The Library
Adenosine A1R/A3R (Adenosine A1 and A3 Receptor) Agonist AST-004 reduces brain infarction in a nonhuman primate model of stroke
Tools
Tools
Tools
Liston, T. E., Hama, A., Boltze, Johannes, Poe, R. B., Natsume, T., Hayashi, I., Takamatsu, H., Korinek, W. S. and Lechleiter, J. D. (2021) Adenosine A1R/A3R (Adenosine A1 and A3 Receptor) Agonist AST-004 reduces brain infarction in a nonhuman primate model of stroke. Stroke, 53 (1). pp. 238-248. doi:10.1161/STROKEAHA.121.036396 ISSN 0039-2499.
|
PDF
WRAP-Adenosine-A1R-A3R-agonist-AST-004-reduces-brain-infarction-nonhuman-primate-2021.pdf - Accepted Version - Requires a PDF viewer. Download (893Kb) | Preview |
|
|
PDF
WRAP-supplemental-2021.pdf - Supplemental Material - Requires a PDF viewer. Download (1632Kb) | Preview |
Official URL: https://doi.org/10.1161/STROKEAHA.121.036396
Abstract
Background and Purpose:
Treatment with A1R/A3R (adenosine A1 and A3 receptor) agonists in rodent models of acute ischemic stroke results in significantly reduced lesion volume, indicating activation of adenosine A1R or A3R is cerebroprotective. However, dosing and timing required for cerebroprotection has yet to be established, and whether adenosine A1R/A3R activation will lead to cerebroprotection in a gyrencephalic species has yet to be determined.
Methods:
The current study used clinical study intervention timelines in a nonhuman primate model of transient, 4-hour middle cerebral artery occlusion to investigate a potential cerebroprotective effect of the dual adenosine A1R/A3R agonist AST-004. Bolus and then 22 hours intravenous infusion of AST-004 was initiated 2 hours after transient middle cerebral artery occlusion. Primary outcome measures included lesion volume, lesion growth kinetics, penumbra volume as well as initial pharmacokinetic-pharmacodynamic relationships measured up to 5 days after transient middle cerebral artery occlusion. Secondary outcome measures included physiological parameters and neurological function.
Results:
Administration of AST-004 resulted in rapid and statistically significant decreases in lesion growth rate and total lesion volume. In addition, penumbra volume decline over time was significantly less under AST-004 treatment compared with vehicle treatment. These changes correlated with unbound AST-004 concentrations in the plasma and cerebrospinal fluid as well as estimated brain A1R and A3R occupancy. No relevant changes in physiological parameters were observed during AST-004 treatment.
Conclusions:
These findings suggest that administration of AST-004 and combined A1R/A3R agonism in the brain are efficacious pharmacological interventions in acute ischemic stroke and warrant further clinical evaluation.
| Item Type: | Journal Article | ||||||
|---|---|---|---|---|---|---|---|
| Subjects: | R Medicine > RC Internal medicine | ||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Science > Mathematics |
||||||
| Library of Congress Subject Headings (LCSH): | Cerebral ischemia -- Treatment, Cerebrovascular disease -- Treatment, Cerebral ischemia -- Diagnosis, Adenosine -- Receptors | ||||||
| Journal or Publication Title: | Stroke | ||||||
| Publisher: | Lippincott Williams & Wilkins | ||||||
| ISSN: | 0039-2499 | ||||||
| Official Date: | 22 November 2021 | ||||||
| Dates: |
|
||||||
| Volume: | 53 | ||||||
| Number: | 1 | ||||||
| Page Range: | pp. 238-248 | ||||||
| DOI: | 10.1161/STROKEAHA.121.036396 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||
| Copyright Holders: | © 2021 American Heart Association, Inc. | ||||||
| Date of first compliant deposit: | 11 October 2021 | ||||||
| Date of first compliant Open Access: | 3 December 2021 | ||||||
| RIOXX Funder/Project Grant: |
|
||||||
| Related URLs: |
Request changes or add full text files to a record
Repository staff actions (login required)
 |
View Item |
Downloads
Downloads per month over past year
