A comparison of adenosine A2A agonism and methylprednisolone in attenuating neuronal damage and improving functional outcome after experimental traumatic spinal cord injury in rabbits.
OBJECTIVE
Steroid agents remain the lone pharmacological treatment in widespread use for acute spinal cord injury (SCI), although their utility remains in dispute in the neurotrauma literature. Adenosine A2A receptor activation with ATL-146e, a selective A2A agonist, has shown potential benefit in treating SCI; however, it has not been compared with the gold standard, methylprednisolone. The authors of this study evaluated ATL-146e and methylprednisolone for their ability to preserve neuronal viability and motor function in experimental SCI.


METHODS
New Zealand White rabbits sustained SCI or sham injury via the Allen weight-drop technique. Ten minutes postinjury, animals received ATL-146e (ATL group, 0.06 microg/kg/min intravenously for 3 hours), methylprednisolone (steroid group, 30 mg/kg intravenously), or saline (trauma control group). Hindlimb motor function was recorded every 12 hours using the Tarlov motor grading scale (0, paralysis-5, normal hop). At 48 hours, fixed spinal cord tissue was evaluated for neuronal viability. Hindlimb motor function in animals treated with ATL-146e was equivalent to that of sham-injured animals and was significantly better than that of trauma control animals at all time points and that of steroid-treated animals at 12 hours (p = 0.05). Motor function in steroid-treated animals was worse than in those given ATL-146e and better than that of trauma control animals at later time points, but was not statistically significant (both p > 0.05). Neuronal viability (measured in neurons/hpf) was significantly higher in both treatment groups compared with the trauma control group (12.1 +/- 1.4 neurons/hpf for the ATL and 13.3 +/- 1.4 neurons/hpf for the steroid group compared with 7.5 +/- 1.5 neurons/hpf for the trauma control group; both p < 0.04). Neuronal viability did not differ among ATL-146e-treated, steroid-treated, and sham-injured groups.


CONCLUSIONS
The use of ATL-146e is at least as effective as methylprednisolone in preserving function and is equivalent to methylprednisolone in preserving the structure of spinal cord tissue after blunt SCI. Adenosine A2A receptor activation may be an effective treatment for acute SCI while avoiding the adverse effects of steroid agents.
Okonkwo
David O
DO
Department of Neurological Surgery, University of Virginia Health System, Charlottesville 22908-0212, USA. doo5a@hscmail.mcc.virginia.edu
Reece
T Brett
TB
Laurent
Jeffrey J
JJ
Hawkins
A Stewart
AS
Ellman
Peter I
PI
Linden
Joel
J
Kron
Irving L
IL
Tribble
Curtis G
CG
Stone
James R
JR
Kern
John A
JA
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002470:Cell Survival; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D006614:Hindlimb / Q000502:physiology; D007262:Infusions, Intravenous; D008775:Methylprednisolone / Q000008:administration & dosage / Q000627:therapeutic use*; D009048:Motor Skills; D009474:Neurons / Q000473:pathology; D011687:Purines / Q000008:administration & dosage / Q000627:therapeutic use*; D011817:Rabbits; D043705:Receptor, Adenosine A2A / Q000187:drug effects / Q000502:physiology; D013119:Spinal Cord Injuries / Q000150:complications*; D016896:Treatment Outcome
C431129:ATL 146e; D000893:Anti-Inflammatory Agents; D003509:Cyclohexanecarboxylic Acids; D011687:Purines; D043705:Receptor, Adenosine A2A; D008775:Methylprednisolone