Blockade of adenosine A2A receptors prevents staurosporine-induced apoptosis of rat hippocampal neurons

Since adenosine A2A receptor (A2ARs) blockade protects against noxious brain insults involving apoptosis, we directly tested if A2AR blockade prevents apoptosis induced by staurosporine (STS). Exposure of rat hippocampal neurons to STS (30 nM, 24 h) decreased neuronal viability while increasing the number apoptotic-like neurons and de-localizing mitochondria and cytochrome c immunoreactivities. This was prevented by the selective A2AR antagonists, SCH58261 and ZM241385 (50 nM). Shorter incubation periods (6 h) with STS caused no neuronal loss but decreased synaptophysin and MAP-2 immunoreactivities, which was prevented by SCH58261. Furthermore, STS (100 nM) decreased MTT reduction and increased caspase-3 activity in rat hippocampal nerve terminals, which was prevented by SCH58261. These results show that A2AR blockade inhibits STS-induced apoptotic-like neuronal cell death. This begins with an apoptotic-like synaptotoxicity, which later evolved into an overt neurotoxicity, and A2ARs effectively control this initial synaptotoxicity, in agreement with their predominant synaptic localization in the hippocampus.