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

Martina Venturini; Federica Cherchi; Clara Santalmasi; Lucia Frulloni; Ilaria Dettori; Daniela Catarzi; Felicita Pedata; Vittoria Colotta; Flavia Varano; Elisabetta Coppi; Anna Maria Pugliese

doi:10.3390/biom13060894

Pharmacological Characterization of P626, a Novel Dual Adenosine A_2A/A_2B Receptor Antagonist, on Synaptic Plasticity and during an Ischemic-like Insult in CA1 Rat Hippocampus

Biomolecules. 2023 May 27;13(6):894. doi: 10.3390/biom13060894.

Affiliations

¹ Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy.
² Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, 50019 Sesto Fiorentino, Italy.

Abstract

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, A_2AAR, A_2BAR, 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 A_2AAR or A_2BAR 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 A_2AARs or A_2BARs 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 A_2AAR/A_2BAR antagonist, P626, in preventing A_2AAR- and/or A_2BAR-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.

Keywords: CA1 neurotransmission; adenosine ligands; adenosine signaling; anoxic depolarization; cerebral ischemia; hippocampal slices; paired-pulse facilitation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine* / pharmacology
Animals
Glucose / pharmacology
Hippocampus*
Hypoxia
Ischemia
Neuronal Plasticity
Oxygen / pharmacology
Rats
Synaptic Transmission

Substances

BAY 60-6583
2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
Adenosine
Oxygen
Glucose

Grants and funding

This research was funded by the University of Florence: RICATEN (V.C., E.C., and A.M.P.); by Fondazione Italiana Sclerosi Multipla (FISM): 2019/R-Single/036 (A.M.P.) and by Fondazione Cassa di Risparmio Firenze: BANDO CONGIUNTO_UNIFICRF_COLOTTA (V.C.).