Mitochondrion 12 (2012) 3540

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Mitochondrion
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / m i t o

Review

Mitochondrial dysfunction in epilepsy

Jaroslava Folbergrov a, Wolfram S. Kunz b,
a
Department of Developmental Epileptology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
b
Division of Neurochemistry, Department of Epileptology, University Bonn Medical Center, Bonn, Germany

a r t i c l e i n f o a b s t r a c t

Available online 20 April 2011 Mitochondrial dysfunction has been identied as one potential cause of epileptic seizures. Impaired
mitochondrial function has been reported for the seizure focus of patients with temporal lobe epilepsy and
Keywords: Ammon's horn sclerosis and of adult and immature animal models of epilepsy. Since mitochondrial oxidative
Epilepsy phosphorylation provides the major source of ATP in neurons and mitochondria participate in cellular Ca2+
Mitochondrial dysfunction homeostasis and generation of reactive oxygen species, their dysfunction strongly affects neuronal excitability
Neurodegeneration
and synaptic transmission. Therefore, mitochondrial dysfunction is proposed to be highly relevant for seizure
generation. Additionally, mitochondrial dysfunction is known to trigger neuronal cell death, which is a
prominent feature of therapy-resistant epilepsy. For this reason mitochondria have to be considered as
promising targets for neuroprotective strategies in epilepsy.
2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
2. Mitochondrial involvement in human temporal lobe epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3. Mitochondrial involvement in adult models of epilepsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
4. Mitochondrial dysfunction in immature brain during seizures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
4.1. Oxidative stress during seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
4.2. Mitochondrial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
4.3. Potential consequences of the decreased complex I activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5. Potential mechanisms underlying hyperexcitability due to mitochondrial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
6. Mitochondrial bioenergetics and oxidative stress-related pathways as potential target of neuroprotective strategies in epilepsy . . . . . . . . . . . 38
Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

1. Introduction channels, neuronal network reorganization, nitric oxide production

Epilepsy is a frequent neurological disorder affecting about 0.5 to
0.7% of the population worldwide. The typical feature of epilepsy is
recurrent seizures, which on a cellular level consist of synchronized
discharges of large groups of neurons that interrupt normal brain
function. Potential causes of epilepsy include gene mutations,
inammation as well as malformations, tumors and trauma of the
brain leading to alterations of neurotransmitter receptors and ion
Corresponding author at: Division of Neurochemistry, Department of Epileptology,
University Bonn Medical Center, Sigmund-Freud-Str. 25, D53105 Bonn, Germany.
Fax: + 49 228 6885 290.
E-mail address: wolfram.kunz@ukb.uni-bonn.de (W.S. Kunz).
and opening of the bloodbrain barrier. Additionally, it is well known
that epileptic seizures can occur as a presenting sign of mitochondrial
dysfunction in the central nervous system. This is due to the fact that
mitochondria generate the ATP that is essential for the excitability
and survival of neurons. Neuronal mitochondria are highly dynamic
organelles that divide, fuse, and move along axons and dendrites
(Hollenbeck and Saxton, 2005). Their functions in neurons include the
regulation of Ca2+, redox signaling, developmental and synaptic
plasticity, and the determination of cell survival and death (Mattson
et al., 2008). The importance of mitochondria for neurons is evident
from the phenotypes of epilepsies caused by mutations in genes
affecting oxidative phosphorylation. Generalized seizures have been
observed in several forms of epilepsy, being associated with mutations
in the mitochondrial DNA polymerase (POLG1) (Naviaux and

1567-7249/$ see front matter 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
doi:10.1016/j.mito.2011.04.004
36 J. Folbergrov, W.S. Kunz / Mitochondrion 12 (2012) 3540
Nguyen, 2004; Zsurka et al., 2008), mitochondrial tRNALys (MT-TK)
(Shoffner et al., 1990, Zeviani et al., 1993) and tRNAPhe (MT-TF) (Zsurka
et al., 2010) genes. More recently, evidence for a more general
involvement of mitochondria also in sporadic forms of epilepsy has
been accumulated (Kann et al., 2005; Kunz, 2002; Kunz et al., 2000).
This might be related to the fact that mitochondria are intimately
involved in pathways leading to neuronal cell death (Blmcke et al.,
1999; Ott et al., 2007) seen in experimental and human epilepsy.
Accumulating evidence indicates that free radicals, oxidative stress
and mitochondrial dysfunction are important factors in the general
pathogenesis of epilepsy (Jarrett et al., 2008a; Kann and Kovcs, 2007;
Kudin et al., 2009; Lin and Beal, 2006; Meldrum, 2002; Patel, 2004;
Waldbaum and Patel, 2010). Therefore, it is reasonable to assume a
considerable pathogenic role of mitochondrial dysfunction in the
process of epileptogenesis and seizure generation.
2. Mitochondrial involvement in human temporal lobe epilepsy
One of the most frequent and devastating forms of epilepsy
involves the development of an epileptic focus in temporal lobe
structures. These brain structures, which include the hippocampus,
have a low seizure threshold and develop usually in the time
course of the disease a severe loss of neurons in the CA1, CA3 and
CA4 hippocampal subelds. While the granular cell layer is
relatively preserved this progressive loss of pyramidal cells of the
CA1, CA3 and CA4 layers are the neuropathological hallmarks of
hippocampal sclerosis (HS) (Margerison and Corsellis, 1966). This
progressive cell loss is suggested to be a major reason that seizures
of temporal lobe origin become at later stages of the disease
particularly resistant to antiepileptic drug therapy. Moreover, this
neuronal cell loss, which resembles features of cell death in other
neurodegenerative diseases, is perhaps the reason for the progres-
sive dramatic memory impairment in temporal lobe epilepsy
(TLE). Consequently, patients with TLE suffer recurrent seizures
and progressive impairment of memory with devastating behav-
ioral and social consequences.
It is well documented that during seizures both neurons and glial
cells undergo necrotic (Fujikawa et al., 2010) and apoptotic cell death
(Bengzon et al., 1977; Lopez-Meraz et al., 2010). Neuropathological
investigations have repeatedly pointed to a similarity between ischemic
and seizure related alterations of neurons characterized by swollen and
often disrupted mitochondria (Meldrum, 1993). In patients with
temporal lobe epilepsy and HS, mitochondrial ultrastructural pathology
was described as the characteristic feature of hilar neurons (Blmcke
et al., 1999), comprising mainly of inhibitory interneurons. In addition to
the neuropathological abnormalities also functional defects of mito-
chondria have been reported in the areas of epileptogenesis. Thus, a
severe impairment of respiratory chain complex I activity was observed
for the CA3 hippocampal subeld from patients with HS and in the
parahippocampal gyrus of patients with parahippocampal lesions (Kunz
et al., 2000). In these reports mitochondrial abnormalities have been
observed only close to or directly in the epileptic focus, while the
investigated surrounding brain tissue (e.g. the parahippocampal gyrus
of patients with pronounced hippocampal pathology and a hippocampal
seizure focus) showed no mitochondrial pathology (Kunz et al., 2000).
This detected mitochondrial dysfunction in the hippocampal CA3 area of
patients with HS has been conrmed by the following independent
observations. (i) In studies applying interictal [18F]uorodeoxyglucose
positron emission tomography the degree of hippocampal glucose
hypometabolism in HS patients determined in vivo strongly correlated
with the respiratory activity of the CA3 subeld determined in vitro
(Vielhaber et al., 2003a). (ii) Applying high resolution NMR spectros-
copy the hippocampal loss of N-acetyl aspartate (NAA) was found to be
restricted to the CA3 subeld, but was not detectable in other subelds,
like CA1 experiencing an even more intense cell loss (Vielhaber et al.,
2008). Furthermore, in agreement with the region-specic mitochon-
drial impairment a considerable increase of lactate and succinate was
observed in the CA3 subeld (Vielhaber et al., 2008). (iii) An about
two-fold decrease in the copy number of mitochondrial DNA and
of aconitase activity was observed in the hippocampal CA3 subeld
of patients with HS, providing a potential molecular cause for the
observed decrease in activity of mitochondrial respiratory chain
(Baron et al., 2007). Pronounced drops of NAD(P)H uorescence
transients compatible with an impairment of mitochondrial function
were observed in human tissue from patients with TLE (Kann et al.,
2005). These ndings were interpreted in support of the hypothesis
that the hypometabolism in the epileptic focus is more a reection of
dysfunction in cellular energy metabolism than due to neuronal cell
loss (O'Brien et al., 1997).
Taken together these ndings strengthen the viewpoint of a
putative underlying metabolic dysfunction as important pathophys-
iological mechanism in human temporal lobe epilepsy with HS.
3. Mitochondrial involvement in adult models of epilepsy
A suitable animal model to study TLE with HS is the pilocarpine-
treated chronic epileptic rat. In this model, the animals are treated
systemically with a dose of the muscarinic agonist pilocarpine that
induces an acute limbic status. The status epilepticus is usually
terminated with diazepam. This acute intoxication is followed by a
latent (i.e. seizure free) period lasting usually 12 weeks, followed by
a chronic epileptic condition with spontaneous seizures, resembling
human TLE (Turski et al., 1983). From the point of view of
hippocampal pathology, pilocarpine-treated rats display changes
closely resembling the HS condition that is seen in the majority of
TLE patients. As mentioned above, it consists of segmental loss of
pyramidal neurons in the CA1, CA3, and CA4 sectors of the Ammon's
horn, and additionally gliosis and recurrent mossy ber sprouting. In
the recent literature there are accumulating hints for the contribution
of oxygen radicals in the process of epileptogenesis and in chronic
experimental epilepsy showing progressive neuronal cell death. There
is evidence for the increased generation of oxygen radicals in status
epilepticus induced by kainate or pilocarpine (Frantseva et al., 2000;
Gluck et al., 2000; Liang et al., 2000; Peterson et al., 2002) and in the
low-magnesium model of epileptoform activity (Kann et al., 2003;
Kovacs et al., 2002). These oxygen radicals are primary generated by
the mitochondrial respiratory chain (Kudin et al., 2004, 2005, 2008;
Malinska et al., 2010). During inhibition of the respiratory chain
considerable amounts of superoxide are produced, which can over-
load the endogenous protective mechanisms (glutathione peroxidase,
superoxide dismutase, catalase) resulting in an oxidative damage of
proteins, phospholipids and of mitochondrial DNA. Since an increased
production of reactive oxygen species is a feature of partially
respiratory chain-inhibited mitochondria, it is noteworthy to mention
in this context that a severe impairment of respiratory chain
complexes has been also observed in the vulnerable CA1 and CA3
hippocampal subelds of pilocarpine-treated chronic epileptic rats
(Kudin et al., 2002). Additionally, there is recent evidence for the
direct involvement of mitochondrial oxidative stress in oxidative DNA
damage occurring during the different phases of epileptogenesis of
kainate and pilocarpine-treated rats (Jarrett et al., 2008a, Waldbaum
et al., 2010).
4. Mitochondrial dysfunction in immature brain during seizures
Epilepsy is particularly frequent in infants and children. However,
the problem of seizure-induced neuronal injury in the immature brain is
controversially discussed in the literature. Some authors have claimed
that the immature brain is relatively resistant to seizure-induced
neuronal injury, but other studies provided evidence that seizures in the
immature brain also can induce neuronal damage and death (Kubov
et al., 2001; Folbergrov et al., 2005; Langmeier et al., 2003; Sankar et al.,
 J. Folbergrov, W.S. Kunz / Mitochondrion 12 (2012) 3540
1998; Schmidt et al., 1999; Wasterlain et al., 2002). In addition, status
epilepticus in early development can have long-term functional
consequences that manifest in adulthood, like adverse effects on brain
maturation, memory and various neurocognitive decits (Jensen, 1999;
Lynch et al., 2000).
4.1. Oxidative stress during seizures
Like with the seizure-induced injury in immature animals, there is
controversy about potential oxidative stress induced by seizures in
the immature brain. This is based on negative ndings concerning ROS
formation and various markers of oxidative stress in immature rats
(1017 days old) during seizures induced by kainate (Bruce and
Baudry, 1995; Patel and Li, 2003; Sullivan et al., 2003). It should be
noted, however, that the kainate model of seizure induction
apparently does not lead to any measurable neuronal damage in
rats prior to postnatal day 21. However, when seizures were induced
in immature 12-day-old rats by homocysteic acid (an endogenous
excitatory amino acid with a potent activity on NMDA receptors),
massive neuronal degeneration has been demonstrated in many brain
regions (Folbergrov et al., 2005). This damage was signicantly
attenuated by treatment with free radical spin trap N-tert-butyl--
phenyl nitrone (PBN) (Folbergrov et al., 2006). The presence of
oxidative stress in this particular model was demonstrated by several
lines of evidence: (i) increased lipid peroxidation, (ii) decreased activity
of aconitase, (iii) increased H2O2 production in isolated mitochondria
and (iv) increased formation of O2. (detected in situ by hydroethidine)
in several brain regions (Folbergrov et al., 2007, 2010; Othal et al.,
2010). Furthermore, a signicant increase of three markers of oxidative
damage, namely 3-nitrotyrosine, 4-hydroxynonenal and protein car-
bonyls, was observed not only during the acute phase of seizures, but
this increase lasted up to 5 weeks following induction of seizures
(Folbergrov et al., 2010).
4.2. Mitochondrial dysfunction
As outlined above (Section 1) the role of mitochondrial function/
dysfunction in relation to temporal lobe epilepsy has been demon-
strated in humans (Kunz et al., 2000; Lee et al., 2008) and in several
experimental models of chronic epilepsy in adult animals (Chuang
et al., 2004; Cock et al., 2002; Kudin et al., 2002; Sleven et al., 2006).
Similar signs of mitochondrial dysfunction were also demonstrated in
immature epileptic animals treated with homocysteic acid. Here the
marked decrease (~ 60%) of complex I activity was shown in cerebral
cortex mitochondria during acute phase of seizures and this decrease
persisted during long periods of survival, up to 5 weeks following the
acute seizures, i.e. the period in which the development of
spontaneous seizures (epileptogenesis) was observed in this model
(Folbergrov et al., 2007, 2009, 2010). By performing electrophoretic
(BN-PAGE and SDS-PAGE) and Western blot (WB) analysis, using
antibodies against several selected subunits of complex I, it was
shown that the decrease was not associated with changes in the size
of the assembled complex I or with changes in mitochondrial content
of complex I. The inhibition of complex I was accompanied by parallel
signicant increases of three markers of oxidative damage, 3-
nitrotyrosine, 4-hydroxynonenal and protein carbonyls. The involve-
ment of oxidative stress is also supported by ndings demonstrating
that the decrease of complex I activity was substantially attenuated by
treatment of animals with FeTPPS (a selective peroxynitrite scavenger
and decomposition catalyst) and the two superoxide dismutase (SOD)
mimetics Tempol and MnTMPYP (Folbergrov et al., 2007, 2010 and
references therein). Thus, all these ndings strongly suggest that
oxidative modication of complex I is very likely responsible for the
sustained decrease of complex I activity in homocysteic acid-treated
immature rats, which is in accordance with its extreme sensitivity to
ROS and RNS.
37
4.3. Potential consequences of the decreased complex I activity
It might be expected that the pronounced inhibition of complex I
activity in the homocysteic acid model will have signicant
implications for mitochondrial function. However, the experimental
data suggest that the major function of mitochondria to produce
energy does not seem to be impaired. ATP levels remained unchanged
not only during the acute phase of seizures (i.e. periods when
production of energy in immature brain is mostly dependent on
glycolysis), but also during long periods of survival (when oxidative
phosphorylation is the main source of ATP). This can be explained by
excess capacity of complex I.
There are, however, other potential consequences of inhibited
complex I. Complex I is not only a target for ROS and RNS, but it is also
the important source of ROS and/or RNS production, especially when
the enzyme complex is partially inhibited (Kudin et al., 2004; Fato et
al., 2008). It can thus be assumed that inhibition of complex I can lead
to the enhanced production of ROS and/or RNS which may contribute
not only to neuronal injury demonstrated in this model of seizures
(Folbergrov et al., 2005, 2006, 2008), but also to epileptogenesis
(Folbergrov et al., 2009). However, it remains to be claried yet to
which extent oxidative stress and mitochondrial dysfunction dem-
onstrated in the homocysteic acid model play a role in other models of
seizures in immature animals.
5. Potential mechanisms underlying hyperexcitability due to
mitochondrial dysfunction
Alterations of mitochondrial substrate oxidation and ATP synthe-
sis due to disease-associated mutations seen in mitochondrial
encephalomyopathies can cause epilepsy. Similarly, direct partial
inhibition of enzymes of mitochondrial respiratory chain of cyto-
chrome c oxidase by cyanide (Yamamoto and Tang, 1996), and of
succinate dehydrogenase by 3-nitropropionic acid (Urbanska et al.,
1998) evokes seizures.
Potential direct links between the observed impairment of mito-
chondrial function and the increased neuronal excitability causing
epileptiform activity are (i) decreased ATP levels, (ii) alterations of
neuronal calcium homeostasis and (iii) ROS-induced modications of
ion channels and neurotransmitter transporters.
(i) The importance of sufcient presynaptic ATP levels generated
by oxidative phosphorylation for normal synaptic transmission
has been directly shown at Drosophila neuromuscular junctions
(Verstreken et al., 2005). Here, mitochondria do not serve as a
calcium sink, but the ATP levels generated by oxidative
phosphorylation are critical for mobilization of the synaptic
vesicle reserve pool. The potential impact of neuronal ATP
levels for generation of seizures is also evident from Leigh
syndrome patients harboring the mutations T8993G and
T8993C in the ATPase 6 gene (Canafoglia et al., 2001). Under
these conditions mitochondria still have a high membrane
potential enabling normal mitochondrial ion transport. There-
fore, cybrids with the T8993G NARP mutation show normal
mitochondrial calcium handling properties at decreased cellu-
lar ATP levels (Brini et al., 1999). Decreased ATP levels could
increase neuronal excitability via decreased neuronal plasma
membrane potential, since mitochondrial oxidative phosphor-
ylation provides the major source of ATP for sodiumpotassium
ATPase, which consumes about 4050% of the energy in
neurons (Astrup et al., 1981, Ames 2000). However, the
available experimental evidence from brain slices of patients
with epilepsy and animal models of TLE apparently does not
support this hypothesis (Kann et al., 2005). Alternatively,
decreased synaptic transmission in inhibitory synapses formed
by mitochondria-rich interneurons could be an attractive
38 J. Folbergrov, W.S. Kunz / Mitochondrion 12 (2012) 3540
Scheme 1. Hypothetical mechanisms of seizure generation by mitochondrial dysfunction.
alternative hypothesis to explain increased network excitabil-
ity in epilepsy related to dysfunction of mitochondrial
oxidative phosphorylation. This hypothesis is shown in
Scheme 1, right part (cf. also Kudin et al., 2009). Especially
parvalbumin-positive, fast-spiking interneurons are known to
contain exceptionally high amounts of mitochondria (Gulys et
al., 2006), which in turn make these cells extremely vulnerable
to the consequences of mitochondrial dysfunction. However,
the hypothesis, which explains increased network excitability
by mitochondrial dysfunction in a similar way as demonstrated
for SCN1A haploinsufciency in Dravet syndrome (Meisler and
Kearney, 2005), remains to be proven yet.
(ii) It is well established that mitochondria are important for
intracellular Ca2+ sequestration in neurons (Tang and Zucker,
1997; Duchen, 2000). Due to this feature, mitochondria also
can modulate neuronal excitability and synaptic transmission
(Bindokas et al., 1998), which is altered in epilepsy. In
agreement with this concept, impaired cellular Ca2+ homeo-
stasis due to substantial alterations of mitochondrial Ca2+
handling is the predominant feature of cybrid cells harboring
the mitochondrial T8356C mutation being associated with the
MERRF syndrome (Brini et al., 1999). Therefore, the altered
calcium homeostasis can be the reason for increased neuronal
excitability in this particular form of myoclonus epilepsy.
(iii) An important factor, which could also potentially contribute to
the increased excitability seen in epilepsy, is the fact that
astroglial and neuronal glutamate transporters, which are
important for the maintaining low levels of synaptic glutamate,
are extremely sensitive to oxidative damage (Trotti et al.,
1998). In this context, it should be noted that inhibition of
complex I activity was reported to induce excess release of
glutamate (Kilbride et al., 2008). Therefore, oxidative stress
might have also direct effects on neuronal excitability, which
are depicted in Scheme 1, left part.
6. Mitochondrial bioenergetics and oxidative stress-related
pathways as potential target of neuroprotective strategies in epilepsy
Apart from the above discussed potential direct link to seizure
generation, mitochondrial dysfunction is known to trigger neuronal
cell death a prominent feature of therapy-resistant forms of
epilepsy. Therefore, mitochondria have to be considered a promising
target for potential new neuroprotective strategies in epilepsy
(Camara et al., 2010; Moreira et al., 2010). For a certain number of
neurodegenerative diseases with established mitochondrial patholo-
gy, like amyotrophic lateral sclerosis and Chorea Huntington
mitochondria-directed neuroprotective strategies have been sug-
gested. The creatine/phosphocreatine system, regulated by mito-
chondrial creatine kinase, plays an important role in maintaining
energy balance in the brain. The proposed treatment is buffering of
neuronal energy levels by systemic creatine administration. The
supplemented creatine passes the bloodbrain barrier and increases
 J. Folbergrov, W.S. Kunz / Mitochondrion 12 (2012) 3540
the total pool of phosphocreatine/creatine available for buffering of
the neuronal ATP levels by creatine kinase. Creatine supplementation
has been shown to protect motor neurons in a transgenic animal
model of amyotrophic lateral sclerosis (Klivenyi et al., 1999) and
striatal neurons in an animal model of Huntington's disease (Ferrante
et al., 2000). The buffering of brain energy levels with creatine
appeared to be effective not only in the mentioned neurodegenerative
disorders but also in hypoxia-induced or traumatic brain injury
(Sullivan et al., 2000). Moreover, 3 g/kg creatine was observed to
reduce hypoxia-induced seizures in rat and rabbit pups (Holtzman
et al., 1999). In contrast to these reports, in the animal model of
temporal lobe epilepsy the pilocarpine-treated rat creatine was
found to have even a negative effect (Vielhaber et al., 2003b).
Therefore, the neuroprotective potential of creatine treatment for
human epilepsy remains still to be critically proven.
Recent ndings suggest that protection of mitochondria and
reduction of oxidative stress-related events represent a promising
therapeutic approach for the treatment of various disorders (Folbergrov
et al., 2006; Liang et al., 2000,2008; MacGregor et al., 1996; Rong et al.,
1999). There are metabolic antioxidants, like e.g. lipoic acid, N-acetyl
cysteine, CoQ10 (Moreira et al., 2010) which remain to be tested for a
potential neuroprotective effect in epilepsy. Interestingly, it has been
reported that ketogenic diets, which are known to have benecial effects
in severe epilepsy of childhood, appear to specically increase
mitochondrial glutathione levels (Jarrett et al., 2008b). The limitation
of standard antioxidant therapy has been the inability to enhance the
antioxidant level within mitochondria. Therefore, recent progress in
developing mitochondria-targeted antioxidants (i.e. antioxidants that
are selectively accumulated in mitochondria, Dickinson et al., 2010;
Plotnikov et al., 2011) is a promising approach for new therapeutic
strategies not only in ischemia/reperfusion, but hopefully also in human
epilepsy.
Summarizing, current results thus suggest that oxidative stress
may play a critical role in mitochondria dysfunction and brain damage
associated with epileptic seizures in humans and in adult as well as
immature animals. It remains to be claried by future studies whether
treatment with compounds possessing antioxidant properties and
targeted to mitochondria can inuence the extent of oxidative stress
and mitochondrial dysfunction, attenuate seizure-induced brain
damage and have a benecial effect on long term consequences of
epilepsy.
Acknowledgments
WSK was supported by grants of the Deutsche Forschungsge-
meinschaft (TR3-A11 and TR3-D12), the BMBF (mitoNET 01GM0868)
and of Stiftung fr Medizinische Wissenschaft (Frankfurt am Main), JF was
supported by grants No 309/05/2015 and 309/08/0292 from the Grant
Agency of the Czech Republic.
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