Role of extracellular signal‐regulated protein kinase in neuronal cell death induced by glutathione depletion in neuron/glia mesencephalic cultures

Bernardo, Sonsoles de; Canals, Santiago; Casarejos, Marı́a José; Solano, Rosa M.; Menéndez, Jaime; Mena, María A.

doi:10.1111/j.1471-4159.2004.02744.x

Cited by 89 publications

(58 citation statements)

References 92 publications

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“…The role of glia is mediated by the secretion of chemical substances into the media (Mena et al, 1997a(Mena et al, , 2002de Bernardo et al, 2003). Dysfunctional astrocytes enhance neuronal degeneration by a diminished secretion of trophic factors (Riederer et al, 1989;Engele et al, 1991Engele et al, , 1996Damier et al, 1993;Makar et al, 1994;Muller et al, 1995;Mena et al, 1997aMena et al, , 1998bMena et al, , 2002Kinor et al, 2001), the release of cytokines, and the increased production of reactive oxidative molecules (Hirsch et al, 1999;Liberatore et al, 1999;Hirsch and Hunot, 2000;Vila et al, 2001;Wu et al, 2002;Canals et al, 2003b;de Bernardo et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Glial Dysfunction in Parkin Null Mice: Effects of Aging

Solano¹,

Casarejos²,

et al. 2008

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Parkin mutations in humans produce parkinsonism whose pathogenesis is related to impaired protein degradation, increased free radicals, and abnormal neurotransmitter release. The role of glia in parkin deficiency is little known. We cultured midbrain glia from wild-type (WT) and parkin knock-out (PK-KO) mice. After 18 -20 d in vitro, PK-KO glial cultures had less astrocytes, more microglia, reduced proliferation, and increased proapoptotic protein expression.PK-KO glia had greater levels of intracellular glutathione (GSH), increased mRNA expression of the GSH-synthesizing enzyme ␥-glutamylcysteine synthetase, and greater glutathione S-transferase and lower glutathione peroxidase activities than WT. The reverse happened in glia cultured in serum-free defined medium (EF12) or in old cultures. PK-KO glia was more susceptible than WT to transference to EF12 or neurotoxins (1-methyl-4-phenylpyridinium, blockers of GSH synthesis or catalase, inhibitors of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3 kinases), aging of the culture, or combination of these insults. PK-KO glia was less susceptible than WT to Fe 2ϩ plus H 2 O 2 and less responsive to protection by deferoxamine. Old WT glia increased the expression of heat shock protein 70, but PK-KO did not. Glia conditioned medium (GCM) from PK-KO was less neuroprotective and had lower levels of GSH than WT. GCM from WT increased the levels of dopamine markers in midbrain neuronal cultures transferred to EF12 more efficiently than GCM from PK-KO, and the difference was corrected by supplementation with GSH. PK-KO-GCM was a less powerful suppressor of apoptosis and microglia in neuronal cultures. Our data prove that abnormal glial function is critical in parkin mutations, and its role increases with aging.

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Section: Introductionmentioning

confidence: 99%

Glial Dysfunction in Parkin Null Mice: Effects of Aging

Solano¹,

Casarejos²,

et al. 2008

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“…All drug solutions were prepared fresh and administered in a volume of 5 ml/kg. BSO has been reported earlier to enhance the generation of reactive oxygen species (ROS) and increase oxidative stress in the nervous system (de Bernardo et al, 2004). After behavioral testing, mice were killed by decapitation, brains were removed, and hypothalamus and amygdala dissected and stored at Ϫ80°C until biochemical and molecular analyses were carried out as shown in Fig.…”

Section: Behavioral Testsmentioning

confidence: 99%

Reversal of Oxidative Stress-Induced Anxiety by Inhibition of Phosphodiesterase-2 in Mice

Masood

Nadeem²,

Mustafa³

et al. 2008

J Pharmacol Exp Ther

201

168

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The pathogenesis of several neuropsychiatric disorders, including anxiety and depression, has been linked to oxidative stress, in part via alterations in cyclic nucleotide signaling. Phosphodiesterase-2 (PDE2), which regulates cGMP and cAMP signaling, may affect anxiety-related behavior through reduction of oxidative stress. The present study evaluated the effects of oxidative stress on behavior and assessed the anxiolytic effects of the PDE2 inhibitor Bay 60-7550 [(2-(3,4-Treatment of mice with L-buthionine-(S,R)-sulfoximine (300 mg/kg), an inducer of oxidative stress, caused anxiety-like behavioral effects in elevated plusmaze, open-field, and hole-board tests through the NADPH oxidase pathway; these effects were antagonized by Bay 60-7550 (3 mg/kg) and apocynin (3 mg/kg), an inhibitor of NADPH oxidase. The Bay 60-7550-mediated decrease in oxidative stress (i.e., superoxide anion and reactive oxygen species generation in cultured neurons and total antioxidant capacity and lipid peroxides in amygdala and hypothalamus) and expression of NADPH oxidase subunits (i.e., p47 phox and gp91 phox expression in amygdala, hypothalamus, and cultured neurons) was associated with increased cGMP and phosphorylation of vasodilator-stimulated phosphoprotein at Ser239, suggesting an important role of cGMP-protein kinase G signaling in reduction of anxiety. Overall, the present results indicate that oxidative stress induces anxiety-like behavior in mice and that PDE2 inhibition reverses it through an increase in cGMP signaling. Thus, PDE2 may be a novel pharmacological target for treatment of anxiety in neuropsychiatric and neurodegenerative disorders that involve oxidative stress.Anxiety and fear are normal emotional responses to threatening stimuli. These responses are abnormal in human anxiety disorders, such as panic disorder, post-traumatic stress disorder, social phobias, and generalized anxiety disorder. The development of anxiety/stress-related disorders involves complex interactions among various body mechanisms involving the limbic system and the hypothalamic-pituitaryadrenal axis; their interactions play a significant role in the manifestation of disease pathology (Chrousos and Gold, 1992;Ray et al., 1993). Exposure to stressful stimuli produces widespread physiological and behavioral effects in animals. In recent studies, oxidative stress has been shown to be associated with anxiety in different behavioral models (Gingrich, 2005;Hovatta et al., 2005;Berry et al., 2007).The nervous system, due to enriched concentrations of polyunsaturated fatty acids, is particularly susceptible to the deleterious effects of oxidative stress; this can lead to loss of membrane integrity, protein damage, and neuronal dysfunction. Recent studies have shown that social phobia, depression, anxiety, and other neuropsychiatric disorders result in signs of oxidative stress such as increased reactive oxygen generation and decreased antioxidant capacity (Arranz et al., 2007;Bouayed et al., 2007). There is increasing evidence that oxidati...

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“…Although activation of the Erk1/2 pathway by growth factors and other mitogens is often associated with cellular growth and survival, its aberrant or sustained activation has also been linked with cell death (Osada et al, 2001;Tikoo et al, 2001;Romashko et al, 2003;Choi et al, 2004;de Bernardo et al, 2004;Dong et al, 2004). Indeed, complete inhibition of Erk1/2 and k-8 phosphorylation by U0126 delayed the onset but did not ultimately prevent the resultant cytotoxicity produced by K3 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that K3 stimulates phosphorylation of the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/Erk) pathway predominantly by arylation of key catalytic cysteine residues within protein tyrosine phosphatases (Osada et al, 2001;Klotz et al, 2002;Abdelmohsen et al, 2003). Although it is generally the case that this pathway serves to stimulate cell growth and survival, recent findings have implicated nonsurvival aspects to excessive MAPK activation (Osada et al, 2001;Tikoo et al, 2001;Choi et al, 2004;de Bernardo et al, 2004;Dong et al, 2004), including induction of a nonapoptotic form of cell death known as oncosis (Trump et al, 1997;Tikoo et al, 2001;Van Cruchte and Van Den Broeck, 2002;Romashko et al, 2003). Thus, identifying early molecular targets of K3-induced cell stress will improve our understanding of quinone effects on cell function and fate.…”

mentioning

confidence: 99%

Vitamin K3 (Menadione)-Induced Oncosis Associated with Keratin 8 Phosphorylation and Histone H3 Arylation

Scott

Atsriku²,

Kaminker³

et al. 2005

Mol Pharmacol

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The vitamin K analog menadione (K3), capable of both redox cycling and arylating nucleophilic substrates by Michael addition, has been extensively studied as a model stress-inducing quinone in both cell culture and animal model systems. Exposure of keratin 8 (k-8) expressing human breast cancer cells (MCF7, T47D, SKBr3) to K3 (50 -100 M) induced rapid, sustained, and site-specific k-8 serine phosphorylation (pSer73) dependent on signaling by a single mitogen activated protein kinase (MAPK) pathway, MEK1/2. Normal nuclear morphology and k-8 immunofluorescence coupled with the lack of DNA laddering or other features of apoptosis indicated that K3-induced cytotoxicity, evident within 4 h of treatment and delayed but not prevented by MEK1/2 inhibition, was due to a form of stress-activated cell death known as oncosis. Independent of MAPK signaling was the progressive appearance of K3-induced cellular fluorescence, principally nuclear in origin and suggested by in vitro fluorimetry to have been caused by K3 thiol arylation. Imaging by UV transillumination of protein gels containing nuclear extracts from K3-treated cells revealed a prominent 17-kDa band shown to be histone H3 by immunoblotting and mass spectrometry (MS). K3 arylation of histones in vitro followed by electrospray ionization-tandem MS analyses identified the unique Cys110 residue within H3, exposed only in the open chromatin of transcriptionally active genes, as a K3 arylation target. These findings delineate new pathways associated with K3-induced stress and suggest a potentially novel role for H3 Cys110 as a nuclear stress sensor.

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Role of extracellular signal‐regulated protein kinase in neuronal cell death induced by glutathione depletion in neuron/glia mesencephalic cultures

Cited by 89 publications

References 92 publications

Glial Dysfunction in Parkin Null Mice: Effects of Aging

Glial Dysfunction in Parkin Null Mice: Effects of Aging

Reversal of Oxidative Stress-Induced Anxiety by Inhibition of Phosphodiesterase-2 in Mice

Vitamin K3 (Menadione)-Induced Oncosis Associated with Keratin 8 Phosphorylation and Histone H3 Arylation

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