Acute stimulation of A3 adenosine receptors has been shown to intensify damage in an in vivo model of global cerebral ischemia and to induce cell death in cell cultures. To investigate the mechanism for these cytotoxic phenomena, adenosine analogs of varied receptor subtype selectivities were applied directly to rat cerebellar granule neurons in culture. Agonists of A1, A(2A) and/or A(2B) receptors (CPA, NECA and CGS 21680) had no effect on neuronal survival during a 16 h incubation period. The highly selective adenosine A3 receptor agonist 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA) at ≤10 μM induced cell death in a concentration-dependent fashion. A structurally related nucleoside, cladribine, which has cytotoxic properties via a non-adenosine receptor related mechanism, had no effect on cell survival. Adding dbcAMP to the culture to activate cyclic AMP-dependent protein kinases attenuated Cl-IB-MECA-induced neurotoxicity, suggesting the Cl-IB-MECA-induced neuronal cell death is mediated by an inhibition of cyclic AMP production. Glutamate (50 μM) induced cell death to a degree comparable to that induced by 10 μM Cl-IB-MECA. Furthermore, a subcytotoxic concentration of Cl-IB-MECA (1 μM) significantly augmented glutamate neurotoxicity. In contrast, the adenosine A1/A2 agonists, the adenosine A1/A2 antagonist XAC, and the A(2A) antagonist SCH 58261 at micromolar concentrations had no effect on neuronal viability or on glutamate neurotoxicity. These results suggest that activation of adenosine A3 receptors may play an important role in regulating neuronal survival and death in cerebellar neurons.
|Titolo:||Adenosine A(2) receptor agonist-induced neurotoxicity in rat cerebellar granule neurons|
|Parole Chiave:||Adenosine receptors; Adenylate cyclase; Brain; Glutamic acid; Neurotoxicity; Nucleosides|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||1997|
|Digital Object Identifier (DOI):||10.1002/(SICI)1098-2299(199703)40:3<267::AID-DDR7>3.0.CO;2-I|
|Appare nelle tipologie:||01 - Articolo su periodico|