Neuroprotective effects of α-tocopherol on oxidative stress in rat striatal cultures

Osakada, Fumitaka; Hashino, Asami; Kume, Toshiaki; Katsuki, Hiroshi; Kaneko, Shuji; Akaike, Akinori

doi:10.1016/s0014-2999(03)01495-x

Cited by 68 publications

(48 citation statements)

References 38 publications

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“…tioxidants can scavenge superoxide. Although vitamin E can scavenge both superoxide and NO, SOD and L-NAME are more potent in scavenging superoxide and NO, respectively (Osakada et al, 2003). It is possible that high levels of ammonia-induced superoxide and NO may generate peroxynitrite and that the effect of peroxynitrite may not be diminished by vitamin E. Thus, whereas ammonia increases phosphorylation of all these kinases, the free radical species involved in activating these various kinases may be different.…”

Section: Antioxidants and Nos Inhibition Prevent Ammonia-induced Mapkmentioning

confidence: 99%

Oxidative Stress and Mitogen-Activated Protein Kinase Phosphorylation Mediate Ammonia-Induced Cell Swelling and Glutamate Uptake Inhibition in Cultured Astrocytes

Jayakumar¹,

Panickar

Murthy³

et al. 2006

J. Neurosci.

190

158

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Hepatic encephalopathy (HE) is a major neurological complication in patients with severe liver failure. Elevated levels of ammonia have been strongly implicated as a factor in HE, and astrocytes appear to be the primary target of its neurotoxicity. Mechanisms mediating key aspects of ammonia-induced astrocyte dysfunction such as cell swelling and inhibition of glutamate uptake are not clear. We demonstrated previously that cultured astrocytes exposed to ammonia increase free radical production. We now show that treatment with antioxidants significantly prevents ammonia-induced astrocyte swelling as well as glutamate uptake inhibition. Because one consequence of oxidative stress is the phosphorylation of mitogen-activated protein kinases (MAPKs), we investigated whether phosphorylation of MAPKs may mediate astrocyte dysfunction. Primary cultured astrocytes exposed to 5 mM NH 4 Cl for different time periods (1-72 h) significantly increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK , and c-Jun N-terminal kinase (JNK) 1/2/3, which was inhibited by appropriate MAPK inhibitors 1, 4-diamino-2, 3-dicyano-1, 4-bis (2-aminophenylthio) butadiene (UO126; for ERK1/2), trans-1-(4-hydroxyclyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole (SB 239063; for p38MAPK ), and anthra[1,9-cd]pyrazol-6(2H)-one (SP600125; for JNK1/2/3), as well as by antioxidants. Kinase inhibitors partially or completely prevented astrocyte swelling. Although SB239063 and SP600125 significantly reversed glutamate uptake inhibition and ammonia-induced decline in glutamate-aspartate transporter protein levels, UO126 did not, indicating a differential effect of these kinases in ammonia-induced astrocyte swelling and glutamate transport impairment. These studies strongly suggest the involvement of oxidative stress and phosphorylation of MAPKs in the mechanism of ammonia-induced astrocyte dysfunction associated with ammonia neurotoxicity.

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Section: Antioxidants and Nos Inhibition Prevent Ammonia-induced Mapkmentioning

confidence: 99%

Oxidative Stress and Mitogen-Activated Protein Kinase Phosphorylation Mediate Ammonia-Induced Cell Swelling and Glutamate Uptake Inhibition in Cultured Astrocytes

Jayakumar¹,

Panickar

Murthy³

et al. 2006

J. Neurosci.

190

158

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“…a-Tocopherol has the highest biological activity as an antioxidant/radical scavenger (Osakada et al, 2003); however, recent studies revealed non-antioxidant neuroprotective effects, for example, reduction of PKC-a activity through dephosphorylation (Zingg and Azzi, 2004).…”

Section: Introductionmentioning

confidence: 99%

α-Tocopherol Protects Against Oxidative Stress in the Fragile X Knockout Mouse: an Experimental Therapeutic Approach for the Fmr1 Deficiency

Diego-Otero¹,

Romero-Zerbo²,

Bekay

et al. 2008

Neuropsychopharmacol

119

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Fragile X syndrome is the most common genetic cause of mental disability. The mechanisms underlying the pathogenesis remain unclear and specific treatments are still under development. Previous studies have proposed an abnormal hypothalamic-pituitary-adrenal axis and high cortisol levels are demonstrated in the fragile X patients. Additionally, we have previously described that NADPH-oxidase activation leads to oxidative stress in the brain, representing a pathological mechanism in the fragile X mouse model. Fmr1-knockout mice develop an altered free radical production, abnormal glutathione homeostasis, high lipid and protein oxidation, accompanied by stressdependent behavioral abnormalities and pathological changes in the first months of postnatal life. Chronic pharmacological treatment with a-tocopherol reversed pathophysiological hallmarks including free radical overproduction, oxidative stress, Rac1 and a-PKC activation, macroorchidism, and also behavior and learning deficits. The restoration of the oxidative status in the fragile X mouse emerges as a new and promising approach for further therapeutic research in fragile X syndrome.

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“…The animals were treated in accordance with the guidelines of the Kyoto University animal experimentation committee, and the guidelines of the Japanese Pharmacological Society. Primary cultures were prepared from the anterior striatum of fetal Wistar rats (Nihon SLC, Shizuoka, Japan) at 17 to 19 days of gestation, according to procedures described previously (Osakada et al, 2003). Briefly, the pregnant rats were anesthetized with sodium pentobarbital.…”

Section: Methodsmentioning

confidence: 99%

“…Three days after plating, cultures were incubated in a medium in the presence or absence of the indicated concentrations of drugs. Cultures were exposed to paraquat or H 2 O 2 for 24 h, according to our previous study (Osakada et al, 2003). Serofendic acid, DMSO, SOD, catalase, Mn-TBAP, EUK-134, or 2,2Ј-dipyridyl was simultaneously applied to the toxin-containing medium for 24 h. After drug treatment, cell viability was determined by immunocytochemistry, MTT assay, or lactate dehydrogenase (LDH) release assay.…”

Section: Methodsmentioning

confidence: 99%

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Serofendic Acid, a Sulfur-Containing Diterpenoid Derived from Fetal Calf Serum, Attenuates Reactive Oxygen Species-Induced Oxidative Stress in Cultured Striatal Neurons

Osakada¹,

Kawato²,

Kume³

et al. 2004

J Pharmacol Exp Ther

Self Cite

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We previously identified a novel endogenous substance, serofendic acid, from a lipophilic extract of fetal calf serum. Serofendic acid protects cultured cortical neurons against the cytotoxicity of glutamate and nitric oxide. Here, we reported the protective effect of serofendic acid on reactive oxygen speciesinduced oxidative stress using primary rat striatal cultures. In addition, we compared the neuroprotective effect and the radical-scavenging activity of serofendic acid with those of dimethyl sulfoxide (DMSO), because serofendic acid possesses a DMSO structure. Paraquat caused neuronal death, which was inhibited by a cell-permeable superoxide dismutase (SOD) mimetic, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (Mn-TBAP); a cell-permeable SOD/catalase mimetic, EUK-134 [manganese 3-methoxy N,NЈ-bis(salicylidene)ethylenediamine chloride]; and a ferrous ion chelator, 2,2Ј-dipyridyl, in rat striatal cultures. Serofendic acid (10 -100 M) suppressed the neurotoxicity of paraquat, whereas DMSO (10 -100 M) did not. By contrast, higher concentrations (30 -300 mM) of DMSO ameliorated the paraquat-induced cell death. Furthermore, H 2 O 2 induced neurotoxicity, which was prevented by EUK-134 and 2,2Ј-dipyridyl. Serofendic acid (10 -100 M) also protected striatal neurons against the H 2 O 2 -induced toxicity. Higher concentrations (30 -300 mM) of DMSO ameliorated H 2 O 2 -induced neuronal death, whereas lower concentrations (10 -100 M) did not. Electron spin resonance spectrometry with a spin-trapping technique revealed that serofendic acid and DMSO had approximately the same ability to inhibit the formation of the hydroxyl radical (⅐OH). These results suggest that the ⅐OH-scavenging activity of serofendic acid is attributable to its DMSO structure and that the remaining components such as the atisane structure play an important role in eliciting neuroprotection at a concentration range of 10 to 100 M.

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Neuroprotective effects of α-tocopherol on oxidative stress in rat striatal cultures

Cited by 68 publications

References 38 publications

Oxidative Stress and Mitogen-Activated Protein Kinase Phosphorylation Mediate Ammonia-Induced Cell Swelling and Glutamate Uptake Inhibition in Cultured Astrocytes

Oxidative Stress and Mitogen-Activated Protein Kinase Phosphorylation Mediate Ammonia-Induced Cell Swelling and Glutamate Uptake Inhibition in Cultured Astrocytes

α-Tocopherol Protects Against Oxidative Stress in the Fragile X Knockout Mouse: an Experimental Therapeutic Approach for the Fmr1 Deficiency

Serofendic Acid, a Sulfur-Containing Diterpenoid Derived from Fetal Calf Serum, Attenuates Reactive Oxygen Species-Induced Oxidative Stress in Cultured Striatal Neurons

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