Kristina Shkirkova, BSc
@KShkirkova
Adenosine A1 and A3 receptors (A1R and A3R) are involved in supply of energy, oxygen, and nutrients to the brain. Under pathological conditions of brain injury, these receptors may play an important role in functional balance and neuroprotection.1 Studies in mice have shown that activation of A1R and A3R with agonists results in reduction of cerebral lesion volume in ischemic stroke models. Adenosine A1 and A3 receptors are viable therapeutic targets for stroke treatment; however, there remains a need to establish appropriate dosing and timing of A1R/A3R agonist treatment that could be translated for its use in clinical studies.
The authors of this recently published study in Stroke used A1R/A3R agonist in a nonhuman primate ischemic stroke model to establish treatment timeline in gyrencephalic species. AST-004, a combined agonist of A1R and A3R receptors, was used in cynomogus monkeys following transient middle cerebral artery occlusion (tMCAO). tMCAO was initiated by placing two clips, one on the MCA trunk and another distal to the orbito-frontal MCA branch, for four hours followed by recanalization. AST-004 was administered as a bolus dose at 2 hours post-occlusion and immediately followed by 22-hour intravenous infusion. There were four dose groups ranging from very low AST-004 dose to high dose (predicted plasma levels range from 35ng/ml to 1660 ng/ml). Results confirmed that average blood plasma and CSF concentrations of the agonist agent were within 2-fold of target levels in all groups, suggesting that bolus followed by continuous infusion is a feasible drug delivery regiment. AST-004 administration resulted in significant reduction in lesion growth rate in the medium- and high-dose groups as observed by series of MRI scans. Furthermore, AST-004 treatment groups had significantly reduced total infarct volume at 24 hours and 5 days post induced tMCAO.
In summary, AST-004, a novel adenosine A1R/A3R receptor agonist, showed efficacy in reducing infarct volume and rate of infarct growth in nonhuman primates acute cerebral ischemia model. However, due to limitations in the sample size, especially with 4 treatment groups, the variability in some measurements was high. Additionally, longer period of follow-up and functional outcome measurements would be required to achieve better generalizability to a clinical treatment model.
References:
1Jacobson KA, Tosh DK, Jain S, Gao ZG. Historical and Current Adenosine Receptor Agonists in Preclinical and Clinical Development. Front Cell Neurosci. 2019;13:124. Published 2019 Mar 28. doi: 10.3389/fncel.2019.00124
