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Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2017) | Viewed by 110619

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Prof. Dr. Wolfram S. Kunz

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Abteilung Neurochemie, Klinik für Epileptologie and LIFE & BRAIN Center, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Interests: mitochondrial epilepsy; brain energy metabolism; neuroprotection; mitochondrial DNA maintenance; mitochondrial diseases; epilepsy genetics

Special Issue Information

Dear Colleagues,

This Special Issue is dedicated to Professor Uwe Heinemann on the occasion of his unexpected passing.

Epilepsy is a very common, severe and disabling neurological disorder with a major disease burden worldwide. Although the seizures can be well controlled by available medications in about two thirds of patients, the development of novel treatment strategies for the remaining third is largely hampered by our poor understanding of the underlying mechanisms. According to the classical view, seizures are the result of an imbalance between excitatory and inhibitory neuronal activities. Classical epilepsy research has been therefore focused on changes of synaptic transmission caused by altered ion channels and neurotransmitter receptors. Due to recent dramatic progress in uncovering the genetic cause of disease conditions associated with epilepsy, there is an emerging body of evidence that epilepsy has to be considered in a much broader context. Particularly, metabolic causes of seizures obtained recent attention.

This Special Issue, “Metabolic Epilepsies”, will cover a selection of recent research topics and current review articles about the contribution of alterations of brain metabolism to seizure activity. We are particularly interested in articles describing: (i) genetic findings in epilepsy not primary related to ion channels and neurotransmitter receptors; (ii) new concepts explaining seizure generation by metabolic alterations; and (iii) the use of new strategies for treatment and neuroprotection in metabolic epilepsies.

Professor Uwe Heinemann is one of the most outstanding and influential scientist in the field of epilepsy research who passed away on 8 September, 2016. He studied medicine at the Ludwig-Maximilians-University, Munich, followed by his doctoral studies and dissertation in Experimental Psychology, Oxford (1968–1971). His first postdoc at the Max Planck Institute for Psychiatry (1971–1981) and his Heisenberg fellowship (1981–1986) paved the way first to his professorship at University of Cologne (1986–1993) and then at the Charité-Medical University of Berlin (1993–2012), where he became the head of the Institute for Neurophysiology and later also the co-director of the NeuroCure Cluster of Excellence. Since 1999 he was the chairman of the Neuroscience Research Center of the Charité, where he continued to work as professor emeritus after his retirement in 2012 until his sudden death. Professor Uwe Heinemann was a member of numerous commissions and governing bodies, from within which he has given numerous impulses that have shaped the field of epilepsy research. These included the Commission on Neurobiology and Epilepsy and the Long Term Planning Commission of the International League Against Epilepsy, Advisory Board for the European Academy of Epilepsy, European Epilepsy Congress, European Neuroscience Conference and the Biannual Congress of the ILAE. He was past president of the German Epilepsy Society (1993–1995), and honorary member of the society since 2012. He was also one of the initiators of the Workshop on Neurobiology of the Epilepsies, which has gone on to become one of the most influential think tanks in epilepsy research today. His scientific excellence and integrative personality has been internationally recognized with numerous awards, including the international Michael Prize for Epilepsy Research (1977 and 1987), the Alfred Hauptmann Prize (1988), the Ambassador for Epilepsy Award (1989), the Basic Science AES Award (1992), and the European Epilepsy Award (2008).

Prof. Wolfram S. Kunz
Guest Editor

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Keywords

Metabolic epilepsy
Brain metabolism
Neuroprotection
Epilepsy genetics
Treatment of metabolic epilepsy

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Published Papers (13 papers)

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Editorial

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485 KiB

Open AccessEditorial

Metabolic Epilepsies—Commemorative Issue in Honor of Professor Uwe Heinemann

by Richard Kovács and Wolfram S. Kunz

Int. J. Mol. Sci. 2017, 18(11), 2499; https://doi.org/10.3390/ijms18112499 - 22 Nov 2017

Viewed by 3645

Abstract

Epilepsy is a very frequent, severe, and disabling neurological disorder with has a considerable disease burden worldwide [...]
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(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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Research

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3969 KiB

Open AccessArticle

Event-Associated Oxygen Consumption Rate Increases ca. Five-Fold When Interictal Activity Transforms into Seizure-Like Events In Vitro

by Karl Schoknecht, Nikolaus Berndt, Jörg Rösner, Uwe Heinemann, Jens P. Dreier, Richard Kovács, Alon Friedman and Agustin Liotta

Int. J. Mol. Sci. 2017, 18(9), 1925; https://doi.org/10.3390/ijms18091925 - 7 Sep 2017

Cited by 12 | Viewed by 5799

Abstract

Neuronal injury due to seizures may result from a mismatch of energy demand and adenosine triphosphate (ATP) synthesis. However, ATP demand and oxygen consumption rates have not been accurately determined, yet, for different patterns of epileptic activity, such as interictal and ictal events. We studied interictal-like and seizure-like epileptiform activity induced by the GABA_A antagonist bicuculline alone, and with co-application of the M-current blocker XE-991, in rat hippocampal slices. Metabolic changes were investigated based on recording partial oxygen pressure, extracellular potassium concentration, and intracellular flavine adenine dinucleotide (FAD) redox potential. Recorded data were used to calculate oxygen consumption and relative ATP consumption rates, cellular ATP depletion, and changes in FAD/FADH₂ ratio by applying a reactive-diffusion and a two compartment metabolic model. Oxygen-consumption rates were ca. five times higher during seizure activity than interictal activity. Additionally, ATP consumption was higher during seizure activity (~94% above control) than interictal activity (~15% above control). Modeling of FAD transients based on partial pressure of oxygen recordings confirmed increased energy demand during both seizure and interictal activity and predicted actual FAD autofluorescence recordings, thereby validating the model. Quantifying metabolic alterations during epileptiform activity has translational relevance as it may help to understand the contribution of energy supply and demand mismatches to seizure-induced injury. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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3696 KiB

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Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of α-Lipoamide Dehydrogenase

by Alexei P. Kudin, Hafiz Mawasi, Arik Eisenkraft, Christian E. Elger, Meir Bialer and Wolfram S. Kunz

Int. J. Mol. Sci. 2017, 18(9), 1912; https://doi.org/10.3390/ijms18091912 - 6 Sep 2017

Cited by 22 | Viewed by 5774

Abstract

The liver toxicity of valproic acid (VPA) is an established side effect of this widely used antiepileptic drug, which is extremely problematic for patients with metabolic epilepsy and particularly epilepsy due to mitochondrial dysfunction. In the present report, we investigated the reason for liver mitochondrial toxicity of VPA and several acid and amide VPA analogues. While the pyruvate and 2-oxoglutarate oxidation rates of rat brain mitochondria were nearly unaffected by VPA, rat liver mitochondrial pyruvate and 2-oxoglutarate oxidation was severely impaired by VPA concentrations above 100 µM. Among the reactions involved in pyruvate oxidation, pyruvate transport and dehydrogenation steps were not affected by VPA, while α-lipoamide dehydrogenase was strongly inhibited. Strong inhibition of α-lipoamide dehydrogenase was also noted for the VPA one-carbon homolog sec-butylpropylacetic acid (SPA) and to a lesser extent for the VPA constitutional isomer valnoctic acid (VCA), while the corresponding amides of the above three acids valpromide (VPD), sec-butylpropylacetamide (SPD) and valnoctamide (VCD) showed only small effects. We conclude that the active inhibitors of pyruvate and 2-oxoglutarate oxidation are the CoA conjugates of VPA and its acid analogues affecting selectively α-lipoamide dehydrogenase in liver. Amide analogues of VPA, like VCD, show low inhibitory effects on mitochondrial oxidative phosphorylation in the liver, which might be relevant for treatment of patients with mitochondrial epilepsy. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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1429 KiB

Open AccessArticle

Contribution of Intrinsic Lactate to Maintenance of Seizure Activity in Neocortical Slices from Patients with Temporal Lobe Epilepsy and in Rat Entorhinal Cortex

by Eskedar Ayele Angamo, Rizwan Ul Haq, Jörg Rösner, Siegrun Gabriel, Zoltán Gerevich, Uwe Heinemann and Richard Kovács

Int. J. Mol. Sci. 2017, 18(9), 1835; https://doi.org/10.3390/ijms18091835 - 23 Aug 2017

Cited by 13 | Viewed by 7303

Abstract

Neuronal lactate uptake supports energy metabolism associated with synaptic signaling and recovery of extracellular ion gradients following neuronal activation. Altered expression of the monocarboxylate transporters (MCT) in temporal lobe epilepsy (TLE) hampers lactate removal into the bloodstream. The resulting increase in parenchymal lactate levels might exert both, anti- and pro-ictogen effects, by causing acidosis and by supplementing energy metabolism, respectively. Hence, we assessed the contribution of lactate to the maintenance of transmembrane potassium gradients, synaptic signaling and pathological network activity in chronic epileptic human tissue. Stimulus induced and spontaneous field potentials and extracellular potassium concentration changes (∆[K⁺]_O) were recorded in parallel with tissue pO₂ and pH in slices from TLE patients while blocking MCTs by α-cyano-4-hydroxycinnamic acid (4-CIN) or d-lactate. Intrinsic lactate contributed to the oxidative energy metabolism in chronic epileptic tissue as revealed by the changes in pO₂ following blockade of lactate uptake. However, unlike the results in rat hippocampus, ∆[K⁺]_O recovery kinetics and field potential amplitude did not depend on the presence of lactate. Remarkably, inhibition of lactate uptake exerted pH-independent anti-seizure effects both in healthy rat and chronic epileptic tissue and this effect was partly mediated via adenosine 1 receptor activation following decreased oxidative metabolism. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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2690 KiB

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Mitochondrial Dysfunction Mediated by Poly(ADP-Ribose) Polymerase-1 Activation Contributes to Hippocampal Neuronal Damage Following Status Epilepticus

by Yi-Chen Lai, J. Scott Baker, Taraka Donti, Brett H. Graham, William J. Craigen and Anne E. Anderson

Int. J. Mol. Sci. 2017, 18(7), 1502; https://doi.org/10.3390/ijms18071502 - 12 Jul 2017

Cited by 16 | Viewed by 4322

Abstract

Mitochondrial dysfunction plays a central role in the neuropathology associated with status epilepticus (SE) and is implicated in the development of epilepsy. While excitotoxic mechanisms are well-known mediators affecting mitochondrial health following SE, whether hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1) also contributes to SE-induced mitochondrial dysfunction remains to be examined. Here we first evaluated the temporal evolution of poly-ADP-ribosylated protein levels in hippocampus following kainic acid-induced SE as a marker for PARP-1 activity, and found that PARP-1 was hyperactive at 24 h following SE. We evaluated oxidative metabolism and found decreased NAD⁺ levels by enzymatic cycling, and impaired NAD⁺-dependent mitochondrial respiration as measured by polarography at 24 h following SE. Stereological estimation showed significant cell loss in the hippocampal CA₁ and CA₃ subregions 72 h following SE. PARP-1 inhibition using N-(6-Oxo-5,6-dihydro-phenanthridin-2-yl)- N,N-dimethylacetamide (PJ-34) in vivo administration was associated with preserved NAD⁺ levels and NAD⁺-dependent mitochondrial respiration, and improved CA₁ neuronal survival. These findings suggest that PARP-1 hyperactivation contributes to SE-associated mitochondrial dysfunction and CA₁ hippocampal damage. The deleterious effects of PARP-1 hyperactivation on mitochondrial respiration are in part mediated through intracellular NAD⁺ depletion. Therefore, modulating PARP-1 activity may represent a potential therapeutic target to preserve intracellular energetics and mitochondrial function following SE. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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Review

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10 pages, 789 KiB

Open AccessReview

Individualizing Treatment Approaches for Epileptic Patients with Glucose Transporter Type1 (GLUT-1) Deficiency

by Armond Daci, Adnan Bozalija, Fisnik Jashari and Shaip Krasniqi

Int. J. Mol. Sci. 2018, 19(1), 122; https://doi.org/10.3390/ijms19010122 - 5 Jan 2018

Cited by 33 | Viewed by 7187

Abstract

Monogenic and polygenic mutations are important contributors in patients suffering from epilepsy, including metabolic epilepsies which are inborn errors of metabolism with a good respond to specific dietetic treatments. Heterozygous variation in solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1) and mutations of the GLUT1/SLC2A2 gene results in the failure of glucose transport, which is related with a glucose type-1 transporter (GLUT1) deficiency syndrome (GLUT1DS). GLUT1 deficiency syndrome is a treatable disorder of glucose transport into the brain caused by a variety of mutations in the SLC2A1 gene which are the cause of different neurological disorders also with different types of epilepsy and related clinical phenotypes. Since patients continue to experience seizures due to a pharmacoresistance, an early clinical diagnosis associated with specific genetic testing in SLC2A1 pathogenic variants in clinical phenotypes could predict pure drug response and might improve safety and efficacy of treatment with the initiation of an alternative energy source including ketogenic or analog diets in such patients providing individualized strategy approaches. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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718 KiB

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Metabolic Dysfunction and Oxidative Stress in Epilepsy

by Jennifer N. Pearson-Smith and Manisha Patel

Int. J. Mol. Sci. 2017, 18(11), 2365; https://doi.org/10.3390/ijms18112365 - 8 Nov 2017

Cited by 200 | Viewed by 9881

Abstract

The epilepsies are a heterogeneous group of disorders characterized by the propensity to experience spontaneous recurrent seizures. Epilepsies can be genetic or acquired, and the underlying mechanisms of seizure initiation, seizure propagation, and comorbid conditions are incompletely understood. Metabolic changes including the production of reactive species are known to result from prolonged seizures and may also contribute to epilepsy development. In this review, we focus on the evidence that metabolic and redox disruption is both cause and consequence of epileptic seizures. Additionally, we discuss the promise of targeting redox processes as a therapeutic option in epilepsy. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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870 KiB

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Hungry Neurons: Metabolic Insights on Seizure Dynamics

by Paolo Bazzigaluppi, Azin Ebrahim Amini, Iliya Weisspapir, Bojana Stefanovic and Peter L. Carlen

Int. J. Mol. Sci. 2017, 18(11), 2269; https://doi.org/10.3390/ijms18112269 - 28 Oct 2017

Cited by 30 | Viewed by 8189

Abstract

Epilepsy afflicts up to 1.6% of the population and the mechanisms underlying the appearance of seizures are still not understood. In past years, many efforts have been spent trying to understand the mechanisms underlying the excessive and synchronous firing of neurons. Traditionally, attention was pointed towards synaptic (dys)function and extracellular ionic species (dys)regulation. Recently, novel clinical and preclinical studies explored the role of brain metabolism (i.e., glucose utilization) of seizures pathophysiology revealing (in most cases) reduced metabolism in the inter-ictal period and increased metabolism in the seconds preceding and during the appearance of seizures. In the present review, we summarize the clinical and preclinical observations showing metabolic dysregulation during epileptogenesis, seizure initiation, and termination, and in the inter-ictal period. Recent preclinical studies have shown that 2-Deoxyglucose (2-DG, a glycolysis blocker) is a novel therapeutic approach to reduce seizures. Furthermore, we present initial evidence for the effectiveness of 2-DG in arresting 4-Aminopyridine induced neocortical seizures in vivo in the mouse. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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1284 KiB

Open AccessReview

Metabolic and Homeostatic Changes in Seizures and Acquired Epilepsy—Mitochondria, Calcium Dynamics and Reactive Oxygen Species

by Stjepana Kovac, Albena T. Dinkova Kostova, Alexander M. Herrmann, Nico Melzer, Sven G. Meuth and Ali Gorji

Int. J. Mol. Sci. 2017, 18(9), 1935; https://doi.org/10.3390/ijms18091935 - 8 Sep 2017

Cited by 91 | Viewed by 9617

Abstract

Acquired epilepsies can arise as a consequence of brain injury and result in unprovoked seizures that emerge after a latent period of epileptogenesis. These epilepsies pose a major challenge to clinicians as they are present in the majority of patients seen in a common outpatient epilepsy clinic and are prone to pharmacoresistance, highlighting an unmet need for new treatment strategies. Metabolic and homeostatic changes are closely linked to seizures and epilepsy, although, surprisingly, no potential treatment targets to date have been translated into clinical practice. We summarize here the current knowledge about metabolic and homeostatic changes in seizures and acquired epilepsy, maintaining a particular focus on mitochondria, calcium dynamics, reactive oxygen species and key regulators of cellular metabolism such as the Nrf2 pathway. Finally, we highlight research gaps that will need to be addressed in the future which may help to translate these findings into clinical practice. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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1181 KiB

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Understanding the Epilepsy in POLG Related Disease

by Omar Hikmat, Tom Eichele, Charalampos Tzoulis and Laurence A. Bindoff

Int. J. Mol. Sci. 2017, 18(9), 1845; https://doi.org/10.3390/ijms18091845 - 24 Aug 2017

Cited by 37 | Viewed by 6758

Abstract

Epilepsy is common in polymerase gamma (POLG) related disease and is associated with high morbidity and mortality. Epileptiform discharges typically affect the occipital regions initially and focal seizures, commonly evolving to bilateral convulsive seizures which are the most common seizure types in both adults and children. Our work has shown that mtDNA depletion—i.e., the quantitative loss of mtDNA—in neurones is the earliest and most important factor of the subsequent development of cellular dysfunction. Loss of mtDNA leads to loss of mitochondrial respiratory chain (MRC) components that, in turn, progressively disables energy metabolism. This critically balanced neuronal energy metabolism leads to both a chronic and continuous attrition (i.e., neurodegeneration) and it leaves the neurone unable to cope with increased demand that can trigger a potentially catastrophic cycle that results in acute focal necrosis. We believe that it is the onset of epilepsy that triggers the cascade of damage. These events can be identified in the stepwise evolution that characterizes the clinical, Electroencephalography (EEG), neuro-imaging, and neuropathology findings. Early recognition with prompt and aggressive seizure management is vital and may play a role in modifying the epileptogenic process and improving survival. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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Pathogenesis of Lafora Disease: Transition of Soluble Glycogen to Insoluble Polyglucosan

by Mitchell A. Sullivan, Silvia Nitschke, Martin Steup, Berge A. Minassian and Felix Nitschke

Int. J. Mol. Sci. 2017, 18(8), 1743; https://doi.org/10.3390/ijms18081743 - 11 Aug 2017

Cited by 52 | Viewed by 9015

Abstract

Lafora disease (LD, OMIM #254780) is a rare, recessively inherited neurodegenerative disease with adolescent onset, resulting in progressive myoclonus epilepsy which is fatal usually within ten years of symptom onset. The disease is caused by loss-of-function mutations in either of the two genes EPM2A (laforin) or EPM2B (malin). It characteristically involves the accumulation of insoluble glycogen-derived particles, named Lafora bodies (LBs), which are considered neurotoxic and causative of the disease. The pathogenesis of LD is therefore centred on the question of how insoluble LBs emerge from soluble glycogen. Recent data clearly show that an abnormal glycogen chain length distribution, but neither hyperphosphorylation nor impairment of general autophagy, strictly correlates with glycogen accumulation and the presence of LBs. This review summarizes results obtained with patients, mouse models, and cell lines and consolidates apparent paradoxes in the LD literature. Based on the growing body of evidence, it proposes that LD is predominantly caused by an impairment in chain-length regulation affecting only a small proportion of the cellular glycogen. A better grasp of LD pathogenesis will further develop our understanding of glycogen metabolism and structure. It will also facilitate the development of clinical interventions that appropriately target the underlying cause of LD. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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1194 KiB

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Inborn Errors of Metabolism and Epilepsy: Current Understanding, Diagnosis, and Treatment Approaches

by Suvasini Sharma and Asuri N. Prasad

Int. J. Mol. Sci. 2017, 18(7), 1384; https://doi.org/10.3390/ijms18071384 - 2 Jul 2017

Cited by 67 | Viewed by 15210

Abstract

Inborn errors of metabolism (IEM) are a rare cause of epilepsy, but seizures and epilepsy are frequently encountered in patients with IEM. Since these disorders are related to inherited enzyme deficiencies with resulting effects on metabolic/biochemical pathways, the term “metabolic epilepsy” can be used to include these conditions. These epilepsies can present across the life span, and share features of refractoriness to anti-epileptic drugs, and are often associated with co-morbid developmental delay/regression, intellectual, and behavioral impairments. Some of these disorders are amenable to specific treatment interventions; hence timely and appropriate diagnosis is critical to improve outcomes. In this review, we discuss those disorders in which epilepsy is a dominant feature and present an approach to the clinical recognition, diagnosis, and management of these disorders, with a greater focus on primarily treatable conditions. Finally, we propose a tiered approach that will permit a clinician to systematically investigate, identify, and treat these rare disorders. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism

by Hueng-Chuen Fan, Herng-Shen Lee, Kai-Ping Chang, Yi-Yen Lee, Hsin-Chuan Lai, Pi-Lien Hung, Hsiu-Fen Lee and Ching-Shiang Chi

Int. J. Mol. Sci. 2016, 17(8), 1242; https://doi.org/10.3390/ijms17081242 - 1 Aug 2016

Cited by 79 | Viewed by 16547

Abstract

Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies)

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Commemorative Issue in Honor of Professor Uwe Heinemann: Metabolic Epilepsies

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