The adenosine 2A receptor agonist ATL-146e attenuates experimental posthemorrhagic vasospasm

Neurosurgery. 2007 Jun;60(6):1110-7; discussion 1117-8. doi: 10.1227/01.NEU.0000255467.22387.5C.

Abstract

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.

Conclusion: 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.

MeSH terms

  • Adenosine A2 Receptor Agonists*
  • Animals
  • Chemotaxis, Leukocyte / drug effects*
  • Cyclohexanecarboxylic Acids / administration & dosage*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Male
  • Purines / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley
  • Subarachnoid Hemorrhage / complications
  • Vasospasm, Intracranial / etiology
  • Vasospasm, Intracranial / pathology
  • Vasospasm, Intracranial / prevention & control*

Substances

  • ATL 146e
  • Adenosine A2 Receptor Agonists
  • Cyclohexanecarboxylic Acids
  • Purines