Glutamate uptake in cultured astrocytes depends on age: a study about the effect of guanosine and the sensitivity to oxidative stress induced by H2O2

Gottfried, Carmem; Tramontina, Francine; Gonçalves, Daniela; Gonçalves, Carlos Alberto; Moriguchi, Emílio Hideyuki; Dias, Renato Dutra; Wofchuk, Susana Tchernin; Souza, Diogo O.

doi:10.1016/s0047-6374(02)00069-6

Cited by 63 publications

(37 citation statements)

References 41 publications

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“…For over 25 years, our group has studied the effects of guanosine on the CNS. Frizzo et al and Gottfried et al [5,110] showed that guanosine increases the glutamate uptake in putatively basal conditions, without focusing on the mechanism involved in this effect. Herein, we revealed that guanosine prevented the decrease in glutamate uptake under a cytotoxic insult, probably by the activation of EAAC1 glutamate transporter and PKC, PI3K, p38 MAPK, and ERK signaling pathways and/or by antioxidant/scavenger activity.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

Gliopreventive effects of guanosine against glucose deprivation in vitro

Quincozes‐Santos

Bobermin

Souza

et al. 2013

Purinergic Signalling

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“…Furthermore, these results support previous hypotheses contending that glial oxidative stress is involved in the aging process. In this context, several authors have demonstrated increased superoxide production, lipoperoxidation, protein oxidation and iron staining in astrocytes aged in culture (Papadopoulos et al, 1998;Gottfried et al, 2002;Klamt et al, 2002;Pertusa et al, 2007). It has been proposed that ROS generated by mitochondria accumulate during aging and are not only responsible for the damage present in mitochondrial components, but also cause degradative processes (Cadenas & Davis, 2000;Lenaz et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Heightened expression of glial fibrillary acidic protein (GFAP) and S100 β protein have been detected during aging in regions of the mouse and rat brain (O'Callaghan & Miller, 1991;Kohama et al ., 1995;Amenta et al ., 1998), as well as in mouse and rat cortical astrocytes aged in culture (Papadopoulos et al ., 1998;Gottfried et al ., 2002;Tramontina et al ., 2002;Pertusa et al ., 2007). Superoxide production, lipoperoxidation, protein oxidation, and iron staining remained elevated in aged astrocyte cultures, even though antioxidant defences had been maintained or increased (Papadopoulos et al ., 1998;Gottfried et al ., 2002;Klamt et al ., 2002;Pertusa et al ., 2007). Mitochondrial membrane potential in old astrocytes proved more depolarized than in young astrocytes (Lin et al ., 2006).…”

Section: Introductionmentioning

confidence: 99%

Dysfunction of astrocytes in senescence‐accelerated mice SAMP8 reduces their neuroprotective capacity

et al. 2008

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SummaryEarly onset increases in oxidative stress and tau pathology are present in the brain of senescence-accelerated mice prone (SAMP8). Astrocytes play an essential role, both in determining the brain's susceptibility to oxidative damage and in protecting neurons. In this study, we examine changes in tau phosphorylation, oxidative stress and glutamate uptake in primary cultures of cortical astrocytes from neonatal SAMP8 mice and senescenceaccelerated-resistant mice (SAMR1). We demonstrated an enhancement of abnormally phosphorylated tau in Ser 199 and Ser 396 in SAMP8 astrocytes compared with that of SAMR1 control mice. Gsk3β β β β and Cdk5 kinase activity, which regulate tau phosphorylation, was also increased in SAMP8 astrocytes. Inhibition of Gsk3β β β β by lithium or Cdk5 by roscovitine reduced tau phosphorylation at Ser 396 .Moreover, we detected an increase in radical superoxide generation, which may be responsible for the corresponding increase in lipoperoxidation and protein oxidation. We also observed a reduced mitochondrial membrane potential in SAMP8 mouse astrocytes. Glutamate uptake in astrocytes is a critical neuroprotective mechanism. SAMP8 astrocytes showed a decreased glutamate uptake compared with those of SAMR1 controls. Interestingly, survival of SAMP8 or SAMR1 neurons cocultured with SAMP8 astrocytes was significantly reduced. Our results indicate that alterations in astrocyte cultures from SAMP8 mice are similar to those detected in whole brains of SAMP8 mice at 1-5 months. Moreover, our findings suggest that this in vitro preparation is suitable for studying the molecular and cellular processes underlying early aging in this murine model. In addition, our study supports the contention that astrocytes play a key role in neurodegeneration during the aging process.

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“…The effects of riluzole in ALS could also be partially explained by increased glucose influx in damaged neurons and skeletal muscle tissues [145], and the drug might act as an antioxidant [143,146,147], offsetting the usual negative regulation of glutamate uptake in response to oxidative stress [148][149][150]. Lastly, riluzole could inhibit GABAergic transmission and potentiate function of postsynaptic GABA (A)-receptors [151].…”

Section: +mentioning

confidence: 99%