Editing Inosine

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[https://en.wikipedia.org/wiki/Inosine Wikipedia page]

Inosine has been thought of in the B vitamin family, although it is not technically a vitamin because your body can synthesize it. It is a basic component of cells and participates in the synthesis of energy. Inosine is naturally formed as a result of purine metabolism. Purines fix nitrogen for use as basic building blocks of RNA and DNA. As inosine is formed it goes on to participate in the synthesis of ATP (cellular energy). Since inosine is readily formed as a byproduct of purine metabolism, we do not typically think of it as a needed dietary supplement. [ [http://www.wellnessresources.com/health/articles/can_inosine_repair_nerve_damage/ health news] ]


== Effects on ALS ==

Inosine acts as a competitor of 6-TG, suggesting that it acts as an N-kinase agonist, and that this kinase is part of a modular signal transduction pathway controlling axon growth. Following unilateral transections of the corticospinal tract in mature rats, inosine applied to the intact sensorimotor cortex stimulated layer 5 pyramidal cells to upregulate GAP-43 expression and to sprout axon collaterals that crossed the midline and reinnervated regions of the cervical spinal cord which had lost their normal afferents. [2]

In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1alpha, and IFN-gamma, but failed to alter the production of the anti-inflammatory cytokine IL-10. [3]

== Discussion threads on the ALSTDI forum ==

[http://www.alstdi.org/forum/yaf_postst47717_regulator-found-for-regenerating-nerve-fibers-in-animals.aspx Regulator found for regenerating nerve fibers in animals]:
:''A possible combined cocktail for nerve regeneration? inosine - target 1. Mst3b 2. GAP-43 3. Talpha-1 tubulin; ibuprofen - target RhoA inhibition; Vitamin D - target CD1c⁺ mDCs/RALDH2 mRNA''


== Regulated pathways ==

Upregulates GAP-43

Probable N-kinase agonist

== References ==

[1]
<bibtex>
@article{Benowitz1999,
abstract = {The purine nucleoside inosine has been shown to induce axon outgrowth from primary neurons in culture through a direct intracellular mechanism. For this study, we investigated the effects of inosine in vivo by examining whether it would stimulate axon growth after a unilateral transection of the corticospinal tract. Inosine applied with a minipump to the rat sensorimotor cortex stimulated intact pyramidal cells to undergo extensive sprouting of their axons into the denervated spinal cord white matter and adjacent neuropil. Axon growth was visualized by anterograde tracing with biotinylated dextran amine and by immunohistochemistry with antibodies to GAP-43. Thus, inosine, a naturally occurring metabolite without known side effects, might help to restore essential circuitry after injury to the central nervous system.},
author = {Benowitz, L I and Goldberg, D E and Madsen, J R and Soni, D and Irwin, N},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
keywords = {Animals,Axons,Axons: drug effects,Inosine,Inosine: pharmacology,Male,Pyramidal Tracts,Pyramidal Tracts: drug effects,Pyramidal Tracts: injuries,Rats,Rats, Sprague-Dawley},
mendeley-groups = {inosine},
month = nov,
number = {23},
pages = {13486--90},
pmid = {10557347},
title = {{Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=23974\&tool=pmcentrez\&rendertype=abstract},
volume = {96},
year = {1999}
}
</bibtex>

[2]
<bibtex>
@article{Benowitz2001,
abstract = {Axon growth is characterized by a distinctive program of gene expression. We present evidence here that this program is regulated through a purine-sensitive mechanism, and that it can be re-activated in mature CNS neurons to induce extensive axon growth in vitro and in vivo. In dissociated goldfish retinal ganglion cells, the purine nucleoside inosine acts intracellularly to stimulate axon outgrowth by inducing the expression of GAP-43, Talpha-1 tubulin, and other growth-associated proteins. The purine analog 6-thioguanine (6-TG) acts in the opposite fashion, blocking axon growth and the underlying program of molecular changes. Prior studies in PC12 cells have shown that 6-TG selectively inhibits the activity of N-kinase, a 47-49 kDa serine-threonine kinase. Inosine acts as a competitor of 6-TG, suggesting that it acts as an N-kinase agonist, and that this kinase is part of a modular signal transduction pathway controlling axon growth. Following unilateral transections of the corticospinal tract in mature rats, inosine applied to the intact sensorimotor cortex stimulated layer 5 pyramidal cells to upregulate GAP-43 expression and to sprout axon collaterals that crossed the midline and reinnervated regions of the cervical spinal cord which had lost their normal afferents. It will now be important to identify the molecular changes that lie upstream and downstream of N-kinase, and to explore the clinical potential of activating this pathway in patients who have sustained CNS injury.},
author = {Benowitz, L I and Goldberg, D E and Irwin, N},
issn = {0922-6028},
journal = {Restorative neurology and neuroscience},
keywords = {Animals,Axons,Axons: physiology,Cell Division,Cell Division: physiology,Humans,Inosine,Inosine: chemistry,Inosine: physiology,Purines,Purines: chemistry,Purines: pharmacology,Retinal Ganglion Cells,Retinal Ganglion Cells: cytology,Retinal Ganglion Cells: physiology,Spinal Cord,Spinal Cord: cytology,Spinal Cord: physiology},
mendeley-groups = {inosine},
month = jan,
number = {1-2},
pages = {41--9},
pmid = {12082228},
title = {{A purine-sensitive mechanism regulates the molecular program for axon growth.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12082228},
volume = {19},
year = {2001}
}
</bibtex>

[3]
<bibtex>
@article{Hasko2000,
abstract = {Extracellular purines, including adenosine and ATP, are potent endogenous immunomodulatory molecules. Inosine, a degradation product of these purines, can reach high concentrations in the extracellular space under conditions associated with cellular metabolic stress such as inflammation or ischemia. In the present study, we investigated whether extracellular inosine can affect inflammatory/immune processes. In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1alpha, and IFN-gamma, but failed to alter the production of the anti-inflammatory cytokine IL-10. The effect of inosine did not require cellular uptake by nucleoside transporters and was partially reversed by blockade of adenosine A1 and A2 receptors. Inosine inhibited cytokine production by a posttranscriptional mechanism. The activity of inosine was independent of activation of the p38 and p42/p44 mitogen-activated protein kinases, the phosphorylation of the c-Jun terminal kinase, the degradation of inhibitory factor kappaB, and elevation of intracellular cAMP. Inosine suppressed proinflammatory cytokine production and mortality in a mouse endotoxemic model. Taken together, inosine has multiple anti-inflammatory effects. These findings, coupled with the fact that inosine has very low toxicity, suggest that this agent may be useful in the treatment of inflammatory/ischemic diseases.},
author = {Hask\'{o}, G and Kuhel, D G and N\'{e}meth, Z H and Mabley, J G and Stachlewitz, R F and Vir\'{a}g, L and Lohinai, Z and Southan, G J and Salzman, A L and Szab\'{o}, C},
issn = {0022-1767},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
keywords = {Animals,Anti-Inflammatory Agents, Non-Steroidal,Anti-Inflammatory Agents, Non-Steroidal: administr,Anti-Inflammatory Agents, Non-Steroidal: pharmacol,Chemokines,Chemokines: antagonists \& inhibitors,Chemokines: biosynthesis,Cytokines,Cytokines: antagonists \& inhibitors,Cytokines: biosynthesis,Enzyme Activation,Enzyme Activation: drug effects,Enzyme Activation: immunology,I-kappa B Proteins,I-kappa B Proteins: metabolism,Immunosuppressive Agents,Immunosuppressive Agents: pharmacology,Inflammation Mediators,Inflammation Mediators: antagonists \& inhibitors,Inflammation Mediators: metabolism,Injections, Intraperitoneal,Inosine,Inosine: administration \& dosage,Inosine: pharmacology,Interferon-gamma,Interferon-gamma: antagonists \& inhibitors,Interferon-gamma: biosynthesis,JNK Mitogen-Activated Protein Kinases,Lipopolysaccharides,Lipopolysaccharides: toxicity,Macrophage Activation,Macrophage Activation: drug effects,Macrophages, Peritoneal,Macrophages, Peritoneal: drug effects,Macrophages, Peritoneal: enzymology,Macrophages, Peritoneal: immunology,Macrophages, Peritoneal: metabolism,Male,Mice,Mice, Inbred BALB C,Mitogen-Activated Protein Kinase 1,Mitogen-Activated Protein Kinase 1: metabolism,Mitogen-Activated Protein Kinase 3,Mitogen-Activated Protein Kinases,Mitogen-Activated Protein Kinases: metabolism,Protein Processing, Post-Translational,Protein Processing, Post-Translational: drug effec,Protein Processing, Post-Translational: immunology,Purinergic P1 Receptor Agonists,Receptors, Purinergic P1,Receptors, Purinergic P1: physiology,Shock, Septic,Shock, Septic: etiology,Shock, Septic: immunology,Shock, Septic: pathology,Shock, Septic: prevention \& control,Th1 Cells,Th1 Cells: drug effects,Th1 Cells: metabolism},
mendeley-groups = {inosine},
month = jan,
number = {2},
pages = {1013--9},
pmid = {10623851},
title = {{Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10623851},
volume = {164},
year = {2000}
}
</bibtex>