Adenosine A1R/A3R (Adenosine A1 and A3 Receptor) Agonist AST-004 Reduces Brain Infarction in a Nonhuman Primate Model of Stroke

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.

Adenosine A1R/A3R Agonist AST-004 Reduces Brain Infarction in Mouse and Rat Models of Acute Ischemic Stroke

“…It is possible that a balance of AST-004 A1R and A3R agonism in rats results in significant efficacy, but at high doses, the peripheral cardiovascular effects of A1R agonism reduce this cerebroprotection. Again, this appears to be a rat-specific phenomenon, since we did not observe any evidence of hormesis or blood pressure effects over a broad dose range in a recent primate stroke efficacy study 14 . More research is required to test the role of A1R agonism at higher doses in our stroke models.…”

“…Hormesis, or a “U-Shaped” biphasic dose-response has been observed with many CNS-active agents 42,43 . Importantly, no hormesis was observed in primate stroke efficacy studies, in which a clear AST-004 dose- and concentration-related effect was observed on inhibition of stroke lesion growth 14 .…”

“…The cerebroprotective benefits of AST-004 were completely blocked by the A3R antagonist MRS1523, suggesting A1R agonism is not required. Receptor binding models indicate significant efficacy is observed at estimated brain receptor occupancy levels as low as 5% in a non-human primate model of stroke 14 . In light of these results, we tested AST-004 efficacy at doses an order of magnitude lower and higher than previously reported in mice 26 .…”

Therapeutic Potential of Highly Selective A3 Adenosine Receptor Ligands in the Central and Peripheral Nervous System

“…Finally, it is worth noting that recent findings from basic research highlighted a promising neuroprotective effect exerted by a new compound, a mixed and partial agonist of A 1 Rs and A 3 Rs, known as AST-004 (MRS4322), a low-molecular-weight nucleoside metabolite recently synthetized by the group of Kenneth Jacobson [ 78 ]. Experimental models of stroke performed in mice [ 78 ] or non-human primates [ 79 ] demonstrated that treatment with the A 1 R/A 3 R agonist after acute ischemic stroke resulted in significantly reduced lesion volume, without alterations in cardiovascular parameters. The cerebroprotective effect of the compound was also found to correlate with unbound AST-004 concentrations in the plasma and cerebrospinal fluid, as well as estimated brain A 1 R and A 3 R occupancy, indicating the activation of adenosine A 1 Rs and/or A 3 Rs [ 79 ].…”

“…Experimental models of stroke performed in mice [ 78 ] or non-human primates [ 79 ] demonstrated that treatment with the A 1 R/A 3 R agonist after acute ischemic stroke resulted in significantly reduced lesion volume, without alterations in cardiovascular parameters. The cerebroprotective effect of the compound was also found to correlate with unbound AST-004 concentrations in the plasma and cerebrospinal fluid, as well as estimated brain A 1 R and A 3 R occupancy, indicating the activation of adenosine A 1 Rs and/or A 3 Rs [ 79 ]. Such encouraging data prompted the evaluation of AST-004 in a Phase I clinical trial for stroke ( ; 12 March 2022).…”