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Hippocampus, Hippocampal Sclerosis and Epilepsy

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Hippocampus, Hippocampal Sclerosis and Epilepsy Pharmacological Reports Copyright © 2013 2013, 65, 555565 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences Review Hippocampus,hippocampalsclerosis andepilepsy KrzysztofSendrowski,WojciechSobaniec 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 possibilitiesofpreventingtheseprocesses. Keywords: hippocampus,hippocampalsclerosis,epilepsy,epileptogenesis Pathophysiologyofepilepsy 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- synapticmembrane. 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 suchdamages[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 occurringovertime. 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- geneexpressionandproteinsynthesis. 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 Hippocampusandepilepsy 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 expressionoccurringsincetheinitialinsult[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 Thehippocampusandepilepsy thorny spines that exit from the proximal apical den- drite of the CA3 pyramidal cells. Then, the CA3 ax- Anatomyofhippocampus 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
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