Pharmacological Reports Copyright © 2013 2013, 65, 555565 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 charac- terized 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 tained by the balancing effects of excitatory and inhibitory neurotransmitters and currents: sodium and Epilepsy is one of the most common neurological dis- calcium with chloride and potassium. Ionic conduc- eases and affects about 1% of the population [7]. An tivity systems and neurotransmitters are closely re- epileptic seizure is the result of functional disorders of lated because the reaction of neurotransmitters to spe- the brain and is formed as a result of abnormal, exces- cific receptors on the cell membrane of neurons sive bioelectrical discharge in the nerve cells [21]. causes movement of ions in both directions: from the This disorder can theoretically occur in every popula- interior of the neuron to the extracellular space and tion of neurons, but it is often observed in the imme- vice versa. An essential element generating and con- diate vicinity of organic brain damage, such as a scar ditioning nervous system activity is the action poten- or a tumor. A group of changed, overly excitable tial. It is created as a result of fast intracellular sodium nerve cells is called an epileptic focus. The cause of current. This leads to a sudden depolarization of the an epileptic seizure is a sudden imbalance between cell membrane of the neuron and its propagation excitatory and inhibitory processes in the neural net- along the axon, and neurotransmitter release from the work [34]. Physiologically, at the cellular and synap- presynaptic ending into the synaptic cleft. There, the tic level, the transmembrane currents and neurotrans- neurotransmitter connects with receptors of the post- mitters provide such a balance. Homeostasis is main- synaptic membrane.
Pharmacological Reports, 2013, 65, 555565 555 Depending on the type of neurotransmitter released sue in experimental animals and in patients with epi- (excitatory or inhibitory), an action potential is trig- lepsy, although it does not always show structural gered in subsequent neurons (the spread of stimulus) changes, differs at the molecular level of normal tis- or conduction is blocked when the inhibitory neuro- sue [63]. During this period, the following processes transmitter is released. The effect of the inhibitory take place: a process of pathological “learning” of the neurotransmitter action on ionotropic receptors is hy- neurons, pathological reorganization of neural activ- perpolarization of the neuronal membrane and the re- ity, but also the reorganization of the nerve tissue mi- lease of inhibitory postsynaptic potential (IPSP), and crostructure. According to the latest research, three excitatory neurotransmitter - its depolarization and re- basic phases can be distinguished in the process of lease of excitatory postsynaptic potential (EPSP). The epileptogenesis: acute brain damage (initial insult), ability to generate action potential by a nerve cell is latent period with “maturation” of the epileptic focus, determined by whether it is “reached” by more EPSP and actual epilepsy, where a process called secondary or IPSP from neurons. A well-developed network of epileptogenesis takes place [77]. The most important connections between inhibitory and excitatory neu- etiological factors include severe craniocerebral rons ensures physiological homeostasis in the brain. trauma, where the risk of post-traumatic epilepsy de- In pathologic conditions, both intrinsic factors (chan- pending on the severity of the injury ranges from 2% nelopathies) and extrinsic factors (extracellular envi- to as much as 25% [63]. High risk factors also in- ronment changes, activity of astrocytes, remodeling clude: stroke, epileptic state, recurrent and prolonged of synaptic endings) may contribute to excessive ex- febrile convulsions, cerebral thrombosis and neuroin- citability of nerve cells and ultimately lead to epilep- fections. Therefore, the neurobiologic basis of epilep- tic seizure. Long-term imbalance of excitation/inhibi- togenesis was analyzed in experimental models of tion, initiated by various pathological factors, starts such damages [43]. the process of epileptogenesis leading to the forma- Epileptic focus formation is often explained by the tion of an active epileptic focus. The condition for the kindling model [68], defined as a progressive increase occurrence of an epileptic seizure is excessive bioe- in neuronal response to rarely used and weak stimula- lectric activity of a group of neurons as well as hyper- tion of a small area in the brain. A stimulus of a sub- synchronization of this activity in the cerebral cortex liminal intensity after a certain time causes epileptic [4]. The gap junctions – formed by directly adjacent discharges at the place of stimulation. If the stimulus cell membranes of neighboring neurons and astro- is repeated, a process of progressive change begins: cytes – are an extremely important ultrastructural ba- first the stimulation causes local, short epileptic dis- sis of hypersynchronization of discharges. The trans- charge, after consecutive stimulation the discharges mission of interneuronal information through gap last longer, spread to larger areas of the brain, and junctions is much faster than transmission through eventually clinical epileptic seizures are observed. synapses [98]. Another important factor in condition- This process is dynamic. The interval between suc- ing hypersynchronization of excitatory discharges is cessive attacks becomes shorter in untreated patients. the reorganization of the cortical microarchitecture Moreover, the primary focus can produce a secondary occurring over time. or mirror focus [53]. The consequence of the so- called initial insult initiating epileptogenesis is imme- diate and gradually progressive processes of varying course over time. Immediate response involves neu- Epileptogenesis ronal activation with intracellular calcium ion accu- mulation and further stages of excitotoxicity, starting The process of epileptogenesis is usually explained in the system of secondary messengers, activation of the literature by the two-hit hypothesis. The term epi- gene expression and protein synthesis. leptogenesis commonly refers to a period of time In the following days, at the site of injury, inflam- from the first hit, such as trauma or stroke, to the oc- matory processes take place and mediators of inflam- currence of the first epileptic seizure. It is a chronic mation, glial and endothelial cell responses are ac- process, in which a series of biochemical and struc- tivated. At a later stage of epileptogenesis, growth tural changes take place in the nerve tissue. Experi- processes occur: the sprouting of new axons, synapto- mental and clinical studies have shown that nerve tis- genesis and angiogenesis. The consequence of these
556 Pharmacological Reports, 2013, 65, 555565 Hippocampus and epilepsy Krzysztof Sendrowski and Wojciech Sobaniec
processes is the reorganization of nerve tissue mi- The main hippocampus afferent pathways originate in croarchitecture [3]. This is usually a clinically silent the enthorinal cortex (EC), the other run from the period. Sometimes these changes are sufficient for the amygdala and various parts of the neocortex. The EC clinical manifestation of epilepsy, sometimes a second has connections to other areas of the cerebral cortex. hit is necessary. It may not only be an external factor, The main output pathway of EC axons project densely such as craniocerebral trauma, but also a “sufficient” to the granule cells in the dentate gyrus; apical den- level of damage to nerve tissue as a result of the pro- drites of CA3 get a less dense projection, and the api- cesses of apoptosis and neuronal necrosis and gene cal dendrites of CA1 get a sparse projection. Thus, the expression occurring since the initial insult [67, 77]. perforant pathway establishes the EC as the main “in- terface” 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 The hippocampus and epilepsy thorny spines that exit from the proximal apical den- drite of the CA3 pyramidal cells. Then, the CA3 ax- Anatomy of hippocampus ons loop up into the region where the apical dendrites are located, extend all the way back into the deep lay- The hippocampus is an essential part of the archeo- ers of the EC - the Shaffer collaterals completing the cortex. In mammals, it is three-layered structure lo- reciprocal circuit. Field CA1 also sends axons back to cated on the medial surface of the temporal lobe in the the EC, but these are more sparse than the CA3 pro- back of each cerebral hemisphere. The name hippo- jection. Within the hippocampus, the flow of informa- campus is derived from Greek and means sea horse, tion from the EC is largely unidirectional, with signals which it resembles in shape. In the literature, it is of- propagating through a series of tightly packed cell ten referred to as Ammon’s horn (cornu Ammonis), layers, first to the dentate gyrus, then to the CA3 which is derived from the distinctive image of an layer, to the CA1 layer, and next out of the hippocam- Egyptian god. The hippocampus is an important part pus to the EC, mainly due to collateralization of the of the limbic system, which plays vital role in the be- CA3 axons [1]. havioral, emotional and memory processes. The hippocampus is an important structure in the The structure of the archeocortex is much simpler pathophysiology of convulsions and epilepsy. Be- than of the neocortex. Histologically, we can divide cause of its relatively simple histological construc- the hippocampal cortex into four sectors: CA1 – CA4, tion, it is often used in experimental and clinical stud- which vary in size and the amount of nerve cells. The ies of this disease. The hippocampal cortex contains CA1 field contains small pyramidal cells, the small two major groups of neurons: principal neurons and CA2 field is made up of small pyramidal cells, the interneurons. Most principal neurons form excitatory CA3 field forms a broad, loose band of pyramidal synapses on the cell bodies of other neurons in the re- neurons. The CA4 field, also referred to as a hilar re- mote areas of the brain, whereas interneurons usually gion, is formed by loosely structured pyramidal cells, form inhibitory synapses on principal neurons and which are surrounded by a U-shaped dark seam of other interneurons. Therefore, they modulate the exci- gray matter (dentate gyrus). Individual fields of the hippocampus show differences in the structure and ar- tatory effect of the principal neurons and prevent ex- rangement of nerve connections. Most of the afferent cessive excitation of the neuronal network, thereby fiber reach the hippocampus through the tractus per- preventing the generation of convulsions. With re- forans. They form synapses with the dendrites of py- spect to the above anatomy of the hippocampus, the ramidal cells. Some afferent fibers switch in the pyramidal neurons are the principal cells. In field granular cell layer, whose axons are called mossy fi- CA3, their function is modulated by projections of the bers, and form synapses with pyramidal cells. In the granule cells of the dentate gyrus, mossy fibers, syn- hippocampus, mossy fibers are only present in the apses of the perforant pathway from the EC, and col- CA3 and CA4 fields. Axons of pyramidal cells form laterals from CA3 interneurons. The function of the afferent pathways. The main afferent pathways of the CA1 sector pyramidal neurons is modulated by the hippocampus lead to the corpora mamilaria to the perforant pathway synapses from the EC and Schaffer front nuclei of the thalamus and to the hypothalamus. collaterals of CA3 (Fig. 1).
Pharmacological Reports, 2013, 65, 555565 557 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 char- acteristic of HS [14]. They constitute a histological Fig. 1. Circulation of nerve impulses between the separates hippo- campal structures. Details in the text basis of functional reorganization of the hippocampus manifested by excessive excitation in the above- mentioned excitatory reciprocal circuit of nerve im- pulses EC – dentate gyrus – CA3 – CA1 – EC. Mossy Temporal lobe epilepsy and hippocampal sclerosis (HS) fibers are axons of dentate gyrus granule cells, which physiologically connect with the neurons of the end- folium and hippocampal CA3 sector. If in the process Temporal lobe epilepsy (TLE) is the most common of HS sector CA3 neurons and end-folium neurons form of epilepsy in adults [104]. TLE patients have focal seizures, some of which with secondary gener- are lost, their feedback projection to granule cells will alization. In most of these patients, the epileptic focus also be lost. The consequence of such deinnervation is located in the medial temporal lobe structures, such will be the projection of these axons to neighboring as the hippocampus, amygdala and parahippocampal mossy fibers (sprouting). Sprouting will cause recip- gyrus. Pharmacological treatment of epilepsy often rocal synaptic stimulation, which may explain the ex- does not provide satisfactory control of seizures. Drug cessive excitability of dentate gyrus neurons observed resistance applies to 25–30% of TLE patients. In such in temporal lobe epilepsy [91]. Experimental studies cases, the treatment of choice is neurosurgery (ante- have shown that the imbalance of excitation/inhibi- rior temporal lobectomy) [33]. tion between the dentate gyrus and the hippocampus HS is an anatomic basis of medial temporal lobe due to the production of even a small number of exci- epilepsy (MTLE), common in experimental models of tatory collaterals is responsible for persistent neuronal convulsions and epilepsy as well as in patients with hyperexcitability [21]. The effect of these changes is drug-resistant epilepsy [11]. In changed hippocampal excessive neuronal excitation stimulating the pro- nerve tissue, significant histological changes (reor- cesses of neuronal epileptogenesis and excitotoxicity. ganization of the hippocampus microarchitecture) and Another histological change in HS is the dispersion functional changes occur. of dentate gyrus granule cells. Under physiological In histological examinations, HS is characterized conditions, the granular layer cross section has 4–5 by degeneration and selective loss of pyramidal neu- cells, whereas in more than 40% of HS the width of rons, pathological proliferation of interneuron net- the granular layer increases and dispersion of cells works, and severe glia reaction [82, 94]. In classical may be over 10. Since many of the cells are spindle- HS, pyramidal cell loss is observed in CA1 and CA3 shaped, resembling migrating embryonic neurons, in and around the end-folium, while the cells of sector the pathogenesis of these changes we take into ac- CA2 are spared. In other less common subtypes of count the active process of neurogenesis in the sub- HS, loss of pyramidal neurons occurs in all fields of granular layer. The possibility of neurogenesis in the the hippocampus (total hippocampal sclerosis), or adult hippocampus has been confirmed in animal only around the end-folium (end-folium hippocampal models [13, 38] and in humans [35], including in pa- sclerosis) [93]. tients with epilepsy [28, 71]. A clinical diagnosis of In an experimental model of TLE, Sloviter demon- hippocampal sclerosis (HS) associated with drug- strated irreversible damage of dentate hilar mossy resistant temporal lobe epilepsy is based on radiologi- cells that provide excitatory inputs onto inhibitory in- cal examination. High-resolution magnetic resonance terneurons. In contrast, most dentate gyrus inhibitory imaging has the greatest practical importance [18], in GABA-basket cells were preserved [87]. On this ba- particular MR volumetry [19]. Preoperative diagnos- sis, the author proposed the “dormant basket cell hy- tics utilize comprehensive exams involving neuroi- pothesis”, which explained TLE with impaired inhibi- maging and electrophysiological techniques [48, 70].
558 Pharmacological Reports, 2013, 65, 555565 Hippocampus and epilepsy Krzysztof Sendrowski and Wojciech Sobaniec
Molecular studies in recent years have added addi- tion of the mGluR with its chemical agonist ACPD tional information on the pathogenesis of TLE and (1-amino-1,3-dicarboxycyclopentane) caused long HS. Processes such as synaptic plasticity and glial re- lasting and synchronous epileptogenic discharges in action play an extremely important role. The most im- the neural network of the hippocampal CA3 sector portant pathogenic factor in synaptic plasticity is the [92]. Subsequent studies have shown that activation reorganization of the structure and function of neu- of mGluR receptors induces a depolarization-acti- ronal membrane receptors. This applies to both iono- vated, voltage-dependent cationic current, which is tropic and metabotropic receptors [10, 69]. Synaptic responsible for lowering the threshold of excitability plasticity is considered to be an important patho- of hippocampal neurons and persistent ictal dis- physiological factor of posttraumatic epilepsy, among charges generated in these cells [10, 25]. others [97]. A patient after severe craniocerebral trauma suffers from a decline in bioelectrical activity Role of glia in the pathogenesis of HS in the first phase, which is associated with damage or and epilepsy death of a certain population of neurons. Due to the dynamic process of synaptic plasticity, which may oc- Most studies on the patophysiology of temporal lobe cur in an uncontrolled manner at times, a develop- epilepsy (TLE) focus on the structure and function of ment of seizure activity takes place in this area [44]. neurons, because of their ability to generate dis- In studies conducted on organotypic cultures of the charges. However, it should be noted that in addition hippocampus, long-term blocking of the electrical ac- to damage to and loss of neurons, HS is constantly ac- companied by glial reaction. It occurs regardless of tivity of neurons with calcium blockers, tetrodotoxin the experimental epilepsy model. Astrogliosis occurs and NMDA receptor inhibitors, resulted in excessive in over 90% of the surgically resected hippocampus excitation of neurons. This effect was induced by syn- of patients with TLE [95]. Until recently, glia was aptic plasticity [6]. On the other hand, recurring sei- only considered “brain glue” for neurons. It turned zures also induce synaptic plasticity in the brain, out, however, that glia, and particularly astroglia, which in time further increases the intensity of sei- plays important functions in the process of neuro- zures. It has been shown for example that ictal epilep- transmission [103]. Astrocyte cell membranes have tiform discharges induced by hyperkalemia of the hip- the same receptors as neurons, although their expres- pocampus culture environment ignited the synaptic sion is different [52, 101]. For example, the density of plasticity process, which resulted in excessive excit- potassium channels on the astrocyte cell membrane is ability of the nerve cells leading to progressive epilep- much higher than the density of sodium channels, togenesis [65]. In an experimental HS model induced which prevents the generation of action potentials by by brain injury, changes in the expression of structural glia. A very important role is played by Kir4.1 potas- proteins of subunits of GABAA receptor have been sium channels belonging to the family of inwardly shown [37]. Both in animal models of epilepsy as rectifying K+ (Kir) channels. They cooperate with well as surgically resected hippocampal tissue from aquaporin-4 (AQP4) channels, which are unique to TLE patients, the authors reported a reduced density astrocytes. The coordinated action of these channels of ionotropic GABAA receptors associated with a loss is crucial for the maintenance of water and ion ho- of GABAergic inhibitory neurons and a compensa- meostasis in the brain [8, 76, 102], and their dysfunc- tory reorganization of the structure of the receptor’s tion was implicated in the pathogenesis of epilepsy subunits in the retained nerve cells [90]. Lasoñ et al. [45]. The astrocytal network, in contrast with neu- also demonstrated a change in the expression of mem- rons, mainly communicates through gap junctions. brane receptors of hippocampal nerve cells for excita- These connections allow for rapid uptake of potas- tory amino acid receptors, among others, in the sium ions and glutamate by astrocytes, which pre- chemical kindling model [60] and the pilocarpine and vents their harmful accumulation in the extracellular kainic acid-induced seizure model [61]. Mathern et al. space. Glial cells by means of specific excitatory also confirmed the reorganization of NMDA receptor amino acid transporters (EAAT) capture excess exci- expression in TLE patients [74]. Since the 1990s, sci- tatory neurotransmitters from the synaptic cleft, thus entists have focused on the role of metabotropic gluta- preventing excitotoxicity processes [96]. Astrocyte mate receptors (mGluRs) in the process of epilepto- cell membranes for neurotransmitters have numerous genic synaptic plasticity. It turned out that the activa- receptors whose activation leads to excessive intracel-
Pharmacological Reports, 2013, 65, 555565 559 2+ lular Ca accumulation, which can spread to adjacent In generally accepted theory and aforementioned astrocytes in the form of a “calcium wave”. This pro- epileptogenesis two-hit hypothesis, the initial insult of cess involves the release of neuroactive substances even a small area of nerve tissue of the brain caused by called “gliotransmitters” from active astrocytes [81], various etiological factors leads to a stretched over which act back on the synapse to regulate the pre- time sequence of histological and biochemical changes synaptic function and modulate postsynaptic response in the area of damage, a so-called maturation of the [105]. Increased gliotransmitter release, including epileptic focus. Subsequent even small second hits ac- glutamate, in typical gliosis areas may play a signifi- tivate the focus and cause epilepsy. In relation to this cant role (for HS) in pathological hypersynchronia of theory, the main factors that initiate HS and epilepto- neuronal firing [2]. genesis are severe head trauma, perinatal trauma, his- In pathologically changed nervous tissue encoun- tory of early childhood status epilepticus or prolonged tered, for example, in HS, glial cells are actively in- or recurrent febrile seizures [73]. The latter is the volved in epileptogenesis. Binder and Steinhäuser most frequently cited cause of HS [23]. In experimen- found that astrocytes in the HS focuses have a unique tal febrile convulsions, severe pathological lesions structure and function [12]. Bordey and Spencer were observed in preparations of rat brain, especially showed significantly increased activity of excitatory within the hippocampus [46]. In an experimental sodium currents through the cell membrane of hippo- model of febrile seizures conducted at our institution, campal astrocytes in patients with HS [17]. On the we have shown that recurrent hyperthermic seizures surface of astrocytes analyzed in the hippocampal tis- cause loss of more than a half of the pyramidal neu- sue of patients with HS, severe expression of genes en- rons in CA1 and CA3 sectors of the hippocampus, but coding proteins involved in the release of glutamate in contrast with HS, without accompanying gliosis was also demonstrated [62]. Other authors have also [85]. In the same experiment, in electron microscopic described significant abnormalities in potassium chan- tests, we also found significant ultrastructural abnor- nels and the function of potassium channel complexes malities in the blood-brain barrier in the hippocampal with the aquaporin channel in HS. Kivi et al. demon- cortex [66]. Reports on patients with epilepsy are am- strated decreased expression of potassium channels in biguous, even though the vast majority of them indi- pathological hippocampal tissue, compared with nor- cate an increased risk of epilepsy in children with feb- mal tissue [54]. Recent studies also indicate that muta- rile seizures [9, 100], and brain MR examinations tions in the KCNJ10 gene encoding the Kir4.1 potas- show pathological lesions in the hippocampus of chil- sium channel are associated with the varying clinical dren with a history of prolonged febrile seizures, par- morphology of epileptic seizures [42]. In the hippo- ticularly focal [83, 99]. In a study analyzing a large campus of patients with TLE associated with HS, group of 572 patients with TLE, Mathern et al. dem- a loss of perivascular Kir4.1 channels has been demon- onstrated that in most cases the occurence of TLE and strated [41]. Failure of the sclerotic hippocampus to HS was preceded by an initial precipitating injury. In buffer excess potassium ions in the extracellular space, the young, the dispersion of granule cells and sprout- impaired function of the transporters for excitatory ing of axons dominated in the pathology of hippocam- amino acid and glutamine synthetase activity – an en- pus, which would rather suggest a developmental ba- zyme that converts glutamate to glutamine – contribute sis of HS [72]. to increased neuronal hyperexcitation, neurotoxicity, An interesting issue in some patients with drug re- and the spread of convulsive activity [31]. sistant TLE is a so-called “dual pathology”. It is based on the coexistence of HS (usually mild) and abnormal epileptogenic changes situated beyond the hippocam- pus [64]. This problem affects 5–30% of patients with HS: cause or effect of epilepsy? drug resistant TLE [24]. A known example of clinical “dual pathology” is the coexistence of severe HS and Despite the well-studied histological and ultrastruc- cortical heterotopia, which in this case could also in- tural basis of HS, its pathophysiology remains un- dicate the “congenital” evolving nature of HS. clear. Whether HS is a primary cause of focal epilepsy Over 100 years ago, Gowers postulated that “sei- or maybe the result of repeated epileptic seizures is zures beget seizures” [39]. According to this theory, is still an unanswered question [47]. HS and corresponding TLE not the result of repeated
560 Pharmacological Reports, 2013, 65, 555565 Hippocampus and epilepsy Krzysztof Sendrowski and Wojciech Sobaniec
subclinical discharges or prolonged epilepsy or status based on their effects on ion channels (sodium and epilepticus? calcium), excitatory and inhibitory amino acid recep- In experimental studies, histopathological changes tors, inhibition of GABA metabolism and synaptic similar to HS were observed in the kindling model transmission [58]. All of these elements lead to the in- [20, 22] and experimental kainic or pilocarpine acid- hibition theory of excessive excitatory neurotransmis- induced status epilepticus [27]. Interestingly, injection sion, resulting in so-called excitotoxicity and associ- of kainic acid into immature rats did not produce sub- ated neuronal death. Since the major pathological stantial loss of hippocampal pyramidal cells or mossy changes of hippocampal nerve cells are found in sec- fiber sprouting in contrast with the changes caused by tors CA1 and CA3, characterized by the highest ex- the substance in adult rats [89]. A similar insensitivity pression of the receptors of glutamic and kainic acid to damage to the hippocampus in immature animals [26], the loss of these neurons occurs most likely in was observed in the kindling model [40]. These facts the mechanism of aponecrosis induced by excitotox- may explain the low sensitivity to excitotoxicity asso- icity processes [75]. These neurons, especially those ciated with immaturity of excitatory amino acid re- located around the hippocampal hilus, are fast-spiking ceptors and kainic acid in the brain of young animals inhibitory cells. Their loss disrupts the balance of ex- and active neurogenesis [80]. However, more recent citation/inhibition, which enables uncontrolled dis- studies indicate that in the model of kainate seizures charge of excitatory neurons. In experimental studies, in the hippocampus of immature animals, a synaptic performed at our institution, effective neuroprotective reorganization of sector CA3 and the subiculum oc- AED activity was demonstrated in cultures of hippo- curs [29]. This leads to an increase in impulse con- campal neurons [84, 86]. Clinical experience sug- duction in sections CA3-CA1, activation of subse- gests, however, that pharmacological treatment of epi- quent micro sections of the hippocampus, and the ef- lepsy in many patients with TLE associated with HS fect of hypersynchronization of bioelectrical activity is ineffective. The treatment of choice is neurosurgery of neurons necessary for the onset of epilepsy in the (anterior temporal lobectomy), after which recurrent future [56]. Studies on the temporal lobe specimens of seizures are rare and AEDs can be safely discontinued patients who died as a result of status epilepticus [78]. The available AEDs can indeed prevent damage showed a significant loss of pyramidal neurons at sec- to neurons by inhibiting excitotoxicity processes, but tors CA1 and CA3 and hippocampus hilus, therefore, their impact on other elements of HS, i.e., the sprout- the changes are similar to those of classical HS [30]. ing of axons and glial reaction, is small. We can there- Damage to the hippocampus has also been reported in fore conclude that AEDs inhibit pathological neuronal the MR of patients with frequent seizures in the discharge, i.e., act as an anticonvulsant, but they do course of cryptogenic, drug resistant TLE [49, 50]. not prevent epileptogenesis. Recent experimental Taking into account the above data, the answer to the studies performed on immature rats genetically pre- question whether HS is the result or the cause of disposed to epilepsy, however, have shown the poten- drug-resistant epilepsy should be that both concepts tial antiepileptogenic effect of levetiracetam and etho- are true and supported by numerous scientific litera- suximide [79]. ture. It seems that, in the pathogenesis of HS, innate Although promising antiepileptogenic effects of predisposing factors to such pathology as well as re- various chemicals e.g., immunosuppressants, anti- petitive, uncontrolled seizures are equally important. inflammatory drugs, neurotrophins and erythropoietin were observed in several preclinical studies (for re- view, see [55]), these compounds have not found practical use as antiepileptogenic agents yet. HS and antiepileptic drugs Eid et al. indicate a key role in the pathogenesis of HS not only of glutamate and the excitotoxicity trail, HS is characterized by three pathological histological but also glia [32]. Recent studies have shown that the changes: loss of neurons, glial reaction (gliosis), and characteristic (for HS) astrogliosis is associated with remodeling of neuronal networks especially interneu- overexpression of adenosine kinase, which enhances rons (sprouting). Therefore, it is interesting to ques- spontaneous bioelectric activity of neurons. The hard- tion whether and how antiepileptic drugs (AEDs) may ened tissue also showed reduced hippocampal expres- prevent HS. AED mechanisms of action are mainly sion of adenosine A1 receptors, which play an impor-
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