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- Nucleotides and their receptors in the nervous system. 1-2 August 1998, Leipzig, Germany.
The maintaining of high level of guanine nucleotides suggests an important role for these nucleotides in ventricular system physiology. Though the precise function of guanine nucleotides is still unclear, however.
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More recent studies suggest the participation of GTP and guanosine in metabotropic P2Y receptors activation during regulation of ATP and adenosine exocytosis [ 17 , 18 , 62 — 66 ]. Additionally, the latest data indicate that guanine nuclotides can act as trophic agents [ 18 ]. Numerous authors claim that brain hypoxia results in ATP degradation and in signifficant increase of degradation products in CNS cells.
Some of the products, like adenosine, can be released in cerebrospinal fluid [ 17 , 18 , 67 — 69 ]. Damaged brain cells constitute another source of purines and pyrimidines [ 19 ].
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The nucleotide receptors were found in all organs and tissues examined so far [ 19 ]. In rodents ventricular system their existence was confirmed immunochemically [ 15 , 16 ]. However, these studies did not successfully determine the exact amount and localization of these receptors on the cell surface. The results presented in this paper indicate that nucleotide receptors P2X 2 , P2X 7 and P2Y 2 are expressed on the ependymocytes of lateral ventricle of porcine brain.
Their amount and distribution has been found to be diverse. The P2X 7 receptors connected with inflammatory reactions and pain [ 71 ] were predominantly expressed on the analysed tissue fragments. The density of P2X 2 i P2Y 2 receptors was low, whereas P2Y receptors were distributed irregularly in form of streaks and P2X receptors were scattered on the ependymocytes surface.
The presence of nucleotide receptors in the areas contacting with CSF suggests the possibility of communication between ependymal cells and cerebrospinal fluid via nucleotides. Furthermore, high density of P2X 7 receptors indicates that ventricular system plays a key role in inflammatory processes in central nervous system since in recent years, the role of ATP and P2X 7 receptors in these processes has been recognised [ 72 — 74 ].
It was also found that injury inflicted on rat brain by heme injection resulted in increased interleukine concentration in CSF [ 75 ]. The results discussed above confirm the thesis about cross-talking between brain and ventricular system functioning in physiological as well as pathological conditions. Nucleotide receptors, like all the receptors of neurotransmitters in the ventricular system, may also be involved in the regulation of cilliae movement [ 5 — 11 ], important for CSF circulation.
The enzymes associated with ependyma and CSF hydrolysed adenosine tri- and diphosphonucleotides effectively while guanine nucleotides were not hydrolysed as efficiently and pyrimidynes were not metabolised at all. Similar substrate specificity was found for soluble nucleotidases in rat CSF [ 25 ]. Moreover, the susceptibility to inhibitors of ecto-nucleotidases and kinases suramine and Ap5A and alkaline phosphatases levamisole indicates that ecto-NTPDases as well as NPPases are active on the ependymocytes.
We also realize the presence of nucleotide kinases in porcine CSF and on the surface of porcine brain ventricle lining. Inconsiderable influence of levamisole on nucleotides hydrolysis data not shown excludes the presence of membranous alkaline phosphatases. In summary, ecto- and exonucleotidases from NTPDase and NPPase family as well as adenylate kinase participate in nucleotides metabolism in ventricular system of porcine brain.
The enzyme with similar properties was found in rat CSF [ 76 ]. Western blot analysis indicated that the proteins interacting with anti-NPPases antibodies have molecular weight of about 52 kDa and 58 kDa. These data are in accordance with molecular weight of soluble NPPases given in literature [ 41 — 48 ]. One of these proteins is NPPase3, analogous to ectoNTPDases in blood vessels [ 76 ], the difference in the molecular weight about 6 kDa suggests that the second protein can be NPPase3 that might have been detached from the membrane and released to CSF.
However, the soluble NTPDases described so far had rather high specificity to diphosphonucleosides and low specificity to triphosphonucleosides [ 40 , 77 , 78 ]. We also found the adenylate kinase activity in cerebrospinal fluid of swine. We detected low 5'-nucleotidase and adenosine deaminase activities in porcine CSF.
Mainly neuronal NTPDases are involved in release of the agonists from nucleotide receptors [ 25 , 29 , 50 ]. In opposition to that, we did not find NTPDase 1 and 2 in ventricular system. The product of the above reactions - extracellular AMP is further hydrolysed by ependymal 5'-nucleotidase to adenosine that is known for its neuroprotective functions [ 67 , 69 ].
Uridine Function in the Central Nervous System | Bentham Science
Nucleotidase activity using di- and triphosphonucleosides was detected in rat CSF, however the precise identification of these NTPDases was imposible [ 76 ]. There is little information about participation of other enzymes, for example exo-nucleotidases, in nucleotide metabolism. Previous experiments indicated the presence of NPPase2 and 3 on chondroid plexus cells [ 79 ]. In recent years the particular attention has been paid to the role of ATP and adenosine in inflammatory reactions. ATP is considered to be specific "danger signal". Released to the extracellular space ATP informs about pathological conditions and damage of cells and activates immunological response [ 80 ].
The presented results not only confirmed the presence of all elements of purinergic signaling in the mammalian brain ventricular system, but also demonstrated numerous P2X 7 receptors expressed on the surface of ependymal cells. These observations suggest that the ventricular system is responsible for initiating the inflammation reactions triggered off by the damage of brain cells.
Acta Peadiatr. J Perinat Med. Holst H, Sollevi A: Increased concentration of hypoxanthine in human central cerebrospinal fluid after subarachnoid haemorrhage.
Acta Neurochir. Stover JF, Lowitzsch K, Kempski OS: Cerebrospinal fluid hypoxanthine, xanthine and uric acidlevels may reflect glutamate - mediated exitotoxicity in different neurological diseases. Neurosci Lett. Tang FR, Sim MK: Metabotropic glutamate receptor subtype alfa mGluR1alfa immunoreactivity in ependymal cells of rat caudal medulla oblongata and spinal cord.
Arch Histol Cytol. J Neurol. Biol Psychiatry. J Neural Transm. Exp Brain Res.
Nucleotides and their receptors in the nervous system. 1-2 August 1998, Leipzig, Germany.
Rodriguez-Nunez A: Neuron-specific enolase, nucleotides, nucleosides, purine bases, oxypurines and urid amid concentration in cerebrospinal fluid of children with meningitis. Brain Dev. Dev Med Child Neurol.
J Comp Neurol. Prog Neurobiol. Int J Devl Neurosci. Ralevic V, Burnstock G: Receptors for purines and pyrimidines. Am J Pharmacol Exp Ther. Ann N Y Acad Sci. Burnstock G: Development and perspectives of the purinoceptors concept. J Auton Pharmacol. Int Rev Cytol. Trends Pharmacol Sci. Zimmermann H: Extracellular purine metabolism. Drug Dev Res. Trends Neurosci.
Burnstock G: Purinergic signalling: past, present and future. Braz J Med Biol Res. Post Biol Kom. Ecto-ATPases and related ectonucleotidases. Epilepsy Res. Van Belle H: Alkaline phosphatase. Kinetics and inhibition by levamisole of purified isoenzymes from humans. Clin Chem. J Neurochem. Eur J Biochem. The results were evaluated through electrophysiological examinations, leading to a significant improvement in the patients.
Thus, it has been found that CDP choline can be used to treat patients with optic neuropathy [ 64 ]. Goldberg and colleagues evaluated the use of a combination of uridine triphosphate UTP , cytidine monophosphate CMP , and hydroxocobalamin in a double-blind, randomized study in the treatment of neuralgia due to degenerative orthopedic alterations with neural compression.
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At the end of the day treatment period, there were reductions in the pain scale scores in both groups; however, there was a significantly larger reduction in the scores of the Group A patients. Based on these findings, the authors concluded that the combination of UTP, CMP, and vitamin B12 has a positive effect on pain and functionality improvement in the treatment of degenerative orthopedic alterations with neural compression [ ].
Nunes and collaborators administered CMP, UTP, and hydroxycobalamin in patients with alcoholic polyneuropathy, a disorder in the peripheral nervous system involving motor, sensorial, and autonomic nerves. This study included patients aged 28—65 years, who were treated with doses intramuscularly for 6 days and orally for 30 days.
Afterward, the efficacy of the treatment was evaluated through sensorial motor tests as well as a visual evaluation of pain. With this, it was concluded that the treatment was effective and safe, reducing pain and improving the motor activity of the patients [ 66 ].