Int. J. Devl Neuroscience 19 (2001) 395–414 Review Involvement of astrocytes in purine-mediated reparative processes in the brain R. Ciccarelli a, *, P. Ballerini a , G. Sabatino b , M.P. Rathbone c , M. D’Onofrio d , F. Caciagli a , P. Di Iorio a a Department of Biomedical Sciences, Section of Pharmacology, Via del Vestini Pal. B, 66013 Chieti, Italy b Department of Medicine and Ageing Sciences, Section of Neonatology, School of Medicine, Uniersity ‘G.D’Annunzio’, Chieti, Italy c Department of Medicine, McMaster Uniersity, Hamilton, Ont., Canada d Neuromed Institute, Pozzilli, Italy Received 25 April 2000; received in revised form 22 November 2000; accepted 23 November 2000 Abstract Astrocytes are involved in multiple brain functions in physiological conditions, participating in neuronal development, synaptic activity and homeostatic control of the extracellular environment. They also actively participate in the processes triggered by brain injuries, aimed at limiting and repairing brain damages. Purines may play a significant role in the pathophysiology of numerous acute and chronic disorders of the central nervous system (CNS). Astrocytes are the main source of cerebral purines. They release either adenine-based purines, e.g. adenosine and adenosine triphosphate, or guanine-based purines, e.g. guanosine and guanosine triphosphate, in physiological conditions and release even more of these purines in pathological conditions. Astrocytes express several receptor subtypes of P1 and P2 types for adenine-based purines. Receptors for guanine-based purines are being characterised. Specific ecto-enzymes such as nucleotidases, adenosine deaminase and, likely, purine nucleoside phosphorylase, metabolise both adenine- and guanine-based purines after release from astrocytes. This regulates the effects of nucleotides and nucleosides by reducing their interaction with specific membrane binding sites. Adenine-based nucleotides stimulate astrocyte proliferation by a P2-mediated increase in intracellular [Ca 2 + ] and isoprenylated proteins. Adenosine also, via A 2 receptors, may stimulate astrocyte proliferation, but mostly, via A 1 and/or A 3 receptors, inhibits astrocyte proliferation, thus controlling the excessive reactive astrogliosis triggered by P2 receptors. The activation of A 1 receptors also stimulates astrocytes to produce trophic factors, such as nerve growth factor, S100 protein and transforming growth factor , which contribute to protect neurons against injuries. Guanosine stimulates the output of adenine-based purines from astrocytes and in addition it directly triggers these cells to proliferate and to produce large amount of neuroprotective factors. These data indicate that adenine- and guanine-based purines released in large amounts from injured or dying cells of CNS may act as signals to initiate brain repair mechanisms widely involving astrocytes. © 2001 ISDN. Published by Elsevier Science Ltd. All rights reserved. www.elsevier.nl/locate/ijdevneu Abbreiations: ABC, ATP binding cassette; ABPs, adenine-based purines; AD, Alzheimer’s disease; ADA, adenosine deaminase; Ado, Adenosine; ADP, adenosine diphosphate; AIT-082, [[3-(1,6-dihydro-6-oxo-9-purin-9-yl)-1-oxopropyl] amino] benzoic acid; AMP, adenosine monophosphate; AMP-PNP, 5 adenosine -imidotriphosphate; ATP, adenosine triphosphate; cAMP, cyclic AMP; BzATP, (4-benzoyl-benzoyl)- adenosine 5-triphosphate; 2-CA, 2-chloro-adenosine; 2-CdA, 2-chloro-2-deoxy-adenosine; CFTR, cystic fibrosis transmembrane conductance regulator; CNS, central nervous system; DPMX, 1,3-dipropyl-7-methylxanthine; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; FGF, fibroblast growth factor; GBPs, guanine-based purines; GFAP, glial fibrillary acidic protein; GDP, guanosine diphosphate; GMP, guanosine monophos- phate; GMP-PNP, 5-guanosine--imidotriphosphate; Guo, Guanosine; GTP, guanosine triphosphate; i 6 A, isopentenyl adenosine; IMP, inosine monophosphate; mGluRs, metabotropic glutamate receptors; MAPK, mitogen-activated protein kinase; MVA, mevalonic acid; MDR, multidrug resistance; NBTI, Nitrobenzylthioinosine; NECA, N-ethylcarboxamidoadenosine; NGF, nerve growth factor; PD, Parkinson’s disease; PNP, purine nucleoside phosphorylase; PRT, Phosphoribosyltransferase; ROS, reactive oxygen species; TGF , transforming growth factor ; VaD, vascular dementia. * Corresponding author. Tel.: +39-0871-355-4015; fax: +39-0871-355-4012. E-mail address: r.ciccarelli@dsb.unich.it (R. Ciccarelli). 0736-5748/01/$ © 2001 ISDN. Published by Elsevier Science Ltd. All rights reserved. PII:S0736-5748(00)00084-8