Purinergic Signalling (2007) 3:299–310 DOI 10.1007/s11302-007-9085-8 ORIGINAL ARTICLE The role of ATP and adenosine in the brain under normoxic and ischemic conditions F. Pedata & A. Melani & A. M. Pugliese & E. Coppi & S. Cipriani & C. Traini Received: 30 May 2007 / Accepted: 25 September 2007 / Published online: 11 October 2007 # Springer Science + Business Media B.V. 2007 Abstract By taking advantage of some recently synthesized compounds that are able to block ecto-ATPase activity, we demonstrated that adenosine triphosphate (ATP) in the hippo- campus exerts an inhibitory action independent of its degrada- tion to adenosine. In addition, tonic activation of P2 receptors contributes to the normally recorded excitatory neurotransmis- sion. The role of P2 receptors becomes critical during ischemia when extracellular ATP concentrations increase. Under such conditions, P2 antagonism is protective. Although ATP exerts a detrimental role under ischemia, it also exerts a trophic role in terms of cell division and differentiation. We recently reported that ATP is spontaneously released from human mesenchymal stem cells (hMSCs) in culture. Moreover, it decreases hMSC proliferation rate at early stages of culture. Increased hMSC differentiation could account for an ATP-induced decrease in cell proliferation. ATP as a homeostatic regulator might exert a different effect on cell trophism according to the rate of its efflux and receptor expression during the cell life cycle. During ischemia, adenosine formed by intracellular ATP escapes from cells through the equilibrative transporter. The protective role of adenosine A1 receptors during ischemia is well accepted. However, the use of selective A1 agonists is hampered by unwanted peripheral effects, thus attention has been focused on A2A and A3 receptors. The protective effects of A2A antagonists in brain ischemia may be largely due to reduced glutamate outflow from neurones and glial cells. Reduced activation of F. Pedata (*) : A. M. Pugliese : E. Coppi : S. Cipriani : C. Traini Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy e-mail: felicita.pedata@unifi.it A. Melani IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy p38 mitogen-activated protein kinases that are involved in neuronal death through transcriptional mechanisms may also contribute to protection by A2A antagonism. Evidence that A3 receptor antagonism may be protective after ischemia is also reported. Keywords Adenosine . Adenosine A2A receptors . ATP . Ecto-ATPase inhibitors . Ischemia . P2 purinergic receptors 6-N,N-diethyl-D-β,γ-dibromomethylene ATP DPCPX fEPSP GIRK hMSCs LTP LTD MAPKs MRS 1191 Abbreviations ATPγS Adenosine-5′-o-(3-thio)triphosphate α,β- Alpha,beta-methylene ATP meATP ARL 67156 BBG BGO 136 CGS 15943 CGS 21680 Cl-IB- MECA Brilliant blue G 1-Hydroxynaphthalene-3,6-disulfonate 9-Chloro-2-(2-furanyl)-[1,2,4] triazolo[1,5-c] quinazolin-5-amine 2-p-(2-Carboxyethyl)phenethylamino-5′-N- ethylcarboxamidoadenosine hydrochloride 1-[2-Chloro-6[[(3-iodophenyl)methyl]amino]- 9H-purin-9-yl]-1-deoxy-N-methyl-ß-D- ribofuranuronamide 8-Cyclopentyl-1,3-dipropylxanthine field extracellular postsynaptic potential Kir 3.2 and 3.4 channels: potassium inward rectifiers Human mesenchymal stem cells Long-term potentiation Long-term depression Mitogen-activated protein kinases 3-Ethyl 5-benzyl-2-methyl-6-phenyl-4- phenylethynyl-1,4-(6)-dihydropyridine-3, 5-dicarboxylate