Extracellular cyclic GMP and its derivatives GMP and guanosine protect from oxidative glutamate toxicity

Albrecht, Philipp; Henke, Nadine; Tien, Mai-Ly Tran; Issberner, Andrea; Bouchachia, Imane; Maher, Pamela; Lewerenz, Jan; Methner, Axel

doi:10.1016/j.neuint.2013.01.019

Cited by 25 publications

(17 citation statements)

References 42 publications

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“…Moreover, cUMP induces chemotaxis in Dictyostelium discoideum [36] and behavioral effects in rat [33]. Extracellular cGMP regulates ligand-gated ion channels [37]. Intestinally localized cGMP modulates secretion and motility [38], and such a function is also feasible for intestinal cUMP.…”

Section: Discussionmentioning

confidence: 99%

cCMP and cUMP occur in vivo

Bähre

Hartwig

Munder

et al. 2015

Biochemical and Biophysical Research Communications

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Mammalian cells contain the cyclic pyrimidine nucleotides cCMP and cUMP. It is unknown whether these tentative new second messenger molecules occur in vivo. We used high performance liquid chromatography quadrupole tandem mass spectrometry to quantitate nucleoside 3′,5′-cyclic monophosphates. cCMP was detected in all organs studied, most notably pancreas, spleen and the female reproductive system. cUMP was not detected in organs, probably due to the intrinsically low sensitivity of mass spectrometry to detect this molecule and organ matrix effects. Intratracheal infection of mice with recombinant Pseudomonas aeruginosa harboring the nucleotidyl cyclase toxin ExoY massively increased cUMP in lung. The identity of cCMP and cUMP in organs was confirmed by high performance liquid chromatography quadrupole time of flight mass spectrometry. cUMP also appeared in serum, urine and faeces following infection. Taken together, this report unequivocally shows for the first time that cCMP and cUMP occur in vivo.

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Section: Discussionmentioning

confidence: 99%

cCMP and cUMP occur in vivo

Bähre

Hartwig

Munder

et al. 2015

Biochemical and Biophysical Research Communications

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“…MGO can impair the antioxidant system by depleting GSH [1]. MGO has been considered as a possible causative agent in a number of pathologies, such as diabetes [4, 5], hyperalgesia and inflammation [6], aging disorders [7], Alzheimer’s disease [8], epilepsy [9], autism [10], and anxiety [11], among others.…”

Section: Introductionmentioning

confidence: 99%

Methylglyoxal, the foe and friend of glyoxalase and Trx/TrxR systems in HT22 nerve cells

Dafre

Goldberg

Wang

et al. 2015

Free Radical Biology and Medicine

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Methylglyoxal (MGO) is a major glycating agent that reacts with basic residues of proteins and promotes the formation of advanced glycation end products (AGEs) which are believed to play key roles in a number of pathologies, such as diabetes, Alzheimer’s disease, and inflammation. Here, we examined the effects of MGO on immortalized mouse hippocampal HT22 nerve cells. The endpoints analyzed were MGO and thiol status, the glyoxalase system, comprising glyoxalase 1 and 2 (GLO1/2), and the cytosolic and mitochondrial Trx/TrxR systems, as well as nuclear Nrf2 and its target genes. We found that nuclear Nrf2 is induced by MGO treatment in HT22 cells, as corroborated by induction of the Nrf2-controlled target genes and proteins glutamate cysteine ligase and heme oxygenase 1. Nrf2 knockdown prevented MGO-dependent induction of glutamate cysteine ligase and heme oxygenase 1. The cystine/glutamate antiporter, system xc−, which is also controlled by Nrf2, was also induced. The increased cystine import (system xc−) activity and GCL expression promoted GSH synthesis, leading to increased levels of GSH. The data indicate that MGO can act as both a foe and a friend of the glyoxalase and the Trx/TrxR systems. At low concentrations of MGO (0.3 mM), GLO2 is strongly induced, but at high MGO (0.75 mM) concentrations, GLO1 is inhibited and GLO2 is downregulated. The cytosolic Trx/TrxR system is impaired by MGO, where Trx is downregulated yet TrxR is induced, but strong MGO-dependent glycation may explain the loss in TrxR activity. We propose that Nrf2 can be the unifying element to explain the observed upregulation of GSH, GCL, HO1, TrxR1, Trx2, TrxR2, and system xc− system activity.

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“…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]. Studies are pointing that GUO may exert its effects through modulation of mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K) signaling pathways [27]–[29], however, the mechanisms of the protective effects of GUO are not fully understood yet.…”

Section: Introductionmentioning

confidence: 99%

“…As previous experimental studies have demonstrated that GUO acts as a neuroprotective agent against stroke and is able to modulate oxidative response and glutamatergic parameters [33], [35], [36], the objectives of this study are to investigate the potential neuroprotective role of GUO using a model of permanent focal cerebral ischemia. For that, the focus of this study is directed to explore the neural intracellular biochemical parameters as well as underlying neuroprotective mechanisms.…”

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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Extracellular cyclic GMP and its derivatives GMP and guanosine protect from oxidative glutamate toxicity

Cited by 25 publications

References 42 publications

cCMP and cUMP occur in vivo

cCMP and cUMP occur in vivo

Methylglyoxal, the foe and friend of glyoxalase and Trx/TrxR systems in HT22 nerve cells

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

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