Guanosine prevents nitroxidative stress and recovers mitochondrial membrane potential disruption in hippocampal slices subjected to oxygen/glucose deprivation

Thomaz, Daniel Tonial; Dal-Cim, Tharine; Martins, Wagner C.; Cunha, Maurício P.; Lanznaster, Débora; de, Andreza Fabro; Tasca, Carla I.

doi:10.1007/s11302-016-9534-3

Cited by 29 publications

(20 citation statements)

References 54 publications

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“…Since A 2A R heteromerizes with A 1 R [17], and some of the physiological effects of guanosine were modulated by A 1 R ligands [32,33], we investigated whether A 1 R/A 2A R heteromer formation affected AR-related guanosine-dependent effects. To this end, we first recreated the formation of A 1 R/A 2A R heteromers in HEK-293T cells by transfecting A 2A R RLuc and A 1 R YFP constructs and monitoring A 2A R/A 1 R heteromerization by a classical BRET approach ( Figure A1).…”

Section: A 2a R Ligand Binding Is Affected By Guanosine Upon a 1 R Comentioning

confidence: 99%

Adenosine A1-A2A Receptor-Receptor Interaction: Contribution to Guanosine-Mediated Effects

Lanznaster

Massari

Marková

et al. 2019

Cells

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Guanosine, a guanine-based purine nucleoside, has been described as a neuromodulator that exerts neuroprotective effects in animal and cellular ischemia models. However, guanosine's exact mechanism of action and molecular targets have not yet been identified. Here, we aimed to elucidate a role of adenosine receptors (ARs) in mediating guanosine effects. We investigated the neuroprotective effects of guanosine in hippocampal slices from A 2A R-deficient mice (A 2A R −/− ) subjected to oxygen/glucose deprivation (OGD). Next, we assessed guanosine binding at ARs taking advantage of a fluorescent-selective A 2A R antagonist (MRS7396) which could engage in a bioluminescence resonance energy transfer (BRET) process with NanoLuc-tagged A 2A R. Next, we evaluated functional AR activation by determining cAMP and calcium accumulation. Finally, we assessed the impact of A 1 R and A 2A R co-expression in guanosine-mediated impedance responses in living cells. Guanosine prevented the reduction of cellular viability and increased reactive oxygen species generation induced by OGD in hippocampal slices from wild-type, but not from A 2A R −/− mice. Notably, while guanosine was not able to modify MRS7396 binding to A 2A R-expressing cells, a partial blockade was observed in cells co-expressing A 1 R and A 2A R. The relevance of the A 1 R and A 2A R interaction in guanosine effects was further substantiated by means of functional assays (i.e., cAMP and calcium determinations), since guanosine only blocked A 2A R agonist-mediated effects in doubly expressing A 1 R and A 2A R cells. Interestingly, while guanosine did not affect A 1 R/A 2A R heteromer formation, it reduced A 2A R agonist-mediated cell impedance responses. Our results indicate that guanosine-induced effects may require both A 1 R and A 2A R co-expression, thus identifying a molecular substrate that may allow fine tuning of guanosine-mediated responses.

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Section: A 2a R Ligand Binding Is Affected By Guanosine Upon a 1 R Comentioning

confidence: 99%

Adenosine A1-A2A Receptor-Receptor Interaction: Contribution to Guanosine-Mediated Effects

Lanznaster

Massari

Marková

et al. 2019

Cells

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“…Furthermore, GUO can modulate glutamatergic transmission by stimulating its uptake through transporters and increasing glutamine synthetase activity and glutamate turnover, thereby reducing extracellular glutamate levels and protecting from excitotoxicity ( Molz et al, 2011 ; Dal-Cim et al, 2016 ). Similarly, GUO-induced neuroprotection in ischemia-like models has been shown to promote the reduction of nitroxidative stress, prevent the alteration of mitochondrial membrane potentials ( Thomaz et al, 2016 ), and control the inflammatory response. These effects occur through inhibition of the transcription factor NF-κB translocation to the nucleus ( Dal-Cim et al, 2013 ), and through the reduction of inflammatory cytokines ( Hansel et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Antiparkinsonian Efficacy of Guanosine in Rodent Models of Movement Disorder

et al. 2017

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Guanosine (GUO) is a guanine-based purine nucleoside with important trophic functions and promising neuroprotective properties. Although the neuroprotective effects of GUO have been corroborated in cellular models of Parkinson’s disease (PD), its efficacy as an antiparkinsonian agent has not been fully explored in PD animal models. Accordingly, we evaluated the effectiveness of GUO in reversing motor impairments in several rodent movement disorder models, including catalepsy, tremor, and hemiparkinsonism. Our results showed that orally administered GUO antagonized reserpine-mediated catalepsy, reduced reserpine-induced tremulous jaw movements, and potentiated the number of contralateral rotations induced by L-3,4-dihydroxyphenylalanine in unilaterally 6-hydroxidopamine-lesioned rats. In addition, at 5 and 7.5 mg/kg, GUO inhibited L-DOPA-induced dyskinesia in rats chronically treated with a pro-dopaminergic agent. Overall, we describe the therapeutic potential of GUO, which may be effective not only for reversing parkinsonian motor impairments but also for reducing dyskinesia induced by treatment for PD.

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“…109,111 Notably, while extracellular adenine-based purines are rapidly metabolized following an insult, guanosine concentration increases progressively, suggesting that it may be an endogenous neuroprotective agent. 110 Indeed, a vast number of reports have shown the neuroprotective effect of guanosine against several injuries, including ischemia, [112][113][114][115][116][117][118][119] sepsis-induced cognitive impairment, 120 ammonia intoxication, 121 hepatic encephalopathy, 122 cytotoxicity induced by MPP þ and 6-hydroxydopamine, 123,124 glutamate, 125 azide-induced oxidative damage, 126 methylmercury, 127 and LPS-induced inflammation. 128 Furthermore, the neuroprotective effect of guanosine was also demonstrated in animal models of Alzheimer's 129 and Parkinson's disease.…”

Section: Guanosinementioning

confidence: 99%

Novel Targets for Fast Antidepressant Responses: Possible Role of Endogenous Neuromodulators

Camargo

Rodrigues

2019

Chronic Stress

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The available medications for the treatment of major depressive disorder have limitations, particularly their limited efficacy, delayed therapeutic effects, and the side effects associated with treatment. These issues highlight the need for better therapeutic agents that provide more efficacious and faster effects for the management of this disorder. Ketamine, an N-methyl-D-aspartate receptor antagonist, is the prototype for novel glutamate-based antidepressants that has been shown to cause a rapid and sustained antidepressant effect even in severe refractory depressive patients. Considering the importance of these findings, several studies have been conducted to elucidate the molecular targets for ketamine’s effect. In addition, efforts are under way to characterize ketamine-like drugs. This review focuses particularly on evidence that endogenous glutamatergic neuromodulators may be able to modulate mood and to elicit fast antidepressant responses. Among these molecules, agmatine and creatine stand out as those with more published evidence of similarities with ketamine, but guanosine and ascorbic acid have also provided promising results. The possibility that these neuromodulators and ketamine have common neurobiological mechanisms, mainly the ability to activate mechanistic target of rapamycin and brain-derived neurotrophic factor signaling, and synthesis of synaptic proteins in the prefrontal cortex and/or hippocampus is presented and discussed.

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Guanosine prevents nitroxidative stress and recovers mitochondrial membrane potential disruption in hippocampal slices subjected to oxygen/glucose deprivation

Cited by 29 publications

References 54 publications

Adenosine A1-A2A Receptor-Receptor Interaction: Contribution to Guanosine-Mediated Effects

Adenosine A1-A2A Receptor-Receptor Interaction: Contribution to Guanosine-Mediated Effects

Antiparkinsonian Efficacy of Guanosine in Rodent Models of Movement Disorder

Novel Targets for Fast Antidepressant Responses: Possible Role of Endogenous Neuromodulators

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