Status epilepticus (SE) is a major clinical emergency resulting in continuous seizure activity that can cause brain injury and many molecular and pathophysiologic changes leading to neuronal plasticity. The neuronal plasticity following SE-induced brain injury can initiate epileptogenesis and lead to the ultimate expression of acquired epilepsy (AE), characterized clinically by spontaneous, recurrent seizures. Epileptogenesis is the process wherein healthy brain tissue is transformed into hyperexcitable neuronal networks that produce AE. Understanding these alterations induced by brain injury is an important clinical challenge and can lend insight into possible new therapeutic targets to halt the development of AE. Currently there are no means to prevent epileptogenesis following brain injury; thus, the elucidation of mechanisms of epileptogenesis will be useful in preventing the long-term clinical sequela. It has been demonstrated in vivo that calcium (Ca2+) dynamics are severely altered during SE and that elevations in intracellular Ca2+ ([Ca2+]i) in hippocampal neurons are maintained well past the duration of the injury itself (Ca2+ plateau). Here we report that similar changes in [Ca2+]i are observed in the hippocampal neuronal culture model of SE-induced AE. As an important second messenger, the maintenance of a Ca2+ plateau following injury can lead to several changes in gene expression, neurotransmitter release, and overall, neuronal plasticity. Thus, changes in post-SE [Ca2+]i and Ca2+ homeostasis may be important in understanding epileptogenesis and eventually preventing the progression to chronic epilepsy. This dissertation examines the development and maintenance of the Ca2+ plateau after SE and demonstrates the novel finding that pharmacological modulation of [Ca2+]i following SE may inhibit epileptogenesis in vitro.

L'épilepsie est l’un des désordres neurologiques les plus courants; environ 1% de la population mondiale en est atteinte. Elle affecte le fonctionnement des neurones qui s'exprime par une survenue de décharges rapides, appelées crises.Les crises peuvent parfois résister aux médicaments antiépileptiques. Cet état de crise, nommé refractory status epilepticus (RSE), se définit par une survenue des décharges de façon continue, qui sont difficiles à arrêter. Malheureusement, un patient en état RSE risque même de mourir.Le dysfonctionnement des neurones peut parfois se propager lentement vers une dépression corticale envahissante, qui se caractérise par une dépolarisation lente des neurones entraînant une baisse transitoire de l’activité cérébrale.Les mécanismes qui initient ces activités pathologiques restent encore mal connus. Mettant en œuvre une approche mathématique, nous présentons une analyse qualitative d’un modèle dit Epileptor, qui reproduit l’activité épileptique, et décrivons l’évolution temporelle de la crise jusqu’au moment où la personne revient à la normale. La transition vers l’état normal est interprétée comme une bifurcation. Nous démontrons qu’il en existe plusieurs types en variant certains paramètres du modèle, permettant ainsi de classer les crises.Une caractérisation de ces activités est nécessaire pour s’en échapper. Pour ce faire, nous explorons un espace des paramètres permettant de conclure que ces activités coexistent dans le cerveau et surviennent de plusieurs façons. Cet espace des paramètres propose plusieurs voies, qui sont validées expérimentalement, pour éviter ces activités pathologiques et retourner à la normale, d’où son importance. / Epilepsy is one of the most common serious neurological disorders affecting about 1% of the population in the world. It is a condition of the nervous system in which neuronal populations manifest as abnormal excessive discharges, called seizures.On rare occasions, a seizure follows another in a series without recovery, and does not respondto antiepileptic drugs. This state of continuous seizure activity is called refractory status epilepticus, which are difficult to treat. Patients suffering from this state are unfortunately at an increased risk of death.The neuronal dysfunction can sometimes spread slowly towards a spreading depression, which corresponds to a slowly propagating depolarization wave (or depolarization block DB) in neuronal networks, followed by a shut down of brain activity.The mechanisms underlying the genesis of these activities remain unknown. Using a mathematical approach, we present a qualitative analysis of a so-called Epileptor model, which generate epileptic dynamics, and describe how seizures evolve toward termination. The transition to the normal state occurs through a bifurcation. We demonstrate that many types of the bifurcation exist, depending on the values of some parameters. As a consequence, we can classify seizures.To escape from these activities, a characterization is going to be necessary. To this, we explore a parameter space of the model which demonstrate that these activities coexist in the brain, and under some ways. In addition, the parameter space can provide pathways to switch between these activities. Interestingly, we could propose how to return to the ’normal’ brain activity.

Abstract Various genetic aetiologies — including mitochondrial diseases, chromosomal disorders, and other monogenic diseases — are involved in status epilepticus (SE), a common neurologic emergency occurring in children and adults that exhibits high rates of morbidity and mortality. The exact frequency of mitochondrial SE is currently undefined. Furthermore, patients with pathogenic variants of POLG1 encoding mitochondrial DNA polymerase gamma have an increased risk of acute liver failure (ALF) induced by the common antiepileptic drug, valproic acid (VPA), which is problematic due to these patients also often experiencing drug-resistant seizures. Overall, the role of liver transplantation (LT) in VPA-ALF due to mitochondrial disease has been controversial. In the present work, large retrospective cohort studies were conducted for two main purposes: (1) to determine the genetic aetiologies of SE among Finnish paediatric and adult patients by specifically focusing on the common mitochondrial genetic defects associated with an increased risk of SE and (2) to examine whether common POLG1 p.Q1236H and p.E1143G variants are connected to liver or pancreatic toxicity upon exposure to VPA monotherapy. This thesis also describes the characteristics of VPA-ALF associated with the pathogenic POLG1 variant p.W748S and the prognosis of LT in a retrospective case series. Mitochondrial diseases explained 4.5% of SE cases in the study cohort. Patients with mitochondrial SE suffered from refractory SE significantly more often than patients with other forms of genetic or non-genetic SE. Additionally, mortality rates were higher in patients with mitochondrial or chromosomal disorders compared with the other groups, reflecting the severity of the underlying condition and the higher frequency of refractory SE. POLG1 variants p.Q1236H and p.E1143G could not be identified as risk factors for VHT or pancreatic toxicity, implying that VPA treatment might be suitable for patients harbouring these variants when other pathogenic variants are absent. Finally, the homozygous status of the pathogenic POLG1 variant p.W748S and older age of the patient during the presentation of VPA-ALF seem to be associated with higher survival rates following LT, which should be considered in the management of VPA-ALF. / Tiivistelmä Useita perinnöllisiä syitä, kuten mitokondriotauteja, kromosomihäiriöitä ja muita geenimuutoksia on tunnistettu status epilepticuksen (SE) eli pitkittyneen epileptisen kohtauksen taustalla. SE on yleinen neurologinen hätätilanne, johon liittyy merkittävää oheissairastavuutta ja kuolleisuutta sekä lapsilla että aikuisilla. Mitokondriotauteihin liittyvän SE:n tarkkaa esiintyvyyttä ei tiedetä. Potilailla, joilla on patogeenisia variantteja mitokondrioiden DNA-polymeraasia koodaavassa tuman POLG1-geenissä, on todettu kohonnut riski yleisesti käytetyn epilepsialääkkeen valproaatin (VPA) aiheuttaman akuutin maksavaurion kehittymiselle. Tämä tekee lääkehoidon valinnasta ongelmallista, koska näillä potilailla on usein epilepsialääkkeille resistenttejä kohtauksia. Maksansiirron merkitys akuutin maksavaurion hoidossa mitokondriotauteja sairastavilla potilailla on ollut kiistanalainen. Tutkimuksen tavoitteena oli selvittää SE:n perinnöllisiä syitä suomalaisilla lapsi- ja aikuispotilailla retrospektiivisesti kerätyssä laajassa potilasaineistossa. Tutkimuksessa keskityttiin yleisimpiin mitokondriaalisiin perinnöllisiin muutoksiin, joiden on aiemmin todettu liittyvän SE:n lisääntyneeseen riskiin. Tutkimuksen toisena päätavoitteena oli selvittää väestössä yleisten POLG1-geenin muutosten eli varianttien p.Q1236H ja p.E1143G yhteyttä maksatoksisuuteen tai haimatoksisuuteen VPA-monoterapian aikana. Lisäksi tutkittiin VPA:n aiheuttaman maksavaurion kliinisiä erityispiirteitä patogeeniseen POLG1-varianttiin p.W748S liittyen sekä mutaatiostatuksen vaikutusta maksansiirron jälkeiseen ennusteeseen. Mitokondriotaudit selittivät 4,5 % SE-tapauksista tämän väitöskirjatyön potilasaineistossa ja näillä potilailla SE pitkittyi hoitoresistentiksi tai erittäin resistentiksi merkitsevästi muita potilasryhmiä useammin. Kuolleisuus oli suurin potilailla, joilla todettiin mitokondriotauti tai kromosomihäiriö, liittyen todennäköisimmin vakavaan taustasairauteen ja hoitoresistentin SE:n suurempaan esiintyvyyteen. Tutkittuja POLG1-variantteja p.Q1236H ja p.E1143G ei voitu tunnistaa maksa- tai haimatoksisuuden riskitekijöiksi, mikä tarkoittaa, että VPA-hoito voisi sopia näille potilaille, mikäli muita patogeenisiä variantteja ei todeta. Patogeenisen POLG1-variantin p.W748S homotsygoottisuus ja nuoruusikä tai varhainen aikuisikä maksavaurion ajankohtana ovat maksansiirron ennustetta parantavia tekijöitä, mikä tulisi ottaa huomioon hoitopäätöksiä tehtäessä.

La recherche d'agents neuroprotecteurs dans le cadre d'un accident ou d'une maladie neurologique est une priorité des Neurosciences. Dans l'équipe, nous avons choisi d'étudier les effets neurobiologiques de l'érythropoïétine (Epo), « molécule phare » dans le domaine de la neuroprotection depuis une dizaine d'années. En analysant l'expression cérébrale de l'Epo et celle des constituants potentiels de son site de liaison (récepteur EpoR et chaîne β commune « βc ») au cours du développement postnatal et du vieillissement chez le rat, nous avons invalidé l'hypothèse selon laquelle la βc fait partie du récepteur de l'Epo. De plus, nous avons observé que divers stimuli environnementaux, tels que l'exposition hypoxique et l'enrichissement du milieu de vie, augmentent l'expression de l'EpoR dans des régions vulnérables du cerveau. Dans un modèle de status epilepticus chez le rat, cette augmentation est indispensable à l'amélioration des effets neuroprotecteurs de l'Epo, sans que la réponse inflammatoire précoce ne soit altérée.

The fundamental attribute of neurons is their cellular electrical excitability, which is based on the expression of a plethora of ligand- and voltage-gated membrane channels that give rise to prominent membrane currents and membrane potential variations that represent the biophysical substrate underlying the transfer and integration of information at the cellular level. Dendrites have both an electrical and a biochemical character, which are closely linked. In contrast, glial cells are non-electrically excitable but nevertheless display a form of excitability that is based on variations of the Ca2+ concentration in the cytosol rather than electrical changes in the membrane. Cytoplasmic Ca2+ serves as an intracellular signal that is responsible for controlling a multitude of cellular processes. The key to this pleiotropic role is the complex spatiotemporal organization of the [Ca2+]i rise evoked by extracellular agonists, which allows selected effectors to be recruited and specific actions to be initiated. Ca2+ handling in the cell is maintained by operation of multiple mechanisms of Ca2+ influx, internal release, diffusion, buffering and extrusion. Ca2+ tends to be a rather parochial operator with a small radius of action from its point of entry at the cytoplasm resulting in the concept of microdomains. Dendritic Ca2+ signaling have been shown to be highly compartmentalized and astrocytic processes have been reported to be constituted by hundreds of microdomains that represent the elementary units of the astrocyte Ca2+ signal, from where it can eventually propagate to other regions of the cell. The astrocyte Ca2+ elevation may thus act as intra and intercellular signal that can propagate within and between astrocytes, signaling to different regions of the cell and to different cells. The spatio-temporal features of neuron-to-astrocyte communication, results from diverse neurotransmitters and signaling pathways that converge and cooperate to shape the Ca2+ signal in astrocytes. Alterations in Ca2+ homeostasis have been shown to be associated with major pathological conditions of the brain such as epilepsy, ischemia and neurodegenerative diseases. Although there are evidences of Ca2+ rise in hippocampal neurons in in vitro models of epilepsy (Pal et al., 1999; Limbrick et al., 2001), there is no information on the Ca2+ regulatory mechanisms operating in discrete compartments of the epileptic neuron following Ca2+ influx through voltage gated calcium channels (VGCCs). In the first part of the work, the spatial and temporal profiles of depolarization induced changes in the intracellular Ca2+ concentration in the dendrites of cultured autaptic hippocampal pyramidal neurons rendered epileptic experimentally have been addressed. Our in vitro epilepsy model consisted of hippocampal neurons in autaptic culture that were grown in the presence of kynurenate and high Mg2+, and subsequently washing the preparation free of the blockers. To understand the differences in Ca2+ handling mechanisms in different compartments of a control neuron and the kynurenate treated neuron, a combination of whole-cell patch-clamp recording and fast Ca2+ imaging methods using the Ca2+ indicator Oregon Green 488 BAPTA-1 was applied. All our analysis was focused on localized regions in the dendrite that showed pronounced Ca2+ transients upon activation of high voltage activated (HVA) Ca2+ channels. The spatial extent of Ca2+ signals suggested the presence of distinct dendritic compartments that respond to the depolarizing stimulus. Further, the local Ca2+ transients were observed even in the presence of NMDA and AMPA receptor antagonists, suggesting that the opening of VGCCs primarily triggered the local Ca2+ changes. The prominent changes in intracellular Ca2+ observed in these dendritic regions appear to be sites where Ca2+ evoked dendritic exocytosis (CEDE) takes place. Since cellular Ca2+ buffers determine the amplitude and diffusional spread of neuronal Ca2+ signals, quantitative estimates of the time-dependent spread of intracellular Ca2+ in the dendritic compartments in the control and treated neurons were done using image processing techniques. Physiological changes in Ca2+ channel functioning were also induced by kynurenate treatment and one such noticeable difference was the observation of Ca2+ dependent inactivation in the treated neurons. We provide evidences of localized Ca2+ changes in the dendrites of hippocampal neurons that are rendered epileptic by kynurenate treatment, suggesting that these sites are more vulnerable (Padmashri et al., 2006). This might contribute to the epileptiform activity by local changes in cellular and membrane properties in complex ways that remains to be clearly understood. Status Epilepticus (SE), stroke and traumatic brain injury are all associated with large increases in extracellular glutamate concentrations. The concentration of glutamate in the extracellular fluid is around 3-4 µM and astrocytes are primarily responsible for the uptake of glutamate at the synapses. The extracellular levels of glutamate has been shown to increase dramatically (16 fold) in human SE suggesting an important role of glutamate in the mechanism of seizure activity and seizure related brain damage (Carlson et al., 1992). Several other studies have also shown a persistent increase in extracellular glutamate concentration to potentially neurotoxic concentrations in the epileptogenic hippocampus (During and Spencer, 1993; Sherwin, 1999; Cavus et al., 2005). We addressed the problem related to the effects of prolonged glutamate pretreatment on Ca2+ signaling in an individual astrocyte and its adjoining astrocyte (astrocyte pair), rather than on a syncytium of astrocytes in culture. Individual astrocytes may have functional domains that respond to an agonist through distinct receptor signaling systems. These are difficult to observe in studies that are done on glial syncytium because of spatial limits of image capture. This was examined with simultaneous somatic patch-pipette recording of a single astrocyte to evoke voltage-gated calcium currents, and Ca2+ imaging using the Ca2+ indicator Oregon Green 488 BAPTA-1 to identify the Ca2+ microdomains. Transient Ca2+ changes locked to the depolarization were observed in certain compartments in the astrocyte processes of the depolarized astrocyte and the responses were more pronounced in the adjoining astrocyte of the astrocyte pair. The Ca2+ transient amplitudes were enhanced on pretreatment of cells with glutamate (500 µM for 20 minutes). Estimation of local Ca2+ diffusion coefficients in the astrocytic processes indicated higher values in the adjoining astrocyte of the glutamate pretreated group. In order to understand the underlying mechanisms, we performed the experiments in the presence of different blockers for the metabotropic glutamate receptor, inositol 1,4,5 triphosphate (IP3) receptors and gap junctions. Ca2+ transients recorded on pretreatment of cells with glutamate showed attenuated responses in the presence of the metabotropic glutamate receptor (mGluR) antagonist α-Methyl(4-Carboxy-Phenyl) Glycine (MCPG). Intracellular heparin (an antagonist of IP3 receptor) introduced in the depolarized astrocyte did not affect the Ca2+ transients in the heparin loaded astrocyte, but attenuated the [Ca2+]i responses in the adjoining astrocyte suggesting that IP3 may be the transfer signal. The uncoupling agent 1-Octanol attenuated the [Ca2+]i responses in the adjoining cell of the astrocyte pair in both the control and glutamate pretreated astrocytes indicating the role of gap junctional communication. The findings of [Ca2+]i responses within discrete regions of astrocytic processes suggest that astrocytes may be comprised of microdomains whose properties are altered by glutamate pretreatment. The data also indicates that glutamate induced alterations in Ca2+ signaling in the astrocyte pair may be mediated through phospholipase C (PLC), IP3, internal Ca2+ stores, VGCCs and gap junction channels (Padmashri and Sikdar, 2006). Neuronal (EAAC-1) and glial (GLT-1 and GLAST) glutamate transporters facilitate glutamate reuptake after synaptic release. Transgenic mice with GLT-1 knockout display spontaneous epileptic activity (Tanaka et al., 1997) and loss of glial glutamate transporters using chronic antisense nucleotide administration was reported to result in elevated extracellular glutamate levels and neurodegeneration characteristic of excitotoxity (Rothstein et al., 1996). Dysfunction of glutamate transporters and the resulting increase of glutamate have been speculated to play an important role in infantile epilepsies (Demarque et al., 2004). We examined the effects of pretreatment with glutamate in the presence of the glutamate transport inhibitor threo-β-hydroxy-aspartate (TBHA) and in Na+-free extracellular medium to understand whether this resulted in any alteration in the astrocytic intracellular Ca2+ dynamics following activation of voltage gated calcium channels. The Ca2+ responses were found to be attenuated in both the cases indicating that the elevated levels of extracellular glutamate due to blockade of glutamate transporters may influence the responses mediated by the astrocytic glutamate receptors. Our studies indicate that the heightened extracellular glutamate concentration is not gliotoxic in our experimental system, although it may have a profound effect on altering the activity of surrounding neurons which was not addressed in the present work. Several studies have indicated that neurons control the level of gap junction mediated communication between astrocytes (Giaume and McCarthy, 1996; Rouach et al, 2000). All our earlier studies were done on process bearing astrocytes that were co-cultured with neurons. We have addressed the question as to whether the spatio-temporal changes in [Ca2+]i in astrocyte pairs differ if the astrocytes are cultured in the absence of neurons. The results indicate that there is indeed a significant reduction in the responses that are evoked in response to the depolarization pulse in the adjoining cell of the astrocyte pair. These experiments demonstrate that neurons in the cocultures may selectively enhance the Ca2+ responses possibly by increasing the coupling between the two cells.

Eine wichtige Folge des Status epilepticus ist die Entwicklung einer chronischen Epilepsie. Die genauen Mechanismen und die Kinetik der Epileptogenese sind weitestgehend unklar. Ziel der vorliegenden Arbeit war ein besseres Verständnis des Prozesses durch die In-vitro-Analyse von Lokalisation und Kinetik funktioneller Folgen des Status epilepticus in vivo. In kombinierten Hippokampus-entorhinaler Kortex Hirnschnittpräparaten von Wistar-Ratten nach elektrisch induziertem selbsterhaltendem Status epilepticus (self-sustaining status epilepticus, SSSE) wurden im Niedrig-Magnesium-Modell anfallsartige Ereignisse (AE) ausgelöst und untersucht. Die In-vitro-Analyse der AE wurde eine, vier und acht Wochen nach SSSE durchgeführt. Um das räumliche Verhalten der epileptischen Aktivität beurteilen zu können, wurde die Messung des extrazellulären Feldpotenzials mit der Analyse intrinsischer optischer Signale kombiniert. Im Verlauf nach SSSE kam es zu einer Latenzverkürzung bis zum Auftreten epileptischer Aktivität und zu einer Zunahme der AE-Frequenz. Vier und acht Wochen nach SSSE stieg der Anteil der AE mit großflächigem Ursprung signifikant an. Im Verlauf nach SSSE wurden außerdem zunehmend diskontinuierliche Ausbreitungsmuster der Anfallsaktivität beobachtet. Acht Wochen nach SSSE zeigten 50% der Präparate zudem eine zeitlich und räumlich von den AE unabhängige, hochfrequente Aktivität im Gyrus dentatus. Zusammenfassend wurden eine Latenzverkürzung und eine Zunahme der AE-Frequenz als Hinweise für eine gesteigerte Exzitabilität des Hirngewebes nach SSSE gesehen. Neben dem großflächigen Ursprung deutet auch die Zunahme diskontinuierlicher Ausbreitungsmuster auf eine gesteigerte Synchronizität des neuronalen Netzwerkes nach SSSE hin. Die autonome Aktivität im Gyrus dentatus spricht dafür, dass die in vorangegangenen Studien beschriebenen strukturellen Änderungen in dieser Region mit einer veränderten Funktionalität einhergehen. / The development of chronic epilepsy is a serious consequence of Status epilepticus. Little is known about the mechanisms and kinetic of the epileptogenic process. The aim of this md-thesis was the analysis of localisation and kinetic of functional deficits in vitro after Status epilepticus in vivo. Using the Low-Magnesium-Model, seizure-like events (SLE) were induced in combined hippocampal-entorhinal cortex slices of wistar rats after electrically induced self-sustaining Status epilepticus (SSSE). One, four and eight weeks after SSSE the in-vitro-analysis of SLE was performed. In order to determine onset and spread-pattern of epileptic activity, the measurement of the extracellular field-potential was combined with the imaging of intrinsic optical signals (IOS). In the time course after SSSE there was a reduction of the latency to onset of seizure activity and an increase of the SLE-frequency. Four and eight weeks after SSSE a significant increase of SLE with regional onset was found. In Addition, there was an increase of non-contiguous propagation of seizure activity. Eight weeks after SSSE 50% of the brain-slices showed autonomous high-frequent activity in the dentate gyrus. In conclusion a reduction of the latency to onset of seizure activity and an increase of the SLE-frequency were found. These changes are indicators of increased excitability after SSSE. Other than the regional onset, the non-contiguous spread-pattern also indicates increased synchronicity of the neuronal network after SSSE. The autonomous activity in the dentate Gyrus shows, that the previously described structural changes in this region lead to functional deficits.

No description available.

L’épilepsie du lobe temporal (ELT) est une pathologie neurologique sévère dont le fort taux de pharmacorésistance nécessite de nouveaux traitements. Le modèle lithium-pilocarpine modélise les caractéristiques et le développement de l’ELT. L’administration du carisbamate au début de l’épileptogenèse empêche l’apparition de l’ELT dans une sous-population de rats et la remplace par une épilepsie de type absence (ETA). L’évaluation cognitive effectuée durant la phase chronique a permis de distinguer les deux sous-populations : le groupe épilepsie de type absence ne développe pas le déficit cognitif sévère observé dans le modèle lithium pilocarpine. La spectroscopie du 13C n’a pas révélé de différence métabolique majeure entre les deux sous populations traitées, qu’elles développent une ELT ou une ETA. Ce travail souligne que l’administration précoce de carisbamate peut transformer l’ELT en une épilepsie moins sévère et fortement améliorer les comorbidités cognitives qui accompagnent l’ELT. / Temporal lobe epilepsy (TLE) is a severe neurological disease with a high refractory rate, which requires new treatments. The lithium-pilocarpine model allows reproducing human TLE features and development. Carisbamate administration at epileptogenesis onset prevents TLE incidence in a rats’ subpopulation, which is substituted by absence-like epilepsy (ALE). Behavioral and cognitive assessment performed during chronic period allowed differentiating the two subpopulations: ALE group did not develop the severe cognitive impairment shown in the lithium-pilocarpine model. 13C spectroscopy did not show major metabolism difference between the two treated subpopulations, whatever they develop TLE or ALE. This work demonstrates that early carisbamate administration can induce a shift from TLE in a less severe epilepsy form, and can strikingly improve TLE-related cognitive comorbidities.

Dans l'épilepsie du lobe temporal (ELT), l'hyperexcitabilité est attribuée à la mort neuronale, la gliose et la plasticité synaptique. Un remodelage vasculaire n'a jamais été recherché dans le tissu épileptique, bien que des données récentes suggèrent que la perméabilité de la barrière hémato-encéphalique (BHE) est épileptogène.<br />Nous avons observé dans l'hippocampe de patients atteints d'ELT réfractaire une dégradation de la BHE, une néo-vascularisation et la surexpression du vascular endothelial growth factor (VEGF) et de son récepteur VEGFR-2. <br />Pour comprendre cette angiogenèse, nous avons modélisé l'épilepsie in vivo et in vitro chez le rat. In vivo, la néo-vascularisation, la surexpression de VEGF/VEGFR-2 et la rupture de BHE sont présentes dans un modèle avec lésions et gliose, mais transitoires dans un modèle non lésionnel. <br />In vitro, nous avons observé que des crises déclenchées sur des cultures organotypiques d'hippocampe (COHs) induisent une angiogenèse et une dégradation de BHE qui ne persiste qu'en présence de lésions.<br /> Nous avons étudié le rôle du VEGF in vitro, en le neutralisant ou en inhibant des voies de signalisation de VEGFR-2 dans les COHs, confirmant l'importance de PKC et src dans l'angiogenèse et la dégradation de la BHE. De plus, nous avons montré un déséquilibre des angiopoiétines en faveur d'Ang2 qui potentialise les effets du VEGF.<br />Chez l'homme et l'animal, la rupture de la BHE persiste dans les foyers chroniques entretenant l'induction des crises. En ciblant des facteurs angiogéniques pour réparer la BHE, nous espérons réduire l'épileptogenèse et donc proposer de nouvelles stratégies pour les épilepsies réfractaires.

The prevalence of epilepsy in society is general knowledge; however the impact on social activity as well as other daily factors are not always fully recognised. Epilepsy frequently poses a problem with regard to work–related activities (Heaney, 1999:44). Moran et al. (2004:425) indicated that the major impacts of epilepsy on life were work and school difficulties, driving prohibition, psychological and social life of which restriction of work or schooling has the greatest impact on epileptic’s life. In all cases the type, severity, and frequency of the seizures as well as the age would be relevant. Davis et al. (2008:451) established that 39% of all epileptics were not adherent to their therapy and in patients over 65 this was even higher at 43 %. Non–adherence with antiepileptic medicine appears to be related to increased health care utilisation and costs and may also lead to an increased probable accidents or injuries The general objective was to investigate anti–epileptic medicine prescribing patterns and treatment cost in a section of the private health care sector by using a medicine claims database. A retrospective drug utilisation study was done on the data claims from a pharmacy benefit management company for the study period 1 January 2005 to 31 December 2008. Firstly epilepsy was investigated in order to understand the disease and to determine the prevalence and treatment thereof. It was found that epilepsy is still one of the most common neurological conditions and according to the findings, 2 out of every hundred patients were using anti–epileptic medicine in this section of the private health care sector. To make this condition socially more acceptable and understandable, public education for special target groups concerning the disorder must be conducted as well as employment training programmes for people with epilepsy themselves. The utilisation patterns of anti–epileptic drugs were reviewed, analysed and interpreted. It was determined that anti–epileptic medicine items are relatively expensive with regards to other medicine items on the total database. With regard to gender, more females are using anti–epileptic medicine than males on the database. The largest age group of patients using anti–epileptic medicine, is between > 40 years and <= 64 years of age. It was also clear that prevalence increase as age increase. With regard to the different prescribers, the number of items prescribed by a general practitioner was almost double that of the other prescribers. It was further established that newer anti–epileptic medicines are more expensive than older anti–epileptic medicine according to the cost per tablet in this section of the private health care sector. Carbamazepine and valproate were the two active ingredients that were most frequently prescribed as a single item on a prescription. After a cost–minimisation analysis was done, R134 685.66 could have been saved when generic substitution was implemented. The refill–adherence rate decreased as age increased. Only 30.46% of the trade names was refilled according to acceptable refill–adherence rates. The refill–adherence rate according to active ingredient showed that medicine items containing, phenobarbitone/vit B or gabapentin had the lowest unacceptable refill–adherence rate. The limitations for this study was stipulated and recommendations for further research regarding anti–epileptic medicine were also made. / Thesis (M.Pharm (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2011.