Importance of Schedule of Administration in the Therapeutic Efficacy of Guanosine: Early Intervention After Injury Enhances Glutamate Uptake in Model of Hypoxia-ischemia

Moretto, Maria Beatriz; Boff, Bruna de Souza; Lavinsky, Daniel; Netto, Carlos Alexandre; Rocha, João Batista Teixeira da; Souza, Diogo O.; Wofchuk, Susana Tchernin

doi:10.1007/s12031-008-9154-7

Cited by 21 publications

(16 citation statements)

References 20 publications

(19 reference statements)

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“…The data from in vitro models suggest that guanosine protects against oxygen and glucose deprivation [22][23][24][25][26], increases glutamate uptake in hypoxia-ischemia models [27,43], and protects against glucose deprivation [17]. In vivo guanosine is neuroprotective against permanent and transient ischemic stroke, promotes functional improvement, and reduces infarct volume [24,28,29].…”

Section: Discussionmentioning

confidence: 99%

“…Several neurodegenerative and neurotoxic models have demonstrated that guanosine plays an important role in the CNS [12][13][14][15][16][17][18], exerting trophic effects on neural cells [19,20], and protective modulatory effects on the glutamatergic system [18,[20][21][22][23]. Studies have shown that guanosine protects against several ischemic models, including oxygen and glucose deprivation [24][25][26], hypoxia-ischemia models [27], and in vivo permanent and transient ischemic stroke [24,28,29]. Researchers have claimed that guanosine is neuroprotective against oxidative and inflammatory processes induced by ischemia via MAPK/ERK pathway activation [22,25,26].…”

Section: Introductionmentioning

confidence: 99%

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Guanosine Protects Against Cortical Focal Ischemia. Involvement of Inflammatory Response

et al. 2014

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Stroke is the major cause of death and the most frequent cause of disability in the adult population worldwide. Guanosine plays an important neuroprotective role in several cerebral ischemic models and is involved in the modulation of oxidative responses and glutamatergic parameters. Because the excessive reactive oxygen species produced during an ischemic event can trigger an inflammatory response, the purpose of this study was to evaluate the hypothesis that guanosine is neuroprotective against focal cerebral ischemia, inhibits microglia/macrophages activation, and mediates an inflammatory response ameliorating the neural damage. Permanent focal cerebral ischemia was induced in adult rats, and guanosine was administered immediately, 1, 3, and 6 h after surgery. Twenty-four hours after ischemia, the asymmetry scores were evaluated by the cylinder test; neuronal damage was evaluated by Fluoro-Jade C (FJC) staining and propidium iodide (PI) incorporation; microglia and immune cells were evaluated by anti-Iba-1 antibody; and inflammatory parameters such as interleukins (IL): IL-1, IL-6, IL-10; tumor necrosis factors alpha (TNF-α); and interferon-gamma (INF-γ) were evaluated in the brain tissue and cerebrospinal fluid. The ischemic event increased the levels of Iba-1-positive cells and pro-inflammatory cytokines and decreased IL-10 levels (an anti-inflammatory cytokine) in the lesion periphery. The guanosine treatment attenuated the changes in these inflammatory parameters and also reduced the infarct volume, PI incorporation, and number of FJC-positive cells, improving the functional recovery. Thus, guanosine may have been a promising therapeutic agent for the treatment of ischemic brain injury by reduction of inflammatory process triggered in an ischemic event.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Guanosine Protects Against Cortical Focal Ischemia. Involvement of Inflammatory Response

et al. 2014

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“…Current evidence suggests that guanosine stimulates glutamate uptake by astrocytes [48–50]. Consequently, guanosine reduces seizures induced by glutamatergic agents [51, 52], and is neuroprotective in response to ischemia-hypoxia [53]. On the behavioral side, guanosine impaired retention on the inhibitory avoidance task and decreased locomotor activity on the open field test [54].…”

Section: Nucleosides In Brain Functionmentioning

confidence: 99%

Modulators of Nucleoside Metabolism in the Therapy of Brain Diseases

Boison¹

2011

CTMC

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Nucleoside receptors are known to be important targets for a variety of brain diseases. However, the therapeutic modulation of their endogenous agonists by inhibitors of nucleoside metabolism represents an alternative therapeutic strategy that has gained increasing attention in recent years. Deficiency in endogenous nucleosides, in particular of adenosine, may causally be linked to a variety of neurological diseases and neuropsychiatric conditions ranging from epilepsy and chronic pain to schizophrenia. Consequently, augmentation of nucleoside function by inhibiting their metabolism appears to be a rational therapeutic strategy with distinct advantages: (i) in contrast to specific receptor modulation, the increase (or decrease) of the amount of a nucleoside will affect several signal transduction pathways simultaneously and therefore have the unique potential to modify complex neurochemical networks; (ii) by acting on the network level, inhibitors of nucleoside metabolism are highly suited to fine-tune, restore, or amplify physiological functions of nucleosides; (iii) therefore inhibitors of nucleoside metabolism have promise for the "soft and smart" therapy of neurological diseases with the added advantage of reduced systemic side effects. This review will first highlight the role of nucleoside function and dysfunction in physiological and pathophysiological situations with a particular emphasis on the anticonvulsant, neuroprotective, and antinociceptive roles of adenosine. The second part of this review will cover pharmacological approaches to use inhibitors of nucleoside metabolism, with a special emphasis on adenosine kinase, the key regulator of endogenous adenosine. Finally, novel gene-based therapeutic strategies to inhibit nucleoside metabolism and focal treatment approaches will be discussed.

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“…This finding led to the investigation of the effects of exogenously administered GUO on stroke models. The data from in vitro models suggests that GUO protects against oxygen and glucose deprivation (OGD) [25]–[29], increases glutamate uptake in hypoxia-ischemia models [30], [31], and is neuroprotective against permanent and transient ischemic stroke [25], [32], [33]. In addition, GUO demonstrates antioxidant activity, protecting DNA from oxidative damage [34], [35], and modulates oxidative and nitrosative stress in neurotoxic models [36], [37].…”

Section: Introductionmentioning

confidence: 99%

The Potential Therapeutic Effect of Guanosine after Cortical Focal Ischemia in Rats

et al. 2014

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Background and PurposeStroke is a devastating disease. Both excitotoxicity and oxidative stress play important roles in ischemic brain injury, along with harmful impacts on ischemic cerebral tissue. As guanosine plays an important neuroprotective role in the central nervous system, the purpose of this study was to evaluate the neuroprotective effects of guanosine and putative cerebral events following the onset of permanent focal cerebral ischemia.MethodsPermanent focal cerebral ischemia was induced in rats by thermocoagulation. Guanosine was administered immediately, 1 h, 3 h and 6 h after surgery. Behavioral performance was evaluated by cylinder testing for a period of 15 days after surgery. Brain oxidative stress parameters, including levels of ROS/RNS, lipid peroxidation, antioxidant non-enzymatic levels (GSH, vitamin C) and enzymatic parameters (SOD expression and activity and CAT activity), as well as glutamatergic parameters (EAAC1, GLAST and GLT1, glutamine synthetase) were analyzed.ResultsAfter 24 h, ischemic injury resulted in impaired function of the forelimb, caused brain infarct and increased lipid peroxidation. Treatment with guanosine restored these parameters. Oxidative stress markers were affected by ischemic insult, demonstrated by increased ROS/RNS levels, increased SOD expression with reduced SOD activity and decreased non-enzymatic (GSH and vitamin C) antioxidant defenses. Guanosine prevented increased ROS/RNS levels, decreased SOD activity, further increased SOD expression, increased CAT activity and restored vitamin C levels. Ischemia also affected glutamatergic parameters, illustrated by increased EAAC1 levels and decreased GLT1 levels; guanosine reversed the decreased GLT1 levels and did not affect the EAAC1 levels.ConclusionThe effects of brain ischemia were strongly attenuated by guanosine administration. The cellular mechanisms involved in redox and glutamatergic homeostasis, which were both affected by the ischemic insult, were also modulated by guanosine. These observations reveal that guanosine may represent a potential therapeutic agent in cerebral ischemia by preventing oxidative stress and excitotoxicity.

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Importance of Schedule of Administration in the Therapeutic Efficacy of Guanosine: Early Intervention After Injury Enhances Glutamate Uptake in Model of Hypoxia-ischemia

Cited by 21 publications

References 20 publications

Guanosine Protects Against Cortical Focal Ischemia. Involvement of Inflammatory Response

Guanosine Protects Against Cortical Focal Ischemia. Involvement of Inflammatory Response

Modulators of Nucleoside Metabolism in the Therapy of Brain Diseases

The Potential Therapeutic Effect of Guanosine after Cortical Focal Ischemia in Rats

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