The Experts below are selected from a list of 186 Experts worldwide ranked by ideXlab platform
Larry I Benowitz - One of the best experts on this subject based on the ideXlab platform.
-
Inosine enhances axon sprouting and motor recovery after spinal cord injury
PLOS ONE, 2013Co-Authors: Colleen Schaffling, Peng Liang, David Ahlborn, Larry I BenowitzAbstract:Although corticospinal tract axons cannot regenerate long distances after spinal cord injury, they are able to sprout collateral branches rostral to an injury site that can help form compensatory circuits in cases of incomplete lesions. We show here that Inosine enhances the formation of compensatory circuits after a dorsal hemisection of the thoracic spinal cord in mature rats and improves coordinated limb use. Inosine is a naturally occurring metabolite of adenosine that crosses the cell membrane and, in neurons, activates Mst3b, a protein kinase that is part of a signal transduction pathway that regulates axon outgrowth. Compared to saline-treated controls, rats with dorsal hemisections that were treated with Inosine showed three times as many synaptic contacts between corticospinal tract collaterals and long propriospinal interneurons that project from the cervical cord to the lumbar level. Inosine-treated rats also showed stronger serotonergic reinnervation of the lumbar cord than saline-treated controls, and performed well above controls in both open-field testing and a horizontal ladder rung-walking test. Inosine was equally effective whether delivered intracranially or intravenously, and has been shown to be safe for other indications in humans. Thus, Inosine might be a useful therapeutic for improving outcome after spinal cord injury.
-
Inosine augments the effects of a nogo receptor blocker and of environmental enrichment to restore skilled forelimb use after stroke
The Journal of Neuroscience, 2011Co-Authors: Christina Ferrari, Carlie Dice, Sathish Subbaiah, Leif A Havton, Giovanni Coppola, Daniel H Geschwind, Nina Irwin, Eric A Huebner, Stephen M Strittmatter, Larry I BenowitzAbstract:Stroke is the leading cause of disability in much of the world, with few treatment options available. Following unilateral stroke in rats, Inosine, a naturally occurring purine nucleoside, stimulates the growth of projections from the undamaged hemisphere into denervated areas of the spinal cord and improves skilled use of the impaired forelimb. Inosine augments neurons' intrinsic growth potential by activating Mst3b, a component of the signal transduction pathway through which trophic factors regulate axon outgrowth. The present study investigated whether Inosine would complement the effects of treatments that promote plasticity through other mechanisms. Following unilateral stroke in the rat forelimb motor area, Inosine combined with NEP1-40, a Nogo receptor antagonist, doubled the number of axon branches extending from neurons in the intact hemisphere into the denervated side of the spinal cord compared with either treatment alone, and restored rats' level of skilled reaching using the impaired forepaw to preoperative levels. Similar functional improvements were seen when Inosine was combined with environmental enrichment (EE). The latter effect was associated with changes in gene expression in layer 5 pyramidal neurons of the undamaged cortex well beyond those seen with Inosine or EE alone. Inosine is now in clinical trials for other indications, making it an attractive candidate for the treatment of stroke patients.
-
Inosine alters gene expression and axonal projections in neurons contralateral to a cortical infarct and improves skilled use of the impaired limb
The Journal of Neuroscience, 2009Co-Authors: Christina Ferrari, Sathish Subbaiah, Leif A Havton, Giovanni Coppola, Daniel H Geschwind, Nina Irwin, Stephen M Strittmatter, Larry I BenowitzAbstract:Recovery after stroke and other types of brain injury is restricted in part by the limited ability of undamaged neurons to form compensatory connections. Inosine, a naturally occurring purine nucleoside, stimulates neurons to extend axons in culture and, in vivo, enhances the ability of undamaged neurons to form axon collaterals after brain damage. The molecular changes induced by Inosine are unknown, as is the ability of Inosine to restore complex functions associated with a specific cortical area. Using a unilateral injury model limited to the sensorimotor cortex, we show that Inosine triples the number of corticospinal tract axons that project from the unaffected hemisphere and form synaptic bouton-like structures in the denervated half of the spinal cord. These changes correlate with improved recovery in animals' ability to grasp and consume food pellets with the affected forepaw. Studies using laser-capture microdissection and microarray analysis show that Inosine profoundly affects gene expression in corticospinal neurons contralateral to the injury. Inosine attenuates transcriptional changes caused by the stroke, while upregulating the expression of genes associated with axon growth and the complement cascade. Thus, Inosine alters gene expression in neurons contralateral to a stroke, enhances the ability of these neurons to form connections on the denervated side of the spinal cord, and improves performance with the impaired limb.
-
Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Larry I Benowitz, David E Goldberg, Joseph R Madsen, Deepa Soni, Nina IrwinAbstract: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.
Michail V Sitkovsky - One of the best experts on this subject based on the ideXlab platform.
-
immunomodulatory and neuroprotective effects of Inosine
Trends in Pharmacological Sciences, 2004Co-Authors: Michail V Sitkovsky, Gyorgy Hasko, Csaba SzaboAbstract:Abstract Adenosine has been considered as a potential immunomodulatory and neuroprotective agent for 30 years. Inosine, a major degradation product of adenosine, was thought originally to have no biological effects. However, recent studies demonstrate that Inosine has potent immunomodulatory and neuroprotective effects. Inosine enhances mast-cell degranulation, attenuates the production of pro-inflammatory mediators by macrophages, lymphocytes and neutrophils, and is protective in animal models of sepsis, ischemia–reperfusion and autoimmunity. Inosine preserves the viability of glial cells and neuronal cells during hypoxia, and stimulates axonal regrowth after injury. The biological actions of Inosine might involve effects on adenosine receptors, poly(ADP-ribose) polymerase and cellular energy levels. In this article, we review recent observations indicating that it might be possible to exploit Inosine therapeutically for the treatment of tissue damage caused by inflammation and ischemia.
-
differential requirement for a2a and a3 adenosine receptors for the protective effect of Inosine in vivo
Blood, 2003Co-Authors: Gregorio Gomez, Michail V SitkovskyAbstract:Inosine is an endogenous nucleoside with immunosuppressive properties that is known to inhibit the accumulation of proinflammatory cytokines and protect mice from endotoxin-induced inflammation and lung tissue damage. There are no known receptors specific for Inosine, but A3 adenosine receptors (A3Rs) have been shown to bind Inosine, resulting in mast cell degranulation and increased vascular permeability. The present study specifically addresses the requirement for A2aR and/or A3R for the protective effect of Inosine in 2 experimental in vivo models of inflammatory disease. The data show that A3R is essential for protection against ConA-induced fulminant hepatitis since only A3R-expressing mice were protected by Inosine whereas wild-type and A2aR-deficient mice exhibited severe liver damage even after administration of Inosine. In addition, we show in a model of LPS-induced endotoxemia that Inosine protected both A2aR-/- and A3R-/- mice from inflammation, but not A2aA3R double-null mice, indicating that in this model both A2aR and A3R were used by Inosine. Thus, we demonstrate that A2a and A3 adenosine receptors are differentially utilized by Inosine for the down-regulation of tissue damage under different inflammatory conditions in vivo. (Blood. 2003;102:4472-4478)
Megumi Shimaoka - One of the best experts on this subject based on the ideXlab platform.
-
Expression of the guanosine-Inosine kinase gene from Exiguobacteriumacetylicum in Corynebacterium ammoniagenes and phosphorylation of Inosine to produce Inosine 5′-monophosphate
World Journal of Microbiology & Biotechnology, 2010Co-Authors: Yoshihiro Usuda, Megumi Shimaoka, Hisashi Kawasaki, Takashi UtagawaAbstract:The guanosine-Inosine kinase gene (gsk) isolated from Exiguobacterium acetylicum was expressed in an ATP-regenerating strain, Corynebacterium ammoniagenes. In order to induce its expression, three promoters (those for the Escherichia coli tac, Escherichia coli trp, and Corynebacterium glutamicum odhA gene) with the corresponding ribosome-binding sequences were examined. The E. coli trp promoter was most efficient with regard to inducing the expression of gsk in C. ammoniagenes. Further, the resulting strain, which has both Inosine kinase activity and ATP-regenerating activity, was used to induce the phosphorylation of Inosine to produce Inosine 5′-monophosphate (5′-IMP), which is widely used as a flavor enhancer; approximately 80 g of 5′-IMP/l was produced with a molar conversion ratio of 80%.
-
effect of amplification of desensitized purf and prs on Inosine accumulation in escherichia coli
Journal of Bioscience and Bioengineering, 2007Co-Authors: Megumi Shimaoka, Yasuhiro Takenaka, Osamu Kurahashi, Hisashi Kawasaki, Hiroshi MatsuiAbstract:The effect of a phosphoribosylpyrophosphate (PRPP) synthetase gene (prs) that was desensitized to feedback inhibition by ADP on Inosine accumulation was investigated using an Inosine-producing mutant of Escherichia coli. At the same time, various types of plasmid having a PRPP amidotransferase gene (purF) that was desensitized to feedback inhibition by AMP and GMP were also investigated to improve Inosine productivity using a compatible plasmid containing prs with a plasmid containing purF. The recombinant E. coli I-9 harboring a low-copy-number plasmid having the desensitized-purF (pMWKQ) accumulated 3.6 g/l Inosine from 40 g/l glucose in a 2-d culture. Furthermore, desensitized-prs amplification, in addition to purF, resulted in the accumulation of 6.2 g/l Inosine. Additionally, through these experiments, a spontaneous mutant with an enhanced Inosine-producing ability compared with the parent strain I-9 was obtained. The spontaneous mutant I-9m harboring only pMWKQ and I-9m harboring both pMWKQ and pSTVDA (a plasmid having the desensitized-prs) accumulated 6.7 g/l and 7.5 g/l Inosine, respectively, from 40 g/l glucose in a 3-d culture.
Hisashi Kawasaki - One of the best experts on this subject based on the ideXlab platform.
-
Expression of the guanosine-Inosine kinase gene from Exiguobacteriumacetylicum in Corynebacterium ammoniagenes and phosphorylation of Inosine to produce Inosine 5′-monophosphate
World Journal of Microbiology & Biotechnology, 2010Co-Authors: Yoshihiro Usuda, Megumi Shimaoka, Hisashi Kawasaki, Takashi UtagawaAbstract:The guanosine-Inosine kinase gene (gsk) isolated from Exiguobacterium acetylicum was expressed in an ATP-regenerating strain, Corynebacterium ammoniagenes. In order to induce its expression, three promoters (those for the Escherichia coli tac, Escherichia coli trp, and Corynebacterium glutamicum odhA gene) with the corresponding ribosome-binding sequences were examined. The E. coli trp promoter was most efficient with regard to inducing the expression of gsk in C. ammoniagenes. Further, the resulting strain, which has both Inosine kinase activity and ATP-regenerating activity, was used to induce the phosphorylation of Inosine to produce Inosine 5′-monophosphate (5′-IMP), which is widely used as a flavor enhancer; approximately 80 g of 5′-IMP/l was produced with a molar conversion ratio of 80%.
-
effect of amplification of desensitized purf and prs on Inosine accumulation in escherichia coli
Journal of Bioscience and Bioengineering, 2007Co-Authors: Megumi Shimaoka, Yasuhiro Takenaka, Osamu Kurahashi, Hisashi Kawasaki, Hiroshi MatsuiAbstract:The effect of a phosphoribosylpyrophosphate (PRPP) synthetase gene (prs) that was desensitized to feedback inhibition by ADP on Inosine accumulation was investigated using an Inosine-producing mutant of Escherichia coli. At the same time, various types of plasmid having a PRPP amidotransferase gene (purF) that was desensitized to feedback inhibition by AMP and GMP were also investigated to improve Inosine productivity using a compatible plasmid containing prs with a plasmid containing purF. The recombinant E. coli I-9 harboring a low-copy-number plasmid having the desensitized-purF (pMWKQ) accumulated 3.6 g/l Inosine from 40 g/l glucose in a 2-d culture. Furthermore, desensitized-prs amplification, in addition to purF, resulted in the accumulation of 6.2 g/l Inosine. Additionally, through these experiments, a spontaneous mutant with an enhanced Inosine-producing ability compared with the parent strain I-9 was obtained. The spontaneous mutant I-9m harboring only pMWKQ and I-9m harboring both pMWKQ and pSTVDA (a plasmid having the desensitized-prs) accumulated 6.7 g/l and 7.5 g/l Inosine, respectively, from 40 g/l glucose in a 3-d culture.
Joel Linden - One of the best experts on this subject based on the ideXlab platform.
-
Inosine binds to a3 adenosine receptors and stimulates mast cell degranulation
Journal of Clinical Investigation, 1997Co-Authors: R K Shepherd, Brian R Duling, Joel LindenAbstract:We investigated the mechanism by which Inosine, a metabolite of adenosine that accumulates to > 1 mM levels in ischemic tissues, triggers mast cell degranulation. Inosine was found to do the following: (a) compete for [125I]N6-aminobenzyladenosine binding to recombinant rat A3 adenosine receptors (A3AR) with an IC50 of 25+/-6 microM; (b) not bind to A1 or A2A ARs; (c) bind to newly identified A3ARs in guinea pig lung (IC50 = 15+/-4 microM); (d) lower cyclic AMP in HEK-293 cells expressing rat A3ARs (ED50 = 12+/-5 microM); (e) stimulate RBL-2H3 rat mast-like cell degranulation (ED50 = 2.3+/-0.9 microM); and (f) cause mast cell-dependent constriction of hamster cheek pouch arterioles that is attenuated by A3AR blockade. Inosine differs from adenosine in not activating A2AARs that dilate vascular smooth muscle and inhibit mast cell degranulation. The A3 selectivity of Inosine may explain why it elicits a monophasic arteriolar constrictor response distinct from the multiphasic dilator/constrictor response to adenosine. Nucleoside accumulation and an increase in the ratio of Inosine to adenosine may provide a physiologic stimulus for mast cell degranulation in ischemic or inflamed tissues.
