Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice

Aoyama, Koji; Wang, Fan; Matsumura, Nobuko; Kanazawa, Hiroshi; Shioi, Go; Kinoshita, Chisato; Kikuchi-Utsumi, Kazue; Watabe, Masahiko; Nakaki, Toshio

doi:10.1016/j.nbd.2011.12.016

Cited by 39 publications

(31 citation statements)

References 29 publications

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“…injection of either the miR-96-5p inhibitor or a negative control inhibitor, we took mesencephalic slices containing SNc and treated them with SIN-1, generating nitric oxide, which reacts with superoxide to produce peroxynitrite, a potent toxic oxidating/nitrating agent. Nitrotyrosine is a permanent marker of peroxynitrite attack on proteins, revealing oxidative/nitrosative stress damage; treatment with SIN-1 thus increases nitrotyrosine expression27. As shown in Fig.…”

Section: Resultsmentioning

confidence: 83%

“…The experiments were initiated by transferring mesencephalic slices to tubes each containing aCSF at 30 °C that was continuously bubbled with 95% oxygen/5% CO 2 . Mesencephalic slices were exposed to 1 mM 3-morpholinosydnonimine (SIN-1, Santa Cruz Biotechnology, Santa Cruz, CA, USA), an NO donor, for 30 min as described previously27. The expression of nitrotyrosine was quantified with an OxiSelect nitrotyrosine ELISA kit (Cell Biolabs, San Diego, CA, USA) according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

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Rhythmic oscillations of the microRNA miR-96-5p play a neuroprotective role by indirectly regulating glutathione levels

et al. 2014

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Glutathione (GSH) is a key antioxidant that plays an important neuroprotective role in the brain. Decreased GSH levels are associated with neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Here we show that a diurnal fluctuation of GSH levels is correlated with neuroprotective activity against oxidative stress in dopaminergic cells. In addition, we found that the cysteine transporter excitatory amino acid carrier 1 (EAAC1), which is involved in neuronal GSH synthesis, is negatively regulated by the microRNA miR-96-5p, which exhibits a diurnal rhythm. Blocking miR-96-5p by intracerebroventricular administration of an inhibitor increased the level of EAAC1 as well as that of GSH and had a neuroprotective effect against oxidative stress in the mouse substantia nigra. Our results suggest that the diurnal rhythm of miR-96-5p may play a role in neuroprotection by regulating neuronal GSH levels via EAAC1.

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Section: Resultsmentioning

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Rhythmic oscillations of the microRNA miR-96-5p play a neuroprotective role by indirectly regulating glutathione levels

et al. 2014

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“…There are a few possible explanations for the opposite effect in a seizure model. EAAC1 −/− mice display markedly decreased levels of the antioxidant glutathione, synthesized from glutamate and cysteine, both of which are transported into neurons by EAAC1 (Kanai and Hediger, 1992; Rothstein et al, 1994; Rothstein et al, 1996; Diamond, 2001; Sepkuty et al, 2002; Chen and Swanson, 2003; Himi et al, 2003; Mathews and Diamond, 2003; Aoyama et al, 2008; Scimemi et al, 2009; Escartin et al, 2011; Aoyama and Nakaki, 2012; Aoyama et al, 2012a). It is possible that maintenance of neuronal glutathione is more important for attenuating ischemia-mediated cell death than for attenuation of seizure-induced cell death.…”

Section: Discussionmentioning

confidence: 99%

“…Three main physiological functions have been attributed to EAAC1: limitation of spillover at excitatory synapses (Rothstein et al, 1994; Diamond, 2001; Scimemi et al, 2009), provision of glutamate for GABA synthesis (Sepkuty et al, 2002; Mathews and Diamond, 2003), and contribution to neuronal uptake of cysteine for synthesis of glutathione (Chen and Swanson, 2003; Himi et al, 2003; Aoyama et al, 2008; Escartin et al, 2011; Aoyama and Nakaki, 2012; Aoyama et al, 2012a; for reviews see Aoyama et al, 2012b; Aoyama and Nakaki, 2013). Most studies suggest that EAAC1 may be neuroprotective.…”

Section: Introductionmentioning

confidence: 99%

Genetic deletion of the neuronal glutamate transporter, EAAC1, results in decreased neuronal death after pilocarpine-induced status epilepticus

Lane

Jackson

Krizman

et al. 2014

Neurochemistry International

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Excitatory amino acid carrier 1 (EAAC1, also called EAAT3) is a Na+-dependent glutamate transporter expressed by both glutamatergic and GABAergic neurons. It provides precursors for the syntheses of glutathione and GABA and contributes to the clearance of synaptically released glutamate. Mice deleted of EAAC1 are more susceptible to neurodegeneration in models of ischemia, Parkinson’s disease, and aging. Antisense knock-down of EAAC1 causes an absence seizure-like phenotype. Additionally, EAAC1 expression increases after chemonvulsant-induced seizures in rodent models and in tissue specimens from patients with refractory epilepsy. The goal of the present study was to determine if the absence of EAAC1 affects the sensitivity of mice to seizure-induced cell death. A chemoconvulsant dose of pilocarpine was administered to EAAC1−/− mice and to wild-type controls. Although EAAC1−/− mice experienced increased latency to seizure onset, no significant differences in behavioral seizure severity or mortality were observed. We examined EAAC1 immunofluorescence 24 hours after pilocarpine administration and confirmed that pilocarpine causes an increase in EAAC1 protein. Forty-eight hours after induction of seizures, cell death was measured in hippocampus and in cortex using Fluoro-Jade C. Surprisingly, there was ~2-fold more cell death in area CA1 of wild-type mice than in the corresponding regions of the EAAC1−/− mice. Together, these studies indicate that absence of EAAC1 results in either a decrease in pilocarpine-induced seizures that is not detectable by behavioral criteria (surprising, since EAAC1 provides glutamate for GABA synthesis), or that the absence of EAAC1 results in less pilocarpine/seizure-induced cell death, possible explanations as discussed.

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“…It is suggested that GTRAP3-18 plays a dominant negative role in cysteine transport when it interacts with EAAC1 [71]. Accordingly, GTRAP3-18 deficient mice show increased intracellular GSH levels, and these mice have demonstrated a decreased sensitivity to oxidative stress and increased cognitive function [72]. Thus, inhibitors of GTRAP3-18 may be effective inducers of GSH accumulation in the nervous system.…”

Section: Therapeutic Approaches To Modulate Gsh In Neurodegenerative mentioning

confidence: 99%

Immunocal® and Preservation of Glutathione as a Novel Neuroprotective Strategy for Degenerative Disorders of the Nervous System

Ross

Gray²,

Winter³

et al. 2012

RPCN

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Oxidative stress and glutathione (GSH) depletion are both recognized as significant contributors to the pathogenesis of many devastating neurodegenerative diseases. In particular, mitochondrial dysfunction leads to the aberrant production and accumulation of reactive oxygen species (ROS), which are capable of oxidizing key cellular proteins, lipids, and DNA, ultimately triggering cell death. In addition to other roles that it plays in the cell, GSH functions as a critical scavenger of these ROS. Therefore, GSH depletion exacerbates cell damage due to free radical generation. Strategies that increase or preserve the levels of intracellular GSH have been shown to act in a neuroprotective manner, suggesting that augmentation of the available GSH pool may be a promising therapeutic target for neurodegeneration. This review discusses the capacity of a cystine-rich, whey protein supplement (Immunocal ® ) to enhance the de novo synthesis of GSH in neurons, and highlights its potential as a novel therapeutic approach to mitigate the oxidative damage that underlies the pathogenesis of various neurodegenerative diseases. Additionally, this review discusses various patents from 1993 to 2012 both with Immunocal ® and other methods that modulate GSH in neurodegeneration.

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Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice

Cited by 39 publications

References 29 publications

Rhythmic oscillations of the microRNA miR-96-5p play a neuroprotective role by indirectly regulating glutathione levels

Rhythmic oscillations of the microRNA miR-96-5p play a neuroprotective role by indirectly regulating glutathione levels

Genetic deletion of the neuronal glutamate transporter, EAAC1, results in decreased neuronal death after pilocarpine-induced status epilepticus

Immunocal® and Preservation of Glutathione as a Novel Neuroprotective Strategy for Degenerative Disorders of the Nervous System

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