Neuroprotection Promoted by Guanosine Depends on Glutamine Synthetase and Glutamate Transporters Activity in Hippocampal Slices Subjected to Oxygen/Glucose Deprivation

Dal-Cim, Tharine; Martins, Wagner C.; Thomaz, Daniel Tonial; Coelho, Victor Vijay; Poluceno, Gabriela Godoy; Lanznaster, Débora; Vandresen-Filho, Samuel; Tasca, Carla I.

doi:10.1007/s12640-015-9595-z

Cited by 34 publications

(22 citation statements)

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“…Particularly, we suggest that NO and ONOO − production are more responsive to nNOS inhibition than eNOS or iNOS in this in vitro ischemia model in hippocampal slices. Guanosine plays a significant role in the defense mechanisms against cerebral ischemia by inducing key cellular functions in this injury situation, as K + channels activation [14], glutamate uptake increase, reduction of inflammatory mediators expression [15,33], and, as firstly shown in this study, reduction of NO and ONOO − production similarly to NOS inhibitors. Although the exact mechanism exerted by GUO on the NO production system is still not completely understood, we reinforce the hypothesis that GUO could be used to devise new strategies for stroke treatment.…”

Section: Discussionsupporting

confidence: 67%

“…In previous studies from our group, the neuroprotective effect of GUO was shown in hippocampal slices subjected to the OGD/reoxygenation protocol. GUO prevents the decrease in cell viability, by increasing glutamate uptake and glutamine synthetase activity, decreasing glutamate release, ROS production and inflammatory mediators expression, including reduction of iNOS expression [14,15,33,40]. The exact interaction site of GUO in cellular membranes is still unknown, although it has been suggested [41,42].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, GUO is effective in reducing ROS production, iNOS expression and NF-kB activation, and preventing the loss of mitochondrial membrane potential. Additionally, it decreased cells membrane permeability and glutamate release, and recovered glutamine synthetase activity in slices subjected to OGD [12,15].…”

Section: Introductionmentioning

confidence: 91%

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

Thomaz

Dal-Cim

Martins

et al. 2016

Purinergic Signalling

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Guanosine, the endogenous guanine nucleoside, prevents cellular death induced by ischemic events and is a promising neuroprotective agent. During an ischemic event, nitric oxide has been reported to either cause or prevent cell death. Our aim was to evaluate the neuroprotective effects of guanosine against oxidative damage in hippocampal slices subjected to an in vitro ischemia model, the oxygen/glucose deprivation (OGD) protocol. We also assessed the participation of nitric oxide synthase (NOS) enzymes activity on the neuroprotection promoted by guanosine. Here, we showed that guanosine prevented the increase in ROS, nitric oxide, and peroxynitrite production induced by OGD. Moreover, guanosine prevented the loss of mitochondrial membrane potential in hippocampal slices subjected to OGD. Guanosine did not present an antioxidant effect per se. The protective effects of guanosine were mimicked by inhibition of neuronal NOS, but not of inducible NOS. The neuroprotective effect of guanosine may involve activation of cellular mechanisms that prevent the increase in nitric oxide production, possibly via neuronal NOS.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

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

Thomaz

Dal-Cim

Martins

et al. 2016

Purinergic Signalling

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“…It has been shown that neuroprotective effects of GUO depend on glutamatergic system modulation, through increasing glutamate uptake or decreasing glutamate release, that may be responsible for increasing glutamine synthetase (GS) activity [13,14,16,18,40,41]. Despite all of this evidence, we did not observe GUO effects on glutamate uptake, release, or GS activity, an enzyme that had been considered as a negative growth regulator in glioma cells [42].…”

Section: Discussioncontrasting

confidence: 63%

Guanosine promotes cytotoxicity via adenosine receptors and induces apoptosis in temozolomide-treated A172 glioma cells

Oliveira

Dal-Cim

Lopes

et al. 2017

Purinergic Signalling

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Gliomas are a malignant tumor group whose patients have survival rates around 12 months. Among the treatments are the alkylating agents as temozolomide (TMZ), although gliomas have shown multiple resistance mechanisms for chemotherapy. Guanosine (GUO) is an endogenous nucleoside involved in extracellular signaling that presents neuroprotective effects and also shows the effect of inducing differentiation in cancer cells. The chemotherapy allied to adjuvant drugs are being suggested as a novel approach in gliomas treatment. In this way, this study evaluated whether GUO presented cytotoxic effects on human glioma cells as well as GUO effects in association with a classical chemotherapeutic compound, TMZ. Classical parameters of tumor aggressiveness, as alterations on cell viability, type of cell death, migration, and parameters of glutamatergic transmission, were evaluated. GUO (500 and 1000 μM) decreases the A172 glioma cell viability after 24, 48, or 72 h of treatment. TMZ alone or GUO plus TMZ also reduced glioma cell viability similarly. GUO combined with TMZ showed a potentiation effect of increasing apoptosis in A172 glioma cells, and a similar pattern was observed in reducing mitochondrial membrane potential. GUO per se did not elevate the acidic vesicular organelles occurrence, but TMZ or GUO plus TMZ increased this autophagy hallmark. GUO did not alter glutamate transport per se, but it prevented TMZ-induced glutamate release. GUO or TMZ did not alter glutamine synthetase activity. Pharmacological blockade of glutamate receptors did not change GUO effect on glioma viability. GUO cytotoxicity was partially prevented by adenosine receptor (A 1 R and A 2A R) ligands. These results point to a cytotoxic effect of GUO on A172 glioma cells and suggest an anticancer effect of GUO as a putative adjuvant treatment, whose mechanism needs to be unraveled.

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“…Similarly, upon excitotoxicity and oxidative stress a failure of cellular bioenergetics occurs [4]. Importantly, a neuroprotective role of guanosine has been extensively investigated in animal and cellular models of ischemia, excitotoxicity and oxidative stress [5][6][7][8][9][10]. Indeed, we have demonstrated that guanosine prevents reactive oxygen species (ROS) generation and cell death in hippocampal slices subjected to the oxygen/glucose deprivation (OGD) [11].…”

Section: Introductionmentioning

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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Neuroprotection Promoted by Guanosine Depends on Glutamine Synthetase and Glutamate Transporters Activity in Hippocampal Slices Subjected to Oxygen/Glucose Deprivation

Cited by 34 publications

References 50 publications

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

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

Guanosine promotes cytotoxicity via adenosine receptors and induces apoptosis in temozolomide-treated A172 glioma cells

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

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