Inosine

Inosine, an endogenous purine nucleoside, has immunomodulatory, neuroprotective, and analgesic properties. In vitro: Inosine has been shown to stimulate axonal growth in cell culture and promote corticospinal tract axons to sprout collateral branches after stroke, spinal cord injury and TBI in rodent models.[1] Inosine dose-dependently stimulates cAMP production mediated through the A2AR. Inosine dose-dependently induces A2AR-mediated ERK1/2 phosphorylation.[2] In vivo: The reference for Inosine is 1 or 10 mg/kg, i.p. Preventive treatment with inosine inhibits the development and progression of EAE in C57Bl/6 mice. neuroinflammation and demyelinating processes are blocked by inosine treatment. Additionally, inosine consistently inhibits IL-17 levels in peripheral lymphoid tissue, as well as IL-4 levels and A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. [3] inosine acting through adenosine receptors (ARs) exerts a wide range of anti-inflammatory and immunomodulatory effects in vivo. [2]

References:
[1]. Moore TL et al. Inosine enhances recovery of grasp following cortical injury to the primary motor cortex of the rhesus monkey. Restor Neurol Neurosci. 2016 Aug 1. [2]. Welihinda AA et al. The adenosine metabolite inosine is a functional agonist of the adenosine A2A receptor with a unique signaling bias. Cell Signal. 2016 Jun;28(6):552-60. [3]. Junqueira SC et al. Inosine, an Endogenous Purine Nucleoside, Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis: a Role for A2A Adenosine Receptor. Mol Neurobiol. 2016 Apr 30.

Oral administration of inosine produces antidepressant-like effects in mice.[Pubmed:24569499]

Sci Rep. 2014 Feb 26;4:4199.

Inosine, a breakdown product of adenosine, has recently been shown to exert immunomodulatory and neuroprotective effects. We show here that the oral administration of Inosine has antidepressant-like effects in two animal models. Inosine significantly enhanced neurite outgrowth and viability of primary cultured neocortical neurons, which was suppressed by adenosine A1 and A2A receptor agonists. Oral administration of Inosine to mice transiently increased its concentration in the brain and enhanced neuronal proliferation in the dentate gyrus, accompanied by phosphorylation of mitogen-activated protein kinase and increase in transcript level of brain-derived neurotrophic factor. In stress models, oral Inosine prevented an increase in immobility time in forced swim test after chronically unexpected stress and mitigated a reduction in sucrose preference after chronic social defeat stress. These results indicate that oral administration of Inosine has the potential to prevent depressive disorder via adenosine receptors.

Preconditioning with gabexate is superior to inosine for ameliorating acute renal ischemia-reperfusion injury in rats.[Pubmed:24507023]

Transplant Proc. 2014 Jan-Feb;46(1):40-5.

OBJECTIVE: The objective of this study was to compare the protease inhibitor gabexate with widely used Inosine for reducing renal ischemia-reperfusion injury. METHOD: A total of 48 rats were divided into 4 groups of 12 and administered gabexate, Inosine, normal saline (NS), or nothing by injection through the vena dorsalis of the penis. Then all rats were subjected to right nephrectomy and 30-minute warm ischemia of the left kidney. At 24 and 48 hours after reperfusion, blood samples were collected from the inferior vena cava and serum creatinine (SCr) was assayed. Left kidney tissue was homogenized and used to assay malondialdehyde (MDA) and superoxide dismutase (SOD). The tissue was also analyzed using hematoxylin-eosin (HE) staining, TUNEL staining, and NF-kappaB immunohistochemistry. RESULTS: SCr level decreased after reperfusion more in the gabexate group than in the other groups. Reperfused kidney tissue in the gabexate group showed lower MDA levels but higher SOD activity than did tissue in the Inosine and saline groups, as well as lower pathology scores based on HE staining, lower necrosis index, and lower levels of NF-kappaB expression (all P < .05). Tissue in the Inosine and saline groups showed similar necrosis index and NF-kappaB expression (P > .05). CONCLUSION: Preconditioning with gabexate is superior to preconditioning with Inosine for ameliorating rat renal ischemia-reperfusion injury. Future studies are needed to verify the effects of gabexate in the clinic, especially for kidney transplantation.

Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.[Pubmed:24366103]

JAMA Neurol. 2014 Feb;71(2):141-50.

IMPORTANCE: Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). OBJECTIVE: To determine the safety, tolerability, and urate-elevating capability of the urate precursor Inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. DESIGN, SETTING, AND PARTICIPANTS: The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of Inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. INTERVENTIONS: Participants were randomized to 1 of 3 treatment arms: placebo or Inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. MAIN OUTCOMES AND MEASURES: The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the Inosine groups relative to placebo. No participant developed gout and 3 receiving Inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 Inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both Inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of Inosine treatment for slowing disability. CONCLUSIONS AND RELEVANCE: Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of Inosine as a potential disease-modifying therapy for PD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00833690.

Inosine induces presynaptic inhibition of acetylcholine release by activation of A3 adenosine receptors at the mouse neuromuscular junction.[Pubmed:23731236]

Br J Pharmacol. 2013 Aug;169(8):1810-23.

BACKGROUND AND PURPOSE: The role of Inosine at the mammalian neuromuscular junction (NMJ) has not been clearly defined. Moreover, Inosine was classically considered to be the inactive metabolite of adenosine. Hence, we investigated the effect of Inosine on spontaneous and evoked ACh release, the mechanism underlying its modulatory action and the receptor type and signal transduction pathway involved. EXPERIMENTAL APPROACH: End-plate potentials (EPPs) and miniature end-plate potentials (MEPPs) were recorded from the mouse phrenic-nerve diaphragm preparations using conventional intracellular electrophysiological techniques. KEY RESULTS: Inosine (100 muM) reduced MEPP frequency and the amplitude and quantal content of EPPs; effects inhibited by the selective A3 receptor antagonist MRS-1191. Immunohistochemical assays confirmed the presence of A3 receptors at mammalian NMJ. The voltage-gated calcium channel (VGCC) blocker Cd(2+) , the removal of extracellular Ca(2+) and the L-type and P/Q-type VGCC antagonists, nitrendipine and omega-agatoxin IVA, respectively, all prevented Inosine-induced inhibition. In the absence of endogenous adenosine, Inosine decreased the hypertonic response. The effects of Inosine on ACh release were prevented by the Gi/o protein inhibitor N-ethylmaleimide, PKC antagonist chelerytrine and calmodulin antagonist W-7, but not by PKA antagonists, H-89 and KT-5720, or the inhibitor of CaMKII KN-62. CONCLUSION AND IMPLICATIONS: Our results suggest that, at motor nerve terminals, Inosine induces presynaptic inhibition of spontaneous and evoked ACh release by activating A3 receptors through a mechanism that involves L-type and P/Q-type VGCCs and the secretory machinery downstream of calcium influx. A3 receptors appear to be coupled to Gi/o protein. PKC and calmodulin may be involved in these effects of Inosine.

Inosine improves functional recovery after experimental traumatic brain injury.[Pubmed:24502983]

Brain Res. 2014 Mar 25;1555:78-88.

Despite years of research, no effective therapy is yet available for the treatment of traumatic brain injury (TBI). The most prevalent and debilitating features in survivors of TBI are cognitive deficits and motor dysfunction. A potential therapeutic method for improving the function of patients following TBI would be to restore, at least in part, plasticity to the CNS in a controlled way that would allow for the formation of compensatory circuits. Inosine, a naturally occurring purine nucleoside, has been shown to promote axon collateral growth in the corticospinal tract (CST) following stroke and focal TBI. In the present study, we investigated the effects of Inosine on motor and cognitive deficits, CST sprouting, and expression of synaptic proteins in an experimental model of closed head injury (CHI). Treatment with Inosine (100 mg/kg i.p. at 1, 24 and 48 h following CHI) improved outcome after TBI, significantly decreasing the neurological severity score (NSS, p<0.04 vs. saline), an aggregate measure of performance on several tasks. It improved non-spatial cognitive performance (object recognition, p<0.016 vs. saline) but had little effect on sensorimotor coordination (rotarod) and spatial cognitive functions (Y-maze). Inosine did not affect CST sprouting in the lumbar spinal cord but did restore levels of the growth-associated protein GAP-43 in the hippocampus, though not in the cerebral cortex. Our results suggest that Inosine may improve functional outcome after TBI.