Download Hippocampus, hippocampal sclerosis and epilepsy

Pharmacological Reports
Copyright © 2013
2013, 65, 555–565
by Institute of Pharmacology
ISSN 1734-1140
Polish Academy of Sciences
Review
Hippocampus, hippocampal sclerosis
and epilepsy
Krzysztof Sendrowski, Wojciech Sobaniec
Department of Pediatric Neurology and Rehabilitation of the Medical University of Bia³ystok, J. Waszyngtona 17,
PL 15-274 Bia³ystok, Poland
Correspondence: Krzysztof
Sendrowski, e-mail: [email protected]
Abstract:
Hippocampal sclerosis (HS) is considered one of the major pathogenic factors of drug-resistant temporal lobe epilepsy. HS is characterized by selective loss of pyramidal neurons – especially of sectors CA1 and CA3 of the hippocampus – pathological proliferation
of interneuron networks, and severe glia reaction. These changes occur in the course of long-term and complex epileptogenesis. The
authors, on the basis of a review of the literature and own experience, present the pathomechanisms leading to hippocampal sclerosis
and epileptogenesis, including various morphological and functional elements of this structure of the brain and pharmacological
possibilities of preventing these processes.
Key words:
hippocampus, hippocampal sclerosis, epilepsy, epileptogenesis
Pathophysiology of epilepsy
Epilepsy is one of the most common neurological diseases and affects about 1% of the population [7]. An
epileptic seizure is the result of functional disorders of
the brain and is formed as a result of abnormal, excessive bioelectrical discharge in the nerve cells [21].
This disorder can theoretically occur in every population of neurons, but it is often observed in the immediate vicinity of organic brain damage, such as a scar
or a tumor. A group of changed, overly excitable
nerve cells is called an epileptic focus. The cause of
an epileptic seizure is a sudden imbalance between
excitatory and inhibitory processes in the neural network [34]. Physiologically, at the cellular and synaptic level, the transmembrane currents and neurotransmitters provide such a balance. Homeostasis is main-
tained by the balancing effects of excitatory and
inhibitory neurotransmitters and currents: sodium and
calcium with chloride and potassium. Ionic conductivity systems and neurotransmitters are closely related because the reaction of neurotransmitters to specific receptors on the cell membrane of neurons
causes movement of ions in both directions: from the
interior of the neuron to the extracellular space and
vice versa. An essential element generating and conditioning nervous system activity is the action potential. It is created as a result of fast intracellular sodium
current. This leads to a sudden depolarization of the
cell membrane of the neuron and its propagation
along the axon, and neurotransmitter release from the
presynaptic ending into the synaptic cleft. There, the
neurotransmitter connects with receptors of the postsynaptic membrane.
Pharmacological Reports, 2013, 65, 555–565
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Depending on the type of neurotransmitter released
(excitatory or inhibitory), an action potential is triggered in subsequent neurons (the spread of stimulus)
or conduction is blocked when the inhibitory neurotransmitter is released. The effect of the inhibitory
neurotransmitter action on ionotropic receptors is hyperpolarization of the neuronal membrane and the release of inhibitory postsynaptic potential (IPSP), and
excitatory neurotransmitter - its depolarization and release of excitatory postsynaptic potential (EPSP). The
ability to generate action potential by a nerve cell is
determined by whether it is “reached” by more EPSP
or IPSP from neurons. A well-developed network of
connections between inhibitory and excitatory neurons ensures physiological homeostasis in the brain.
In pathologic conditions, both intrinsic factors (channelopathies) and extrinsic factors (extracellular environment changes, activity of astrocytes, remodeling
of synaptic endings) may contribute to excessive excitability of nerve cells and ultimately lead to epileptic seizure. Long-term imbalance of excitation/inhibition, initiated by various pathological factors, starts
the process of epileptogenesis leading to the formation of an active epileptic focus. The condition for the
occurrence of an epileptic seizure is excessive bioelectric activity of a group of neurons as well as hypersynchronization of this activity in the cerebral cortex
[4]. The gap junctions – formed by directly adjacent
cell membranes of neighboring neurons and astrocytes – are an extremely important ultrastructural basis of hypersynchronization of discharges. The transmission of interneuronal information through gap
junctions is much faster than transmission through
synapses [98]. Another important factor in conditioning hypersynchronization of excitatory discharges is
the reorganization of the cortical microarchitecture
occurring over time.
Epileptogenesis
The process of epileptogenesis is usually explained in
the literature by the two-hit hypothesis. The term epileptogenesis commonly refers to a period of time
from the first hit, such as trauma or stroke, to the occurrence of the first epileptic seizure. It is a chronic
process, in which a series of biochemical and structural changes take place in the nerve tissue. Experimental and clinical studies have shown that nerve tis556
Pharmacological Reports, 2013, 65, 555–565
sue in experimental animals and in patients with epilepsy, although it does not always show structural
changes, differs at the molecular level of normal tissue [63]. During this period, the following processes
take place: a process of pathological “learning” of the
neurons, pathological reorganization of neural activity, but also the reorganization of the nerve tissue microstructure. According to the latest research, three
basic phases can be distinguished in the process of
epileptogenesis: acute brain damage (initial insult),
latent period with “maturation” of the epileptic focus,
and actual epilepsy, where a process called secondary
epileptogenesis takes place [77]. The most important
etiological factors include severe craniocerebral
trauma, where the risk of post-traumatic epilepsy depending on the severity of the injury ranges from 2%
to as much as 25% [63]. High risk factors also include: stroke, epileptic state, recurrent and prolonged
febrile convulsions, cerebral thrombosis and neuroinfections. Therefore, the neurobiologic basis of epileptogenesis was analyzed in experimental models of
such damages [43].
Epileptic focus formation is often explained by the
kindling model [68], defined as a progressive increase
in neuronal response to rarely used and weak stimulation of a small area in the brain. A stimulus of a subliminal intensity after a certain time causes epileptic
discharges at the place of stimulation. If the stimulus
is repeated, a process of progressive change begins:
first the stimulation causes local, short epileptic discharge, after consecutive stimulation the discharges
last longer, spread to larger areas of the brain, and
eventually clinical epileptic seizures are observed.
This process is dynamic. The interval between successive attacks becomes shorter in untreated patients.
Moreover, the primary focus can produce a secondary
or mirror focus [53]. The consequence of the socalled initial insult initiating epileptogenesis is immediate and gradually progressive processes of varying
course over time. Immediate response involves neuronal activation with intracellular calcium ion accumulation and further stages of excitotoxicity, starting
the system of secondary messengers, activation of
gene expression and protein synthesis.
In the following days, at the site of injury, inflammatory processes take place and mediators of inflammation, glial and endothelial cell responses are activated. At a later stage of epileptogenesis, growth
processes occur: the sprouting of new axons, synaptogenesis and angiogenesis. The consequence of these
Hippocampus and epilepsy
Krzysztof Sendrowski and Wojciech Sobaniec
processes is the reorganization of nerve tissue microarchitecture [3]. This is usually a clinically silent
period. Sometimes these changes are sufficient for the
clinical manifestation of epilepsy, sometimes a second
hit is necessary. It may not only be an external factor,
such as craniocerebral trauma, but also a “sufficient”
level of damage to nerve tissue as a result of the processes of apoptosis and neuronal necrosis and gene
expression occurring since the initial insult [67, 77].
The hippocampus and epilepsy
Anatomy of hippocampus
The hippocampus is an essential part of the archeocortex. In mammals, it is three-layered structure located on the medial surface of the temporal lobe in the
back of each cerebral hemisphere. The name hippocampus is derived from Greek and means sea horse,
which it resembles in shape. In the literature, it is often referred to as Ammon’s horn (cornu Ammonis),
which is derived from the distinctive image of an
Egyptian god. The hippocampus is an important part
of the limbic system, which plays vital role in the behavioral, emotional and memory processes.
The structure of the archeocortex is much simpler
than of the neocortex. Histologically, we can divide
the hippocampal cortex into four sectors: CA1 – CA4,
which vary in size and the amount of nerve cells. The
CA1 field contains small pyramidal cells, the small
CA2 field is made up of small pyramidal cells, the
CA3 field forms a broad, loose band of pyramidal
neurons. The CA4 field, also referred to as a hilar region, is formed by loosely structured pyramidal cells,
which are surrounded by a U-shaped dark seam of
gray matter (dentate gyrus). Individual fields of the
hippocampus show differences in the structure and arrangement of nerve connections. Most of the afferent
fiber reach the hippocampus through the tractus perforans. They form synapses with the dendrites of pyramidal cells. Some afferent fibers switch in the
granular cell layer, whose axons are called mossy fibers, and form synapses with pyramidal cells. In the
hippocampus, mossy fibers are only present in the
CA3 and CA4 fields. Axons of pyramidal cells form
afferent pathways. The main afferent pathways of the
hippocampus lead to the corpora mamilaria to the
front nuclei of the thalamus and to the hypothalamus.
The main hippocampus afferent pathways originate in
the enthorinal cortex (EC), the other run from the
amygdala and various parts of the neocortex. The EC
has connections to other areas of the cerebral cortex.
The main output pathway of EC axons project densely
to the granule cells in the dentate gyrus; apical dendrites of CA3 get a less dense projection, and the apical dendrites of CA1 get a sparse projection. Thus, the
perforant pathway establishes the EC as the main “interface” between the hippocampus and other parts of
the cerebral cortex. The dentate granule cell axons
(mossy fibers) pass on the information from the EC on
thorny spines that exit from the proximal apical dendrite of the CA3 pyramidal cells. Then, the CA3 axons loop up into the region where the apical dendrites
are located, extend all the way back into the deep layers of the EC - the Shaffer collaterals completing the
reciprocal circuit. Field CA1 also sends axons back to
the EC, but these are more sparse than the CA3 projection. Within the hippocampus, the flow of information from the EC is largely unidirectional, with signals
propagating through a series of tightly packed cell
layers, first to the dentate gyrus, then to the CA3
layer, to the CA1 layer, and next out of the hippocampus to the EC, mainly due to collateralization of the
CA3 axons [1].
The hippocampus is an important structure in the
pathophysiology of convulsions and epilepsy. Because of its relatively simple histological construction, it is often used in experimental and clinical studies of this disease. The hippocampal cortex contains
two major groups of neurons: principal neurons and
interneurons. Most principal neurons form excitatory
synapses on the cell bodies of other neurons in the remote areas of the brain, whereas interneurons usually
form inhibitory synapses on principal neurons and
other interneurons. Therefore, they modulate the excitatory effect of the principal neurons and prevent excessive excitation of the neuronal network, thereby
preventing the generation of convulsions. With respect to the above anatomy of the hippocampus, the
pyramidal neurons are the principal cells. In field
CA3, their function is modulated by projections of the
granule cells of the dentate gyrus, mossy fibers, synapses of the perforant pathway from the EC, and collaterals from CA3 interneurons. The function of the
CA1 sector pyramidal neurons is modulated by the
perforant pathway synapses from the EC and Schaffer
collaterals of CA3 (Fig. 1).
Pharmacological Reports, 2013, 65, 555–565
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Fig. 1. “Circulation” of nerve impulses between the separates hippocampal structures. Details in the text
Temporal lobe epilepsy and hippocampal
sclerosis (HS)
Temporal lobe epilepsy (TLE) is the most common
form of epilepsy in adults [104]. TLE patients have
focal seizures, some of which with secondary generalization. In most of these patients, the epileptic focus
is located in the medial temporal lobe structures, such
as the hippocampus, amygdala and parahippocampal
gyrus. Pharmacological treatment of epilepsy often
does not provide satisfactory control of seizures. Drug
resistance applies to 25–30% of TLE patients. In such
cases, the treatment of choice is neurosurgery (anterior temporal lobectomy) [33].
HS is an anatomic basis of medial temporal lobe
epilepsy (MTLE), common in experimental models of
convulsions and epilepsy as well as in patients with
drug-resistant epilepsy [11]. In changed hippocampal
nerve tissue, significant histological changes (reorganization of the hippocampus microarchitecture) and
functional changes occur.
In histological examinations, HS is characterized
by degeneration and selective loss of pyramidal neurons, pathological proliferation of interneuron networks, and severe glia reaction [82, 94]. In classical
HS, pyramidal cell loss is observed in CA1 and CA3
and around the end-folium, while the cells of sector
CA2 are spared. In other less common subtypes of
HS, loss of pyramidal neurons occurs in all fields of
the hippocampus (total hippocampal sclerosis), or
only around the end-folium (end-folium hippocampal
sclerosis) [93].
In an experimental model of TLE, Sloviter demonstrated irreversible damage of dentate hilar mossy
cells that provide excitatory inputs onto inhibitory interneurons. In contrast, most dentate gyrus inhibitory
GABA-basket cells were preserved [87]. On this basis, the author proposed the “dormant basket cell hypothesis”, which explained TLE with impaired inhibi558
Pharmacological Reports, 2013, 65, 555–565
tion by “latent (dormant)” GABA interneurons of
bioelectrical activity of the principal neurons. The
“latency” of these interneurons is due to the lack of
their physiological stimulation by damaged hilar
mossy cells [88]. In addition to neuronal degeneration
and gliosis, the so called mossy fiber sprouting and
the dentate gyrus granule cell dispersion are also characteristic of HS [14]. They constitute a histological
basis of functional reorganization of the hippocampus
manifested by excessive excitation in the abovementioned excitatory reciprocal circuit of nerve impulses EC – dentate gyrus – CA3 – CA1 – EC. Mossy
fibers are axons of dentate gyrus granule cells, which
physiologically connect with the neurons of the endfolium and hippocampal CA3 sector. If in the process
of HS sector CA3 neurons and end-folium neurons
are lost, their feedback projection to granule cells will
also be lost. The consequence of such deinnervation
will be the projection of these axons to neighboring
mossy fibers (sprouting). Sprouting will cause reciprocal synaptic stimulation, which may explain the excessive excitability of dentate gyrus neurons observed
in temporal lobe epilepsy [91]. Experimental studies
have shown that the imbalance of excitation/inhibition between the dentate gyrus and the hippocampus
due to the production of even a small number of excitatory collaterals is responsible for persistent neuronal
hyperexcitability [21]. The effect of these changes is
excessive neuronal excitation stimulating the processes of neuronal epileptogenesis and excitotoxicity.
Another histological change in HS is the dispersion
of dentate gyrus granule cells. Under physiological
conditions, the granular layer cross section has 4–5
cells, whereas in more than 40% of HS the width of
the granular layer increases and dispersion of cells
may be over 10. Since many of the cells are spindleshaped, resembling migrating embryonic neurons, in
the pathogenesis of these changes we take into account the active process of neurogenesis in the subgranular layer. The possibility of neurogenesis in the
adult hippocampus has been confirmed in animal
models [13, 38] and in humans [35], including in patients with epilepsy [28, 71]. A clinical diagnosis of
hippocampal sclerosis (HS) associated with drugresistant temporal lobe epilepsy is based on radiological examination. High-resolution magnetic resonance
imaging has the greatest practical importance [18], in
particular MR volumetry [19]. Preoperative diagnostics utilize comprehensive exams involving neuroimaging and electrophysiological techniques [48, 70].
Hippocampus and epilepsy
Krzysztof Sendrowski and Wojciech Sobaniec
Molecular studies in recent years have added additional information on the pathogenesis of TLE and
HS. Processes such as synaptic plasticity and glial reaction play an extremely important role. The most important pathogenic factor in synaptic plasticity is the
reorganization of the structure and function of neuronal membrane receptors. This applies to both ionotropic and metabotropic receptors [10, 69]. Synaptic
plasticity is considered to be an important pathophysiological factor of posttraumatic epilepsy, among
others [97]. A patient after severe craniocerebral
trauma suffers from a decline in bioelectrical activity
in the first phase, which is associated with damage or
death of a certain population of neurons. Due to the
dynamic process of synaptic plasticity, which may occur in an uncontrolled manner at times, a development of seizure activity takes place in this area [44].
In studies conducted on organotypic cultures of the
hippocampus, long-term blocking of the electrical activity of neurons with calcium blockers, tetrodotoxin
and NMDA receptor inhibitors, resulted in excessive
excitation of neurons. This effect was induced by synaptic plasticity [6]. On the other hand, recurring seizures also induce synaptic plasticity in the brain,
which in time further increases the intensity of seizures. It has been shown for example that ictal epileptiform discharges induced by hyperkalemia of the hippocampus culture environment ignited the synaptic
plasticity process, which resulted in excessive excitability of the nerve cells leading to progressive epileptogenesis [65]. In an experimental HS model induced
by brain injury, changes in the expression of structural
proteins of subunits of GABAA receptor have been
shown [37]. Both in animal models of epilepsy as
well as surgically resected hippocampal tissue from
TLE patients, the authors reported a reduced density
of ionotropic GABAA receptors associated with a loss
of GABAergic inhibitory neurons and a compensatory reorganization of the structure of the receptor’s
subunits in the retained nerve cells [90]. Lasoñ et al.
also demonstrated a change in the expression of membrane receptors of hippocampal nerve cells for excitatory amino acid receptors, among others, in the
chemical kindling model [60] and the pilocarpine and
kainic acid-induced seizure model [61]. Mathern et al.
also confirmed the reorganization of NMDA receptor
expression in TLE patients [74]. Since the 1990s, scientists have focused on the role of metabotropic glutamate receptors (mGluRs) in the process of epileptogenic synaptic plasticity. It turned out that the activa-
tion of the mGluR with its chemical agonist ACPD
(1-amino-1,3-dicarboxycyclopentane) caused long
lasting and synchronous epileptogenic discharges in
the neural network of the hippocampal CA3 sector
[92]. Subsequent studies have shown that activation
of mGluR receptors induces a depolarization-activated, voltage-dependent cationic current, which is
responsible for lowering the threshold of excitability
of hippocampal neurons and persistent ictal discharges generated in these cells [10, 25].
Role of glia in the pathogenesis of HS
and epilepsy
Most studies on the patophysiology of temporal lobe
epilepsy (TLE) focus on the structure and function of
neurons, because of their ability to generate discharges. However, it should be noted that in addition
to damage to and loss of neurons, HS is constantly accompanied by glial reaction. It occurs regardless of
the experimental epilepsy model. Astrogliosis occurs
in over 90% of the surgically resected hippocampus
of patients with TLE [95]. Until recently, glia was
only considered “brain glue” for neurons. It turned
out, however, that glia, and particularly astroglia,
plays important functions in the process of neurotransmission [103]. Astrocyte cell membranes have
the same receptors as neurons, although their expression is different [52, 101]. For example, the density of
potassium channels on the astrocyte cell membrane is
much higher than the density of sodium channels,
which prevents the generation of action potentials by
glia. A very important role is played by Kir4.1 potassium channels belonging to the family of inwardly
rectifying K+ (Kir) channels. They cooperate with
aquaporin-4 (AQP4) channels, which are unique to
astrocytes. The coordinated action of these channels
is crucial for the maintenance of water and ion homeostasis in the brain [8, 76, 102], and their dysfunction was implicated in the pathogenesis of epilepsy
[45]. The astrocytal network, in contrast with neurons, mainly communicates through gap junctions.
These connections allow for rapid uptake of potassium ions and glutamate by astrocytes, which prevents their harmful accumulation in the extracellular
space. Glial cells by means of specific excitatory
amino acid transporters (EAAT) capture excess excitatory neurotransmitters from the synaptic cleft, thus
preventing excitotoxicity processes [96]. Astrocyte
cell membranes for neurotransmitters have numerous
receptors whose activation leads to excessive intracelPharmacological Reports, 2013, 65, 555–565
559
lular Ca2+ accumulation, which can spread to adjacent
astrocytes in the form of a “calcium wave”. This process involves the release of neuroactive substances
called “gliotransmitters” from active astrocytes [81],
which act back on the synapse to regulate the presynaptic function and modulate postsynaptic response
[105]. Increased gliotransmitter release, including
glutamate, in typical gliosis areas may play a significant role (for HS) in pathological hypersynchronia of
neuronal firing [2].
In pathologically changed nervous tissue encountered, for example, in HS, glial cells are actively involved in epileptogenesis. Binder and Steinhäuser
found that astrocytes in the HS focuses have a unique
structure and function [12]. Bordey and Spencer
showed significantly increased activity of excitatory
sodium currents through the cell membrane of hippocampal astrocytes in patients with HS [17]. On the
surface of astrocytes analyzed in the hippocampal tissue of patients with HS, severe expression of genes encoding proteins involved in the release of glutamate
was also demonstrated [62]. Other authors have also
described significant abnormalities in potassium channels and the function of potassium channel complexes
with the aquaporin channel in HS. Kivi et al. demonstrated decreased expression of potassium channels in
pathological hippocampal tissue, compared with normal tissue [54]. Recent studies also indicate that mutations in the KCNJ10 gene encoding the Kir4.1 potassium channel are associated with the varying clinical
morphology of epileptic seizures [42]. In the hippocampus of patients with TLE associated with HS,
a loss of perivascular Kir4.1 channels has been demonstrated [41]. Failure of the sclerotic hippocampus to
buffer excess potassium ions in the extracellular space,
impaired function of the transporters for excitatory
amino acid and glutamine synthetase activity – an enzyme that converts glutamate to glutamine – contribute
to increased neuronal hyperexcitation, neurotoxicity,
and the spread of convulsive activity [31].
HS: cause or effect of epilepsy?
Despite the well-studied histological and ultrastructural basis of HS, its pathophysiology remains unclear. Whether HS is a primary cause of focal epilepsy
or maybe the result of repeated epileptic seizures is
still an unanswered question [47].
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Pharmacological Reports, 2013, 65, 555–565
In generally accepted theory and aforementioned
epileptogenesis two-hit hypothesis, the initial insult of
even a small area of nerve tissue of the brain caused by
various etiological factors leads to a stretched over
time sequence of histological and biochemical changes
in the area of damage, a so-called maturation of the
epileptic focus. Subsequent even small second hits activate the focus and cause epilepsy. In relation to this
theory, the main factors that initiate HS and epileptogenesis are severe head trauma, perinatal trauma, history of early childhood status epilepticus or prolonged
or recurrent febrile seizures [73]. The latter is the
most frequently cited cause of HS [23]. In experimental febrile convulsions, severe pathological lesions
were observed in preparations of rat brain, especially
within the hippocampus [46]. In an experimental
model of febrile seizures conducted at our institution,
we have shown that recurrent hyperthermic seizures
cause loss of more than a half of the pyramidal neurons in CA1 and CA3 sectors of the hippocampus, but
in contrast with HS, without accompanying gliosis
[85]. In the same experiment, in electron microscopic
tests, we also found significant ultrastructural abnormalities in the blood-brain barrier in the hippocampal
cortex [66]. Reports on patients with epilepsy are ambiguous, even though the vast majority of them indicate an increased risk of epilepsy in children with febrile seizures [9, 100], and brain MR examinations
show pathological lesions in the hippocampus of children with a history of prolonged febrile seizures, particularly focal [83, 99]. In a study analyzing a large
group of 572 patients with TLE, Mathern et al. demonstrated that in most cases the occurence of TLE and
HS was preceded by an initial precipitating injury. In
the young, the dispersion of granule cells and sprouting of axons dominated in the pathology of hippocampus, which would rather suggest a developmental basis of HS [72].
An interesting issue in some patients with drug resistant TLE is a so-called “dual pathology”. It is based
on the coexistence of HS (usually mild) and abnormal
epileptogenic changes situated beyond the hippocampus [64]. This problem affects 5–30% of patients with
drug resistant TLE [24]. A known example of clinical
“dual pathology” is the coexistence of severe HS and
cortical heterotopia, which in this case could also indicate the “congenital” evolving nature of HS.
Over 100 years ago, Gowers postulated that “seizures beget seizures” [39]. According to this theory, is
HS and corresponding TLE not the result of repeated
Hippocampus and epilepsy
Krzysztof Sendrowski and Wojciech Sobaniec
subclinical discharges or prolonged epilepsy or status
epilepticus?
In experimental studies, histopathological changes
similar to HS were observed in the kindling model
[20, 22] and experimental kainic or pilocarpine acidinduced status epilepticus [27]. Interestingly, injection
of kainic acid into immature rats did not produce substantial loss of hippocampal pyramidal cells or mossy
fiber sprouting in contrast with the changes caused by
the substance in adult rats [89]. A similar insensitivity
to damage to the hippocampus in immature animals
was observed in the kindling model [40]. These facts
may explain the low sensitivity to excitotoxicity associated with immaturity of excitatory amino acid receptors and kainic acid in the brain of young animals
and active neurogenesis [80]. However, more recent
studies indicate that in the model of kainate seizures
in the hippocampus of immature animals, a synaptic
reorganization of sector CA3 and the subiculum occurs [29]. This leads to an increase in impulse conduction in sections CA3-CA1, activation of subsequent micro sections of the hippocampus, and the effect of hypersynchronization of bioelectrical activity
of neurons necessary for the onset of epilepsy in the
future [56]. Studies on the temporal lobe specimens of
patients who died as a result of status epilepticus
showed a significant loss of pyramidal neurons at sectors CA1 and CA3 and hippocampus hilus, therefore,
the changes are similar to those of classical HS [30].
Damage to the hippocampus has also been reported in
the MR of patients with frequent seizures in the
course of cryptogenic, drug resistant TLE [49, 50].
Taking into account the above data, the answer to the
question whether HS is the result or the cause of
drug-resistant epilepsy should be that both concepts
are true and supported by numerous scientific literature. It seems that, in the pathogenesis of HS, innate
predisposing factors to such pathology as well as repetitive, uncontrolled seizures are equally important.
HS and antiepileptic drugs
HS is characterized by three pathological histological
changes: loss of neurons, glial reaction (gliosis), and
remodeling of neuronal networks especially interneurons (sprouting). Therefore, it is interesting to question whether and how antiepileptic drugs (AEDs) may
prevent HS. AED mechanisms of action are mainly
based on their effects on ion channels (sodium and
calcium), excitatory and inhibitory amino acid receptors, inhibition of GABA metabolism and synaptic
transmission [58]. All of these elements lead to the inhibition theory of excessive excitatory neurotransmission, resulting in so-called excitotoxicity and associated neuronal death. Since the major pathological
changes of hippocampal nerve cells are found in sectors CA1 and CA3, characterized by the highest expression of the receptors of glutamic and kainic acid
[26], the loss of these neurons occurs most likely in
the mechanism of aponecrosis induced by excitotoxicity processes [75]. These neurons, especially those
located around the hippocampal hilus, are fast-spiking
inhibitory cells. Their loss disrupts the balance of excitation/inhibition, which enables uncontrolled discharge of excitatory neurons. In experimental studies,
performed at our institution, effective neuroprotective
AED activity was demonstrated in cultures of hippocampal neurons [84, 86]. Clinical experience suggests, however, that pharmacological treatment of epilepsy in many patients with TLE associated with HS
is ineffective. The treatment of choice is neurosurgery
(anterior temporal lobectomy), after which recurrent
seizures are rare and AEDs can be safely discontinued
[78]. The available AEDs can indeed prevent damage
to neurons by inhibiting excitotoxicity processes, but
their impact on other elements of HS, i.e., the sprouting of axons and glial reaction, is small. We can therefore conclude that AEDs inhibit pathological neuronal
discharge, i.e., act as an anticonvulsant, but they do
not prevent epileptogenesis. Recent experimental
studies performed on immature rats genetically predisposed to epilepsy, however, have shown the potential antiepileptogenic effect of levetiracetam and ethosuximide [79].
Although promising antiepileptogenic effects of
various chemicals e.g., immunosuppressants, antiinflammatory drugs, neurotrophins and erythropoietin
were observed in several preclinical studies (for review, see [55]), these compounds have not found
practical use as antiepileptogenic agents yet.
Eid et al. indicate a key role in the pathogenesis of
HS not only of glutamate and the excitotoxicity trail,
but also glia [32]. Recent studies have shown that the
characteristic (for HS) astrogliosis is associated with
overexpression of adenosine kinase, which enhances
spontaneous bioelectric activity of neurons. The hardened tissue also showed reduced hippocampal expression of adenosine A1 receptors, which play an impor-
Pharmacological Reports, 2013, 65, 555–565
561
tant role in inhibitory neurotransmission [15]. The
possibilities to modulate gene expression of astrocyte
membrane receptors, especially potassium channels,
and effect on adenosine kinase may be interesting
in the search for AEDs with new mechanisms of action [16].
With regard to the mechanisms of action of AEDs
and structural and functional abnormalities occurring
in HS, there is a very interesting new issue in epigenetics, i.e., the possibility of AEDs modulating the
gene structure of nerve tissue cells [5]. This occurs
through the neuronal plasticity discussed previously
[59]. Commonly used to treat epilepsy valproic acid
has the ability to inhibit histone deacetylase, an enzyme crucial for the regulation of histone acetylation,
chromatin remodeling and gene expression [57]. The
intensification by valproic acid of acetylation of histones H3 and H4 and the associated change transcription of genes [36] can attenuate excitotoxicity processes and thus degeneration and neuronal death [51].
In summary, the hippocampus fulfills an extremely
important role in the pathogenesis of epilepsy and
convulsions. The majority of patients with drug resistant TLE have a characteristic pathology of the brain
structure – HS, characterized by loss of pyramidal
neurons, severe glial reaction and remodeling of neuronal networks. Studies on the pathogenesis of HS,
supported by numerous literature on the subject, do
not provide a clear answer to the question whether HS
is a cause or consequence of repeated seizures. We believe that both concepts are true and should be treated
as of equal importance.
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Received: November 8, 2012; in the revised form: March 10, 2013;
accepted: March 13, 2013.
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