Adenosine A2A analogue reduces long-term neurologic injury after blunt spinal trauma.
BACKGROUND
ATL-146e is an adenosine A(2A) agonist that has recently been demonstrated to improve neurological outcome in spinal cord injury in animals. In the current study, we extended the treatment paradigm and tested neurobehavioral functioning out to 1 week after injury to assess if early neurological improvement is sustained long term by an adenosine analogue.


METHODS
New Zealand White rabbits (3.0-3.5 kg) sustained mid-thoracic blunt spinal cord injury using a weight-drop model (10 g weight dropped from 6 cm directly onto dura). Animals received either (1) 3 h iv infusion of saline carrier (Trauma, N = 21); (2) 3 h iv infusion of 0.06 microg/kg/min ATL-146e followed by intraperitoneal bolus of 10.8 microg/kg ATL-146e at 3 h postinjury (ATL, N = 14); or (3) 3 h iv infusion of 0.06 microg/kg/min ATL-146e followed by intraperitoneal bolus injection of 10.8 microg/kg ATL-146e at 3, 12, and 24 h postinjury (ATL-PLUS, N = 11). Fourteen animals underwent sham injury. Hemodynamic parameters were monitored and hind limb motor functioning was assessed by Tarlov scores (0 = paralyzed to 5 = normal hop) for 7 days after injury.


RESULTS
ATL-146e significantly improved Tarlov scores of ATL-146e groups compared with saline-treated controls (P < 0.01 12, 24, 36, and 48 h). Control animals, severely neurologically impaired at 48 h (Tarlov 1.61 +/- 0.35), were euthanized early due to ethical concerns, thus not permitting later statistical comparisons. Early neurological improvements in both ATL-146e-treated groups were sustained longer term (7 day mean Tarlov, SHAM 4.9 +/- 0.30, ATL 5.0 +/- 0, ATL-PLUS 4.25 +/- 0.31).


CONCLUSIONS
ATL-146e given immediately after blunt spinal cord trauma significantly improves neurological outcome, which is sustained through 7 days. Early adenosine A2A receptor agonism may be critical since additional IP administration afforded no further neurological improvement. The current data further support the potential clinical utility of adenosine A(2A) agonists in the treatment of spinal cord injury.
Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA. tbr5q@virginia.edu
T Brett
TB
Reece
Jonathan D
JD
Davis
David O
DO
Okonkwo
Thomas S
TS
Maxey
Peter I
PI
Ellman
Xinning
X
Li
Joel
J
Linden
Curtis G
CG
Tribble
Irving L
IL
Kron
John A
JA
Kern
D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use*; D011817:Rabbits; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D014949:Wounds, Nonpenetrating / Q000188:drug therapy*
C431129:ATL 146e; D058908:Adenosine A2 Receptor Agonists; D003509:Cyclohexanecarboxylic Acids; D011687:Purines; D043705:Receptor, Adenosine A2A