guanosine-triphosphate and Brain-Diseases

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.

Topics: Adenine; Adenosine Triphosphate; Animals; Astrocytes; Brain; Brain Diseases; Brain Injuries; Cell Division; Chickens; Energy Metabolism; Extracellular Space; Guanine; Guanosine Triphosphate; Humans; Ion Transport; Mice; Nerve Growth Factors; Nerve Tissue Proteins; Neuroprotective Agents; Nucleosides; Nucleotides; Rats; Receptors, Purinergic P1; Receptors, Purinergic P2; Signal Transduction; Transforming Growth Factor beta

Topics: Adenosine Triphosphate; Brain; Brain Chemistry; Brain Diseases; Cell Nucleolus; Cell Nucleus; Chronic Disease; DNA; Guanosine Triphosphate; Humans; Liver Diseases; Microscopy, Electron; Mitosis; Nerve Degeneration; Neuroglia; Portacaval Shunt, Surgical

De novo mutations in

Topics: Brain Diseases; Child; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Proteins; Guanosine Triphosphate; Humans; Ions; Mutation

Topics: Brain Diseases; Child; Eukaryotic Initiation Factor-2B; Guanosine Diphosphate; Guanosine Triphosphate; Humans

3-Nitropropionic acid (3-NPA) inhibited synaptosomal respiration in a dose-dependent manner; the degree of inhibition by the same concentration of the compound was greater, however, when respiration was stimulated by concomitant increase in ATP usage. The most rapid event after addition of 3-NPA was a decrease in [creatine phosphate]/[creatine] ([CrP]/[Cr]) and an increase in [lactate]/[pyruvate]. A fall in [ATP]/[ADP] and [GTP]/[GDP] was initially less pronounced but closely followed that in [CrP]/[Cr]. In the absence of glutamine, 3-NPA caused a pronounced decrease in internal aspartate level and a small reduction in glutamate concentration, whereas [GABA] rose; the sum of these three amino acids inside synaptosomes fell, but there were no increases in their external levels. With glutamine in the medium, the reduction in intrasynaptosomal aspartate was accompanied by increases in intrasynaptosomal glutamate and GABA. The external concentration of glutamate rose substantially in the presence of the inhibitor. 3-NPA had no effect on basal release of either glutamate (and GABA) or biogenic amines but increased efflux occurring upon addition of nonsaturating concentrations of the depolarizing agents veratridine and KCl. The results allow the following predictions with respect to the behavior of brain metabolism in neurodegenerative diseases that involve restrictions of mitochondrial function: (1) The extent of inhibition of mitochondrial ATP generation is expected to be greater in cells with high energy demand. The earliest signs of impairment of the respiratory chain function are a fall in [PCr]/[Cr] (or a rise in [Pi]/[CrP]) and an increase in [lactate]/[pyruvate]. (2) A fall in [GTP]/[GDP] can limit protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Brain Diseases; Cell Death; Creatine; Energy Metabolism; gamma-Aminobutyric Acid; Glutamates; Glutamic Acid; Glutamine; Guanosine Diphosphate; Guanosine Triphosphate; Lactates; Lactic Acid; Male; Neurotransmitter Agents; Nitro Compounds; Oxygen Consumption; Phosphocreatine; Propionates; Pyruvates; Pyruvic Acid; Rats; Rats, Sprague-Dawley; Synaptosomes