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Modification of Astrocyte Metabolism as an Approach to the Treatment of Epilepsy: Triheptanoin and Acetyl-l-Carnitine

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Abstract

Epilepsy is a severe neurological disorder characterized by altered electrical activity in the brain. Important pathophysiological mechanisms include disturbed metabolism and homeostasis of major excitatory and inhibitory neurotransmitters, glutamate and GABA. Current drug treatments are largely aimed at decreasing neuronal excitability and thereby preventing the occurrence of seizures. However, many patients are refractory to treatment and side effects are frequent. Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults. In rodents, the pilocarpine-status epilepticus model reflects the pathology and chronic spontaneous seizures of TLE and the pentylenetetrazole kindling model exhibits chronic induced limbic seizures. Accumulating evidence from studies on TLE points to alterations in astrocytes and neurons as key metabolic changes. The present review describes interventions which alleviate these disturbances in astrocyte–neuronal interactions by supporting mitochondrial metabolism. The compounds discussed are the endogenous transport molecule acetyl-l-carnitine and the triglyceride of heptanoate, triheptanoin. Both provide acetyl moieties for oxidation in the tricarboxylic acid cycle whereas heptanoate is also provides propionyl-CoA, which after carboxylation can produce succinyl-CoA, resulting in anaplerosis—the refilling of the tricarboxylic acid cycle.

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Abbreviations

18FDG-PET:

18F-fluorodeoxyglucose positron emission tomography

GAD:

Glutamate decarboxylase

GLN:

Glutamine

GLU:

Glutamate

GS:

Glutamine synthetase

GVG:

γ-VinylGABA

α-KG:

α-Ketoglutarate

MRS:

Magnetic resonance spectroscopy

PC:

Pyruvate carboxylase

PDH:

Pyruvate dehydrogenase

SE:

Status epilepticus

TCA:

Tricarboxylic acid

TLE:

Temporal lobe epilepsy

PTZ:

Penetylenethetrazole

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    Authors and Affiliations

    1. Department of Pharmacy, College of Health Sciences, Mekelle University, Tigray, Ethiopia

      Mussie Ghezu Hadera

    2. Department of Pharmacology, School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia

      Tanya McDonald & Karin Borges

    3. NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407, Oslo, Norway

      Olav B. Smeland

    4. Department of Neurology and Clinical Neurophysiology, St. Olav’s University Hospital, Trondheim, Norway

      Tore W. Meisingset

    5. Department of Neuroscience, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan

      Haytham Eloqayli

    6. Princes Haya Biotechnology Center, Jordan University of Science and Technology, Irbid, Jordan

      Saied Jaradat

    7. Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Olav Kyrresgt. 3, 7489, Trondheim, Norway

      Ursula Sonnewald

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    1. Mussie Ghezu Hadera
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    2. Tanya McDonald
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    3. Olav B. Smeland
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    4. Tore W. Meisingset
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    5. Haytham Eloqayli
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    6. Saied Jaradat
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    7. Karin Borges
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    8. Ursula Sonnewald
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    Correspondence to Ursula Sonnewald.

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    Conflict of interest

    KB has applied for a US patent for the use of triheptanoin in seizure disorders.

    Additional information

    Special Issue: 40th Year of Neurochemical Research.

    Olav B. Smeland and Tore W. Meisingset have contributed equally to this work.

    Borges’ and Sonnewald’s labs have contributed equally.

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    Hadera, M.G., McDonald, T., Smeland, O.B. et al. Modification of Astrocyte Metabolism as an Approach to the Treatment of Epilepsy: Triheptanoin and Acetyl-l-Carnitine. Neurochem Res 41, 86–95 (2016). https://doi.org/10.1007/s11064-015-1728-5

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    • DOI: https://doi.org/10.1007/s11064-015-1728-5

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