The adenosine 2A receptor agonist ATL-146e attenuates experimental posthemorrhagic vasospasm.
OBJECTIVE
Selective adenosine 2A receptor agonists, such as ATL-146e, are known to be potent anti-inflammatory agents devoid of systemic side effects and have been used clinically in a number of disease states. However, adenosine 2A receptor agonists have not been studied in the treatment of cerebral vasospasm after subarachnoid hemorrhage. The present study investigated the efficacy of ATL-146e in the prevention of leukocyte infiltration and attenuation of posthemorrhagic vasospasm.


METHODS
The rodent femoral artery model of vasospasm was used. Forty male Sprague-Dawley rats were randomly assigned to four different groups (vehicle, 1 ng/kg/min, 10 ng/kg/min, or 100 ng/kg/min ATL-146e administered via subcutaneous osmotic minipump). Vasospasm was evaluated at posthemorrhage Day 8 (period of peak constriction) by calculating the lumen cross-sectional area (expressed as percent change in luminal area: ratio of blood-exposed vessel to normal saline-exposed vessel) and radial wall thickness. Immunostaining with anti-CD45 monoclonal antibody to detect leukocytes was used to evaluate localized inflammation.


RESULTS
Significant vasospasm was noted in the vehicle-treated (blood-exposed) control group (78.5%, P < 0.001; expressed as a ratio of luminal area of the saline [no blood] control), but not in the ATL-146e-treated groups (lumen ratio to control: 105.0, 83.4, and 91.3% for the 1, 10, and 100 ng/kg/min groups, respectively). Additionally, infiltration of inflammatory cells was reduced significantly and radial wall thickness was decreased in the ATL-146e-treated groups compared with the vehicle-treated control group.


CONCLUSIONS
Selective activation of the adenosine 2A receptor with ATL-146e prevented posthemorrhagic vasospasm and reduced leukocyte infiltration in this experimental model. This agent is worthy of further investigation and lends credence to the hypothesis supporting a role for inflammation in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage.
Chang
Chih-Zen
CZ
Department of Neurological Surgery, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Dumont
Aaron S
AS
Simsek
Serkan
S
Titus
Brian J
BJ
Kwan
Aij-Lie
AL
Kassell
Neal F
NF
Solenski
Nina J
NJ
D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D011687:Purines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
C431129:ATL 146e; D058908:Adenosine A2 Receptor Agonists; D003509:Cyclohexanecarboxylic Acids; D011687:Purines