Anticonvulsant doses of inosine result in brain levels sufficient to inhibit [3H] diazepam binding

Pj, Marangos; Trams, Eberhard G.; Clark-Rosenberg, R L; Paul, Steven M.; Skolnick, P.

doi:10.1007/bf00432183

Cited by 23 publications

(4 citation statements)

References 21 publications

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“…Besides its effects on axon sprouting, inosine has been reported to suppress the response of cortical neurons to glutamate [59], enhance inhibition via benzodiazepine receptors [60], limit the production of inflammatory cytokines [61,62], and attenuate hypoxia-induced astrocyte death [63,64]. Uric acid, a primary metabolite of inosine, prevents peroxynitrite-induced protein damage, protects the blood-brain barrier, and has potent anti-inflammatory effects [65,66].…”

Section: Discussionmentioning

confidence: 99%

Inosine Enhances Axon Sprouting and Motor Recovery after Spinal Cord Injury

et al. 2013

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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.

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Section: Discussionmentioning

confidence: 99%

Inosine Enhances Axon Sprouting and Motor Recovery after Spinal Cord Injury

et al. 2013

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“…In addition to promoting axon rewiring, inosine suppresses the response of cortical neurons to glutamate (Shen et al, 2005), enhances inhibition via benzodiazepine receptors (Marangos et al, 1981), limits the production of inflammatory cytokines (Hasko et al, 2000, 2004), and attenuates hypoxia-induced astrocyte death (Haun et al, 1996; Jurkowitz et al, 1998). Uric acid, a metabolite of inosine, prevents peroxynitrite-induced protein damage, protects the blood-brain barrier, and has potent anti-inflammatory effects (Scott et al, 2002, 2005).…”

Section: Discussionmentioning

confidence: 99%

Inosine Augments the Effects of a Nogo Receptor Blocker and of Environmental Enrichment to Restore Skilled Forelimb Use after Stroke

Zai¹,

Ferrari²,

Dice³

et al. 2011

J. Neurosci.

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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 to 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.

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“…Inosine did not show obvious neuroprotective effects in our study, as judged by the absence of changes in lesion size or in caspase-3 activation. Inosine has also been reported to suppress the response of cortical neurons to glutamate (Shen et al, 2005), enhance inhibition by binding to benzodiazepine receptors (Marangos et al, 1981), limit the production of inflammatory cytokines (Haskó et al, 2000, 2004) and, at high concentrations, block hypoxia-induced astrocyte death (Haun et al, 1996; Jurkowitz et al, 1998). In addition, uric acid, a primary metabolite of inosine, prevents peroxynitrite-induced protein damage, protects the blood–brain barrier, and has potent anti-inflammatory effects (Scott et al, 2002, 2005).…”

Section: Discussionmentioning

confidence: 99%

Inosine Alters Gene Expression and Axonal Projections in Neurons Contralateral to a Cortical Infarct and Improves Skilled Use of the Impaired Limb

Zai¹,

Ferrari²,

Subbaiah³

et al. 2009

Journal of Neuroscience

124

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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.

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Anticonvulsant doses of inosine result in brain levels sufficient to inhibit [3H] diazepam binding

Cited by 23 publications

References 21 publications

Inosine Enhances Axon Sprouting and Motor Recovery after Spinal Cord Injury

Inosine Enhances Axon Sprouting and Motor Recovery after Spinal Cord Injury

Inosine Augments the Effects of a Nogo Receptor Blocker and of Environmental Enrichment to Restore Skilled Forelimb Use after Stroke

Inosine Alters Gene Expression and Axonal Projections in Neurons Contralateral to a Cortical Infarct and Improves Skilled Use of the Impaired Limb

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