Inosine

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Information on nutritional supplements people with ALS have been taking

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Inosine has been thought of in the B vitamin family, although it is not technically a vitamin because the 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. [ health news ]


Effects on ALS[edit]

[1]

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]

Inosine antagonizes glutamate-induced electrophysiological excitation in rat cerebral cortical neurons.[4]

Inosine protects rat oligodendrocytes from hypoxic injury as an antioxidant and ATP provider, and the protective effects of inosine on oligodendrocytes vary with cell differentiation, possibly due to the adenosine receptors expression profile.[5]

In mouse spinal culture under hypoxic conditions, inosine preserved both total cell and neuronal viability in a concentration-dependent manner.[6]

A Phase 1 clinical trial on the effects of inosine on ALS through elevating uric acid is due to be completed in March 2016.

http://cleantalkorg2.ru/article - k

ALSUntangled evaluation[edit]

Inosine is a low-cost supplement that increases the levels of urate, a naturally occurring antioxidant. With appropriate blood and urine monitoring, it appears reasonably safe. Epidemiologic data suggest that high urate levels may be associated with improved survival in ALS, which prompted pre-clinical studies and clinical trials of inosine. These are still ongoing and will help determine whether inosine could be a useful treatment for ALS.[7]


Regulated pathways[edit]

Upregulates GAP-43

Probable N-kinase agonist

Inhibits TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1alpha, and IFN-gamma,

References[edit]

  1. Benowitz et al.: Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury. Proc. Natl. Acad. Sci. U.S.A. 1999;96:13486-90. PMID: 10557347. 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.
  2. Benowitz et al.: A purine-sensitive mechanism regulates the molecular program for axon growth. Restor. Neurol. Neurosci. 2001;19:41-9. PMID: 12082228. 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.
  3. Haskó et al.: Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. J. Immunol. 2000;164:1013-9. PMID: 10623851. 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.
  4. Shen et al.: Inosine reduces ischemic brain injury in rats. Stroke 2005;36:654-9. PMID: 15692110. DOI. BACKGROUND AND PURPOSE: Purinergic nucleoside inosine elicits protection and regeneration during various injuries. The purpose of this study was to examine the protective effects of inosine against cerebral ischemia. METHODS: Adult Sprague-Dawley rats were anesthetized. Inosine, hypoxathine, or vehicle was administered intracerebroventricularly before transient right middle cerebral artery occlusion (MCAo). Animals were placed in behavioral chambers 2 days to 2 weeks after MCAo and then euthanized for tri-phenyl-tetrazolium chloride staining. Glutamate release was measured by microdialysis/high-performance liquid chromatography, and single-unit action potentials were recorded from neurons in the parietal cortex. RESULTS: Stroke animals receiving inosine pretreatment demonstrated a higher level of locomotor activity and less cerebral infarction. Intracerebroventricular administration of the same dose of hypoxanthine did not confer protection. Coadministration of selective A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1, 4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS1191) significantly reduced inosine-mediated protection. Inosine did not alter basal glutamate release, nor did it reduce ischemia-evoked glutamate overflow from cerebral cortex. However, inosine antagonized glutamate-induced electrophysiological excitation in cerebral cortical neurons. CONCLUSIONS: Inosine inhibits glutamate postsynaptic responses and reduces cerebral infarction. Its protective effect against ischemia/reperfusion-related insults may involve activation of adenosine A3 receptors.
  5. Ma et al.: The protective effects of inosine against chemical hypoxia on cultured rat oligodendrocytes. Cell. Mol. Neurobiol. 2011;31:1171-86. PMID: 21643997. DOI. Inosine is a purine nucleoside and is considered protective to neural cells including neurons and astrocytes against hypoxic injury. However, whether oligodendrocytes (OLs) could also be protected from hypoxia by inosine is not known. Here we investigated the effects of inosine on primarily cultured rat OLs injured by rotenone-mediated chemical hypoxia, and the mechanisms of the effects using ATP assay, MTT assay, PI-Hoechst staining, TUNEL, and immunocytochemistry. Results showed that rotenone exposure for 24 h caused cell death and impaired viability in both immature and mature OLs, while pretreatment of 10 mM inosine 30 min before rotenone administration significantly reduced cell death and improved the viability of OLs. The same concentration of inosine given 120 min after rotenone exposure also improved viability of injured mature OLs. Immunocytochemistry for nitrotyrosine and cellular ATP content examination indicated that inosine may protect OLs by providing ATP and scavenging peroxynitrite for cells. In addition, immature OLs were more susceptible to hypoxia than mature OLs; and at the similar degree of injury, inosine protected immature and mature OLs differently. Quantitative real-time PCR revealed that expression of adenosine receptors was different between these two stages of OLs. These data suggest that inosine protect OLs from hypoxic injury as an antioxidant and ATP provider, and the protective effects of inosine on OLs vary with cell differentiation, possibly due to the adenosine receptors expression profile. As OLs form myelin in the central nervous system, inosine could be used as a promising drug to treat demyelination-involved disorders.
  6. Litsky et al.: Inosine and guanosine preserve neuronal and glial cell viability in mouse spinal cord cultures during chemical hypoxia. Brain Res. 1999;821:426-32. PMID: 10064830. Murine spinal cord primary mixed cultures were treated with the respiratory inhibitor, rotenone, to mimic hypoxic conditions. Under these conditions neurons rapidly underwent oncosis (necrosis) with a complete loss in viability occurring within 260 min; however, astrocytes, which accounted for most of the cell population, died more slowly with 50% viability occurring at 565 min. Inosine preserved both total cell and neuronal viability in a concentration-dependent manner. The time of inosine addition relative to hypoxic insult was critical with the most effective protection occurring when inosine was added just prior to or within 5 min after insult. Inosine was ineffective when added 30 min after hypoxic insult. The effect of guanosine was similar to that of inosine. Treatment of cultures with BCX-34, a purine nucleoside phosphorylase inhibitor, prevented protection by inosine or guanosine, suggesting involvement of a purine nucleoside phosphorylase in the nucleoside protective effect.
  7. ALSUntangled Group: ALSUntangled No. 37: Inosine. Amyotroph Lateral Scler Frontotemporal Degener 2016;1-4. PMID: 27575981. DOI.