Blockade of adenosine A(2A) receptors prevents staurosporine-induced apoptosis of rat hippocampal neurons.
Since adenosine A(2A) receptor (A(2A)Rs) blockade protects against noxious brain insults involving apoptosis, we directly tested if A(2A)R 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 A(2A)R 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 A(2A)R blockade inhibits STS-induced apoptotic-like neuronal cell death. This begins with an apoptotic-like synaptotoxicity, which later evolved into an overt neurotoxicity, and A(2A)Rs effectively control this initial synaptotoxicity, in agreement with their predominant synaptic localization in the hippocampus.
Silva
Carla G
CG
Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.
Porciúncula
Lisiane O
LO
Canas
Paula M
PM
Oliveira
Catarina R
CR
Cunha
Rodrigo A
RA
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D019311:Staurosporine / Q000633:toxicity*; D016708:Synaptophysin / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D058917:Adenosine A2 Receptor Antagonists; D004791:Enzyme Inhibitors; D016708:Synaptophysin; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C049301:microtubule-associated protein-2 phosphatase; D010749:Phosphoprotein Phosphatases; D019311:Staurosporine