Neuronal NOS activation during oxygen and glucose deprivation triggers cerebellar granule cell death in the later reoxygenation phase

Scorziello, Antonella; Pellegrini, C; Secondo, Agnese; Sirabella, Rossana; Formisano, Luigi; Sibaud, Luigi; Amoroso, Salvatore; Canzoniero, Lorella M.T.; Annunziato, Lucio; Renzo, G. F. Di

doi:10.1002/jnr.20096

Cited by 25 publications

(14 citation statements)

References 47 publications

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“…Our findings and interpretations are consistent with restricted opening of hemichannels in normal cells adequate to allow release of signaling molecules and with greater opening that may accelerate death under pathological conditions such as ischemia, in which there is enhanced NO generation (25,26). Mutations of the cysteine residues should give a clearer view of hemichannels as a sensor of redox potential and possible target for therapeutic intervention.…”

Section: Discussionsupporting

confidence: 83%

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S-nitrosylation and permeation through connexin 43 hemichannels in astrocytes: Induction by oxidant stress and reversal by reducing agents

Retamal

Cortés

Reuss

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

268

329

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Marked increase in cell permeability ascribed to open connexin (Cx)43 hemichannels is induced by metabolic inhibition (MI) of cortical astrocytes in culture, but the molecular mechanisms are not established. Dephosphorylation and͞or oxidation of Cx43 hemichannels was proposed as a potential mechanism to increase their open probability. We now demonstrate that MI increases the number of hemichannels on the cell surface assayed by biotinylation and Western blot, and that this change is followed by increased dephosphorylation and S-nitrosylation. The increase in rate of dye uptake caused by MI is comparable to the increase in surface expression; thus, open probability and permeation per hemichannel may be unchanged. Reducing agents did not affect dephosphorylation of Cx43 hemichannels but reduced dye uptake and S-nitrosylation. Uptake was also reduced by elevated intracellular but not extracellular levels of reduced glutathione. Moreover, nitric oxide donors induced dye uptake and nitrosylation of surface Cx43 but did not affect its abundance or phosphorylation. Thus, permeability per channel is increased, presumably because of increase in open probability. We propose that increased dye uptake induced by MI is mediated by an increased number of Cx43 hemichannels in the surface and is associated with multiple molecular changes, among which nitrosylation of intracellular Cx43 cysteine residues may be a critical factor. astroglia ͉ ischemia ͉ nitric oxide ͉ permeabilization

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Section: Discussionsupporting

confidence: 83%

“…Because the generation of NO, a free radical, is increased in astrocytes during MI (25,26), and NO can oxidize cysteine residues (24, 27, 28), we tested whether NO donors induce dye uptake by astrocytes. Application of 100 M nitrosoglutathione (GSNO) (Fig.…”

Section: Intracellular But Not Extracellular Gsh Blocks the Dye Uptakmentioning

confidence: 99%

S-nitrosylation and permeation through connexin 43 hemichannels in astrocytes: Induction by oxidant stress and reversal by reducing agents

Retamal

Cortés

Reuss

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

268

329

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“…The means ± SD from six independent experiments (n = 6). * Differences statistically significant vs. control (one-way ANOVA followed by Dunnett's test, p < 0.05) [28,31,32]. Our previous research has confirmed that the CGC model is suitable for mechanistic studies on toxicity for neurons caused by excitotoxic challenges, calcium imbalance and mitochondrial dysfunction [40,42,43].…”

mentioning

confidence: 54%

“…# Differences statistically significant vs. 5 µM TBBPA (one-way ANOVA followed by Dunnett's test, p < 0.05) When examining the putative mechanism of TBBPA and OGD synergy we considered calcium imbalance, mitochondrial disfunction and oxidative stress. According to literature data, these processes might be common to both of toxic factors studied here [9,14,22,23,25,27,28,32]. Therefore, using standard methods we measured…”

Section: Ros Mediate Tbbpa and Ogd Synergy In Cgc Culturesmentioning

confidence: 96%

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Synergistic neurotoxicity of oxygen-glucose deprivation and tetrabromobisphenol A in vitro: role of oxidative stress

Ziemińska

Stafiej

Toczyłowska

et al. 2012

Pharmacological Reports

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Abstract:Background: Tetrabromobisphenol A (TBBPA) is a toxic brominated flame retardant. Previous studies have demonstrated that exposure of primary cultures of rat cerebellar granule cells (CGC) to ³ 10 µM TBBPA induces toxicity and excitotoxicity, and the underlying mechanism may involve calcium imbalance and oxidative stress. Here we examined whether the application of TBBPA at subtoxic concentrations may exacerbate acute damage of CGC challenged with oxygen-glucose deprivation (OGD), and evaluated with fluorescent indicators the involvement of calcium imbalance, mitochondrial depolarization and oxidative stress. Methods: Survival of CGC was assessed 24 h after OGD/TBBPA using fluorescent dyes. An OGD challenge lasting for 45, 60 or 75 min induced a duration-dependent injury to the neurons. Results: Application of 2.5, 5 or 7.5 µM TBBPA for 45 min to normoxic and glucose-containing incubation medium did not reduce the viability of cultured CGC, but this compound exacerbated the toxic effects of OGD in a concentration-dependent way. Moreover, TBBPA had a slight effect on calcium homeostasis and mitochondrial membrane potential, but significantly activated the production of reactive oxygen species in CGC. The application of H 2 O 2 at 5, 10 and 25 µM mimicked the effects of TBBPA on OGD toxicity, while 0.1 mM ascorbic acid or 1 mM glutathione ameliorated this toxicity. Conclusion: These results suggest the involvement of oxidative stress in the synergistic neurotoxic effects of TBBPA and OGD.

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Whole exome sequencing of families with 1q21.1 microdeletion or microduplication

Qiao

Badduke

Tang

et al. 2017

American J of Med Genetics Pt A

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Recurrent microduplications/microdeletions of 1q21.1 are characterized by variable phenotypes ranging from normal development to developmental delay (DD) and congenital anomalies. Their interpretation is challenging especially in families with affected and unaffected carriers. We used whole exome sequencing (WES) to look for sequence variants in two male probands with inherited 1q21.1 CNVs that could explain their more severe phenotypes. One proband had a 1q21.1 deletion transmitted from maternal grandmother, while the other had a paternal duplication. We found mutations in five genes (SMPD1, WNK3, NOS1, ATF6, and EFHC1) that could contribute to the more severe phenotype in the probands in comparison to their mildly affected or unaffected 1q21.1 CNV carrying relatives. Interestingly, all genes have roles in stress responses (oxidative/Endoplasmic Reticulum (ER)/osmotic). One of the variants was in an X-linked gene WNK3 and segregated with the developmental features and X inactivation pattern in the family with 1q21.1 deletion transmitted from maternal grandmother. In silico analysis of all rare deleterious variants in both probands identified enrichment in nervous system diseases, metabolic pathways, protein processing in the ER and protein export. Our studies suggest that rare deleterious variants outside of the 1q21.1 CNV, individually or as a pool, could contribute to phenotypic variability in carriers of this CNV. Rare deleterious variants in stress response genes are of interest and raise the possibility of susceptibility of carriers to variable environmental influences. Next generation sequencing of additional familial cases with 1q21.1 CNV could further help determine the possible causes of phenotypic variability in carriers of this CNV.

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Neuronal NOS activation during oxygen and glucose deprivation triggers cerebellar granule cell death in the later reoxygenation phase

Cited by 25 publications

References 47 publications

S-nitrosylation and permeation through connexin 43 hemichannels in astrocytes: Induction by oxidant stress and reversal by reducing agents

S-nitrosylation and permeation through connexin 43 hemichannels in astrocytes: Induction by oxidant stress and reversal by reducing agents

Synergistic neurotoxicity of oxygen-glucose deprivation and tetrabromobisphenol A in vitro: role of oxidative stress

Whole exome sequencing of families with 1q21.1 microdeletion or microduplication

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