Different roles of adenosine A1, A2A and A3 receptors in controlling kainate-induced toxicity in cortical cultured neurons.
Adenosine is a neuromodulator that can control brain damage through activation of A(1), A(2A) and A(3) receptors, which are located in both neurons and other brain cells. We took advantage of cultured neurons to investigate the role of neuronal adenosine receptors in the control of neurotoxicity caused by kainate and cyclothiazide. Both A(1), A(2A) and A(3) receptors were immunocytochemically identified in cortical neurons. Activation of A(1) receptors with 100 nM CPA did not modify the extent of neuronal death whereas the A(1) receptor antagonist, DPCPX (50 nM), attenuated neurotoxicity by 28 +/- 5%, and effect similar to that resulting from the removal of endogenous adenosine with 2U/ml of adenosine deaminase (27 +/- 3% attenuation of neurotoxicity). In the presence of adenosine deaminase, DPCPX had no further effect and CPA now exacerbated neurotoxicity by 42 +/- 4%. Activation of A(2A) receptor with 30 nM CGS21680 attenuated neurotoxicity by 40 +/- 8%, an effect prevented by the A(2A) receptor antagonists, SCH58261 (50 nM) or ZM241385 (50 nM), which by themselves were devoid of effect. Finally, neither A(3) receptor activation with Cl-IB-MECA (100-500 nM) nor blockade with MRS1191 (5 microM) modified neurotoxicity. These results show that A(1) receptor activation enhances and A(2A) receptor activation attenuates neurotoxicity in cultured cortical neurons, indicating that these two neuronal adenosine receptors directly control neurodegeneration. Interestingly, the control by adenosine of neurotoxicity in cultured neurons is similar to that observed in vivo in newborn animals and is the opposite of what is observed in adult brain preparations where A(1) receptor activation and A(2A) receptor blockade are neuroprotective.
Rebola
Nelson
N
Center for Neurosciences of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Portugal.
Rodrigues
Ricardo J
RJ
Oliveira
Catarina R
CR
Cunha
Rodrigo A
RA
D000241:Adenosine / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001581:Benzothiadiazines / Q000494:pharmacology; D016923:Cell Death; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000502:physiology*; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D043684:Receptor, Adenosine A3 / Q000502:physiology*
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D001581:Benzothiadiazines; D004232:Diuretics; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D000241:Adenosine; C004639:cyclothiazide; D007608:Kainic Acid