with improved neurologic functional outcome.. Thirty rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group of animals (n = 14) received 0.06 microg/kg per minute of ATL-146e infused intravenously for 3 hours, beginning 15 minutes before reperfusion. A second group of animals (n = 16) underwent spinal cord ischemia with saline vehicle alone and served as ischemic controls. Animals (n = 9, 11) from each group survived for 48 hours and assessed for neurologic impairment with the Tarlov (0-5) scoring system. Four animals from each group were humanely killed at the end of the 3-hour treatment period, and the remainder killed after 48 hours' survival. In all animals, lumbar spinal cord tissue specimens were frozen for subsequent Western blot analysis of heat shock protein 70 (HSP 70), and for the p85 fragment of poly (ADP-ribose) polymerase (PARP). Neuronal viability indices were determined at 48 hours with hematoxylin and eosin staining.. There was improvement in neurologic function in rabbits receiving ATL-146e (P <.001) compared with ischemic controls. At the end of the 3-hour treatment period there was a 46% (P <.05) decrease in HSP 70 expression in the ATL-146e group compared with the control group, but no difference in PARP expression. At 48 hours, there was no difference between control and ATL-146e groups in HSP 70 expression, but there was a 65% (P <.05) reduction in PARP in the spinal cords of animals that had received ATL-146e. There was a significant improvement in neuronal viability indices in animals receiving ATL-146e compared with ischemic controls (P <.05).. Systemic ATL-146e infusion during reperfusion after spinal cord ischemia results in preservation of hindlimb motor function. There is evidence of decreased spinal cord inflammatory stress immediately after treatment with ATL-146e as indicated by reduced HSP 70 induction. Treatment with ATL-146e is associated with a reduction in neuronal apoptosis as suggested by a substantial decrease in the fragmentation of PARP at 48 hours. These results suggest that inflammation during reperfusion and subsequent apoptosis contribute to paralysis after restoration of blood flow to the ischemic spinal cord.

Topics: Animals; Apoptosis; Cyclohexanecarboxylic Acids; Ischemia; Paralysis; Purinergic P1 Receptor Agonists; Purines; Rabbits; Receptor, Adenosine A2A; Reperfusion; Spinal Cord