Guanosine is neuroprotective against oxygen/glucose deprivation in hippocampal slices via large conductance Ca2+-activated K+ channels, phosphatidilinositol-3 kinase/protein kinase B pathway activation and glutamate uptake

Dal-Cim, Tharine; Martins, Wagner C.; Santos, Adair R.S.; Tasca, Carla I.

doi:10.1016/j.neuroscience.2011.03.022

Cited by 65 publications

(84 citation statements)

References 62 publications

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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: 66%

“…The exact interaction site of GUO in cellular membranes is still unknown, although it has been suggested [41,42]. GUO effects over adenosinergic system are controversial [43], but we have shown that neuroprotective effects of GUO depend on adenosine receptors modulation [33] and on activation of a calcium-dependent potassium channel [14]. It has also recently been shown that GUO may regulate the extracellular disposition of adenosine in some cell types by an unknown mechanism, but this effect seems not to occur in neuronal cells [44].…”

Section: Discussionmentioning

confidence: 76%

“…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%

“…It was showed that after focal stroke in rats, GUO levels are elevated within 2 h and remain high for 7 days in the brain tissue [13]. In oxygen/glucose deprivation (OGD) protocol, an in vitro model for ischemia, we showed that GUO is protective by improving extracellular glutamate uptake [14]. Moreover, GUO is effective in reducing ROS production, iNOS expression and NF-kB activation, and preventing the loss of mitochondrial membrane potential.…”

Section: Introductionmentioning

confidence: 90%

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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: 66%

Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

See 2 more Smart Citations

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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show abstract

“…Guanosine is released from astrocytes and confers neuroprotective effects in several in vivo and in vitro studies [3,[6][7][8][9][10][11]. Guanosine can effectively protect cells against hypoxia [12,13], cytotoxicity induced by the β-amyloid peptide [14], chronic cerebral hypoperfusion [15], ischemic insults [16][17][18], and other glutamatergic excitotoxic damage, such as seizures that are induced by quinolinic acid [3,9,19,20] and methylmercury-induced oxidative stress [21]. Although there is increasing evidence showing the neuroprotective effects of guanosine on models of neurotoxicity, its mechanisms are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Gliopreventive effects of guanosine against glucose deprivation in vitro

Quincozes‐Santos

Bobermin

Souza

et al. 2013

Purinergic Signalling

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Guanosine, a guanine-based purine, is recognized as an extracellular signaling molecule that is released from astrocytes and confers neuroprotective effects in several in vivo and in vitro studies. Astrocytes regulate glucose metabolism, glutamate transport, and defense mechanism against oxidative stress. C6 astroglial cells are widely used as an astrocyte-like cell line to study the astrocytic function and signaling pathways. Our previous studies showed that guanosine modulates the glutamate uptake activity, thus avoiding glutamatergic excitotoxicity and protecting neural cells. The goal of this study was to determine the gliopreventive effects of guanosine against glucose deprivation in vitro in cultured C6 cells. Glucose deprivation induced cytotoxicity, an increase in reactive oxygen and nitrogen species (ROS/RNS) levels and lipid peroxidation as well as affected the metabolism of glutamate, which may impair important astrocytic functions. Guanosine prevented glucose deprivation-induced toxicity in C6 cells by modulating oxidative and nitrosative stress and glial responses, such as the glutamate uptake, the glutamine synthetase activity, and the glutathione levels. Glucose deprivation decreased the level of EAAC1, the main glutamate transporter present in C6 cells. Guanosine also prevented this effect, most likely through PKC, PI3K, p38 MAPK, and ERK signaling pathways. Taken together, these results show that guanosine may represent an important mechanism for protection of glial cells against glucose deprivation. Additionally, this study contributes to a more thorough understanding of the glial-and redox-related protective properties of guanosine in astroglial cells.

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In Vitro Oxygen-Glucose Deprivation to Study Ischemic Cell Death

Tasca

Dal-Cim

Cimarosti

2014

Methods in Molecular Biology

122

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Oxygen-glucose deprivation (OGD ) is widely used as an in vitro model for stroke, showing similarities with the in vivo models of brain ischemia. In order to perform OGD, cell or tissue cultures, such as primary neurons or organotypic slices, and acutely prepared tissue slices are usually incubated in a glucose-free medium under a deoxygenated atmosphere, for example in a hypoxic chamber. Here, we describe the step-by-step procedure to expose cultures and acute slices to OGD, focusing on the most suitable methods for assessing cellular death and/or viability. OGD is a simple yet highly useful technique, not only for the elucidation of the role of key cellular and molecular mechanisms underlying brain ischemia, but also for the development of novel neuroprotective strategies.

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Guanosine is neuroprotective against oxygen/glucose deprivation in hippocampal slices via large conductance Ca2+-activated K+ channels, phosphatidilinositol-3 kinase/protein kinase B pathway activation and glutamate uptake

Cited by 65 publications

References 62 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

Gliopreventive effects of guanosine against glucose deprivation in vitro

In Vitro Oxygen-Glucose Deprivation to Study Ischemic Cell Death

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