Neuroprotective effects of levetiracetam target <scp>xCT</scp> in astrocytes in parkinsonian mice

Miyazaki, Ikuko; Murakami, Shinki; Torigoe, Nao; Kitamura, Yoshihisa; Asanuma, Masato

doi:10.1111/jnc.13405

Cited by 46 publications

(29 citation statements)

References 43 publications

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“…One possibility is that the upregulation of xCT might be a compensatory protective reaction to increased oxidative stress. Consistent with this idea, treatments that elevate neuronal levels of GSH show protection in a variety of PD models [36,37]. On the other hand, as an exchanger, xCT elevates extracellular levels of glutamate that in turn may have toxic effects on dopaminergic neurons via glutamate receptors.…”

Section: Xct/slc7a11 Is Induced In Pd Cellular Modelsmentioning

confidence: 83%

Manipulation and Study of Gene Expression in Neurotoxin- Treated Neuronal PC12 and SH-SY5Y Cells for In Vitro Studies of Parkinson’s Disease

Aimé¹,

Sun²,

Greene³

2018

Gene Expression and Regulation in Mammalian Cells - Transcription Toward the Establishment of Novel Therapeutics

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Neuronal PC12 and SH-SY5Y cells are highly suitable in vitro models for study of the neurodegenerative mechanisms occurring in Parkinson's disease (PD). Differentiated PC12 and SH-SY5Y cells bear many similarities to the neuronal populations affected in PD, and they provide a convenient source of large amounts of homogeneous material for biochemical and molecular downstream applications. In the present review, we describe how to differentiate PC12 and SH-SY5Y cells into neuron-like cells and provide protocols for their transfection with plasmids and infection with viral particles to manipulate gene expression. We also describe how to treat neuronal PC12 and SH-SY5Y cells with the classical PD neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-pyridinium ion (MPP+). Finally, we give detailed methods for several downstream applications useful for the analysis of cell death pathways in PD.

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Section: Xct/slc7a11 Is Induced In Pd Cellular Modelsmentioning

confidence: 83%

Manipulation and Study of Gene Expression in Neurotoxin- Treated Neuronal PC12 and SH-SY5Y Cells for In Vitro Studies of Parkinson’s Disease

Aimé¹,

Sun²,

Greene³

2018

Gene Expression and Regulation in Mammalian Cells - Transcription Toward the Establishment of Novel Therapeutics

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“…Repeated injections of the anti‐epileptic agent, zonisamide (benzo[d]isoxazol‐3‐ylmethanesulfonamide), into 6‐hydroxydopamine (6(OH)DA)‐treated mice improve the cardinal symptoms of PD (Asanuma et al ., ) by increasing GSH through enhanced activity of the x c − exchanger. Similar results using levetiracetam have recently been reported (Miyazaki et al ., ). On the other hand, Massie and colleagues observed that mice lacking the xCT subunit of the x c − exchanger were less susceptible to toxicity by 6(OH)DA, possibly because of reduced glutamate release (Massie et al ., ).…”

Section: Thiol‐based Redox Therapies In Neurodegenerative Diseasementioning

confidence: 97%

Redox‐based therapeutics in neurodegenerative disease

McBean

López

Wallner

2016

British J Pharmacology

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This review describes recent developments in the search for effective therapeutic agents that target redox homeostasis in neurodegenerative disease. The disruption to thiol redox homeostasis in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis is discussed, together with the experimental strategies that are aimed at preventing, or at least minimizing, oxidative damage in these diseases. Particular attention is given to the potential of increasing antioxidant capacity by targeting the Nrf2 pathway, the development of inhibitors of NADPH oxidases that are likely candidates for clinical use, together with strategies to reduce nitrosative stress and mitochondrial dysfunction. We describe the shortcomings of compounds that hinder their progression to the clinic and evaluate likely avenues for future research. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations 6(OH)DA, 6-hydroxydopamine; AD, Alzheimer's disease; ADME(T), absorption, distribution, metabolism and excretion/toxicity; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; ARE, antioxidant response element; ASSNAC, S-allylmercapto-N-acetyl cysteine; Aβ, amyloid-β; CA, carnosic acid; DMF, dimethylfumarate; EAE, experimental autoimmune encephalomyelitis; EpRE, electrophile response element; GCL, glutamate cysteine ligase; GR, glutathione reductase; Grx, glutaredoxin; GSK-3β, glycogen synthase kinase-3β; Keap1, Kelch-like ECH-associated protein-1; MMF, monomethylfumarate; MPTP, 1-methyl, 4-phenyl-1,2,3,6-tetrahydropyridine; MS, multiple sclerosis; MPO, myeloperoxidase; NAC, N-acetylcysteine; NACA, N-acetylcysteine amide; NOX, NADPH oxidase; NQO1, NAD(P)H quinone oxidoreductase-1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PD, Parkinson's disease; PS1, pre-senelin-1; RNS, reactive nitrogen species; SN, substantia nigra; Trx, thioredoxin; TrxR, thioredoxin reductase; xCT, functional subunit of the x c À exchanger Disruption of cerebral redox homeostasis is a common occurrence in a range of human neurodegenerative disorders, and although much is understood of mechanistic dysfunction, the gap between knowledge and the availability of effective therapies remains wide. In this review, we focus on the potential for developing therapeutic agents that promote the availability of thiol redox antioxidants or boost the antioxidant capacity of cells via stimulation of the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, we discuss options for reducing ROS production by inhibition of NADPH oxidases (NOXs), limiting nitrative stress or targeting mitochondrial dysfunction. Other potential strategies for limiting oxidative stress in neurodegenerative disease include nutrient and vitamin supplementation and metal chelators, which are excluded from the discussion. These approaches are t...

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“…xCT (the cysteine/glutamate exchanger) seems to be another. 11) Besides these amino acid transporters, organic ion transporters are also promising candidates as drug-targetable astrocyte transporters. Unlike the above-mentioned astroglia-specific transporters, the expression of organic ion transporters is not always limited to astrocytes (as described later); therefore, their potential as a pharmacological target in astrocytes has yet to be established.…”

Section: 7)mentioning

confidence: 99%

Functional Expression of Organic Ion Transporters in Astrocytes and Their Potential as a Drug Target in the Treatment of Central Nervous System Diseases

Furihata

Anzai

2017

Biological & Pharmaceutical Bulletin

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It has become widely acknowledged that astrocytes play essential roles in maintaining physiological central nervous system (CNS) activities. Astrocytes fulfill their roles partly through the manipulation of their plasma membrane transporter functions, and therefore these transporters have been regarded as promising drug targets for various CNS diseases. A representative example is excitatory amino acid transporter 2 (EAAT2), which works as a critical regulator of excitatory signal transduction through its glutamate uptake activity at the tripartite synapse. Thus, enhancement of EAAT2 functionality is expected to accelerate glutamate clearance at synapses, which is a promising approach for the prevention of over-excitation of glutamate receptors. In addition to such well-known astrocyte-specific transporters, cumulative evidence suggests that multi-specific organic ion transporters (i.e., organic cation/anion transporters [OCTs/OATs], carnitine/organic cation transporters [OCTNs], and organic anion transporting polypeptides [OATPs]) are also functionally expressed in astrocytes. Even though identification and characterization of their physiological/pathophysiological roles in astrocytes are in the initial stage, the findings obtained so far indicate that OCT3 and plasma membrane monoamine transporter are significantly involved in the clearance of biogenic amine neurotransmitters in the synaptic cleft, and that OCTN2 and OATP1C1 provide a cellular entry gate for carnitine/acetyl-L-carnitine and thyroxine, respectively. Therefore, organic ion transporters, including those mentioned above, are expected to become emerging pharmacological targets for various CNS diseases. With such expectations in mind, this review will briefly summarize the functional expression of organic ion transporters in astrocytes.

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Neuroprotective effects of levetiracetam target xCT in astrocytes in parkinsonian mice

Cited by 46 publications

References 43 publications

Manipulation and Study of Gene Expression in Neurotoxin- Treated Neuronal PC12 and SH-SY5Y Cells for In Vitro Studies of Parkinson’s Disease

Manipulation and Study of Gene Expression in Neurotoxin- Treated Neuronal PC12 and SH-SY5Y Cells for In Vitro Studies of Parkinson’s Disease

Redox‐based therapeutics in neurodegenerative disease

Functional Expression of Organic Ion Transporters in Astrocytes and Their Potential as a Drug Target in the Treatment of Central Nervous System Diseases

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