Involvement of astrocytes in purine-mediated reparative processes in the brain.
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 [Ca2+] and isoprenylated proteins. Adenosine also, via A2 receptors, may stimulate astrocyte proliferation, but mostly, via A1 and/or A3 receptors, inhibits astrocyte proliferation, thus controlling the excessive reactive astrogliosis triggered by P2 receptors. The activation of A1 receptors also stimulates astrocytes to produce trophic factors, such as nerve growth factor, S100beta protein and transforming growth factor beta, 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.
Ciccarelli
R
R
Department of Biomedical Sciences, Section of Pharmacology, Via del Vestini Pal. B, 66013, Chieti, Italy. r.ciccarelli@dsb.unich.it
Ballerini
P
P
Sabatino
G
G
Rathbone
M P
MP
D'Onofrio
M
M
Caciagli
F
F
Di Iorio
P
P
D000225:Adenine / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001927:Brain Diseases / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D002645:Chickens; D004734:Energy Metabolism; D005110:Extracellular Space / Q000378:metabolism; D006147:Guanine / Q000502:physiology*; D006160:Guanosine Triphosphate / Q000502:physiology; D006801:Humans; D017136:Ion Transport; D051379:Mice; D009414:Nerve Growth Factors / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009705:Nucleosides / Q000502:physiology; D009711:Nucleotides / Q000502:physiology; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology
D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009705:Nucleosides; D009711:Nucleotides; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; D016212:Transforming Growth Factor beta; D006147:Guanine; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D000225:Adenine