Pharmacological Characterization of P626, a Novel Dual Adenosine A2A/A2B Receptor Antagonist, on Synaptic Plasticity and during an Ischemic-like Insult in CA1 Rat Hippocampus

by Selleckchem | Nov 02 2023

In recent years, the use of multi-target compounds has become an increasingly pursued strategy to treat complex pathologies, including cerebral ischemia. Adenosine and its receptors (A1AR, A2AAR, A2BAR, A3AR) are known to play a crucial role in synaptic transmission either in normoxic or ischemic-like conditions. Previous data demonstrate that the selective antagonism of A2AAR or A2BAR delays anoxic depolarization (AD) appearance, an unequivocal sign of neuronal injury induced by a severe oxygen-glucose deprivation (OGD) insult in the hippocampus. Furthermore, the stimulation of A2AARs or A2BARs by respective selective agonists, CGS21680 and BAY60-6583, increases pre-synaptic neurotransmitter release, as shown by the decrease in paired-pulse facilitation (PPF) at Schaffer collateral-CA1 synapses. In the present research, we investigated the effect/s of the newly synthesized dual A2AAR/A2BAR antagonist, P626, in preventing A2AAR- and/or A2BAR-mediated effects by extracellular recordings of synaptic potentials in the CA1 rat hippocampal slices. We demonstrated that P626 prevented PPF reduction induced by CGS21680 or BAY60-6583 and delayed, in a concentration-dependent manner, AD appearance during a severe OGD. In conclusion, P626 may represent a putative neuroprotective compound for stroke treatment with the possible translational advantage of reducing side effects and bypassing differences in pharmacokinetics due to combined treatment.

Comments:

The research you described focuses on investigating the effects of a newly synthesized dual A2AAR/A2BAR antagonist called P626 in the context of cerebral ischemia, specifically in the CA1 region of the rat hippocampus. The use of multi-target compounds has gained attention as a strategy to treat complex pathologies like cerebral ischemia.

Adenosine and its receptors, namely A1AR, A2AAR, A2BAR, and A3AR, have been found to play a critical role in synaptic transmission under normal and ischemic conditions. Previous studies have shown that selective antagonism of A2AAR or A2BAR delays the appearance of anoxic depolarization (AD), which is an indication of neuronal injury caused by severe oxygen-glucose deprivation (OGD) insult in the hippocampus.

Additionally, the stimulation of A2AARs or A2BARs by selective agonists, CGS21680 and BAY60-6583 respectively, increases the release of neurotransmitters in the pre-synaptic terminals. This is evidenced by a decrease in paired-pulse facilitation (PPF) at Schaffer collateral-CA1 synapses, which reflects enhanced neurotransmitter release.

In this study, the researchers aimed to investigate the effects of P626, a newly synthesized dual A2AAR/A2BAR antagonist, on A2AAR- and/or A2BAR-mediated effects. They conducted extracellular recordings of synaptic potentials in rat hippocampal slices from the CA1 region. The results demonstrated that P626 prevented the reduction of PPF induced by CGS21680 or BAY60-6583. Moreover, P626 exhibited a concentration-dependent delay in the appearance of AD during severe OGD.

Based on these findings, the researchers suggest that P626 could be a potential neuroprotective compound for the treatment of stroke. Its dual antagonistic action on A2AAR and A2BAR may provide an advantage by reducing side effects and overcoming differences in pharmacokinetics associated with combined treatments. This research opens up possibilities for the development of novel therapeutic approaches targeting adenosine receptors to mitigate the effects of cerebral ischemia.