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This study investigated whether IL-1β and TNF-α have a role in the pathophysiology of seizures by altering neuronal excitability and cell survival and also probed new targets to achieve an effective anticonvulsive action. The first set of experiments evaluated if acute and spontaneous seizures can be effectively inhibited by blocking the brain production of IL-1β using a selective inhibitor of caspase-1, the key enzyme specifically involved in the production of the releasable and biologically active form of IL-1β. Caspase-1 inhibition significantly reduced the number and the total time spent in seizures, indicating that this treatment represents an effective and novel anticonvulsive strategy.

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In this study, the whole-cell patch clamp technique and fura-2 calcium (Ca²⁺) imaging techniques were employed to investigate and compare the effects of the novel antiepileptic/ antihyperalgesic drugs pregabalin and gabapentin. Investigations were done on cultured dorsal root ganglion neurones as they form a neuronal system that is a potential target for gabapentin/pregabalin pain control. The effects of pregabalin on the action potential properties of hyperexcitable multiple-firing cells were similar to those previously found for gabapentin. The changes on action potential properties suggested that pregabalin and gabapentin inhibition of repetitive firing of action potential spikes in DRG neurones is due to inhibition of Ca²⁺ dependent K⁺currents as a result of Ca²⁺ current attenuation. Pregabalin and gabapentin inhibited voltage-activated Ca²⁺ currents to a similar maximal level and no additive inhibition was seen during simultaneous application of both drugs, suggesting a common site of action. The current inhibited was not conducted by L-type voltage-activated Ca²⁺ channels and was not due to a shift in the voltage dependence of activation. The continual presence of GABA or the GABA_B receptor antagonist CGP52432 or intracellular photorelease of GTP-<span style='font-family:Symbol'>g-S had no effect on pregabalin-induced inhibition of Ca²⁺currents. Inhibition of voltage-dependent Ca²⁺ current by pregabalin did not involve the actions a G-protein coupled receptor sensitive to the selective modulator SCH-202676 and unlike previous findings for gabapentin, pertussis toxin pre-treatment did not effect inhibition of Ca²⁺ currents. Ca²⁺-imaging techniques supported the magnitude of inhibition produced by pregabalin but also indicated the possibility of pregabalin having other actions that could produce an apparent increase in intracellular Ca²⁺ flux. This research indicates that pregabalin reduces excitatory properties of cultured DRG neurones by modulating both voltage-activated Ca²⁺ and K⁺channels and its pharmacological activity is similar to that of gabapentin.

No description available.

Dans le cadre du programme commun d’études pharmaco-épidémiologiques de la caisse nationale de l'assurance maladie et de l’agence nationale de sécurité du médicament, visant à évaluer l'impact sanitaire en France de l'exposition in utero à l’acide valproïque à partir des bases de données médico-administratives (BDMA) françaises, l’objectif de cette thèse était d’étudier l’utilisation des antiépileptiques pendant la grossesse et les risques de malformations congénitales et de troubles neuro-développementaux associés chez l’enfant. Le premier volet de cette thèse a consisté à formaliser et publier un algorithme d’identification des grossesses spécifiquement adapté aux BDMA françaises. L’application de cet algorithme à la description de l’utilisation des antiépileptiques pendant la grossesse a permis d’estimer à 6,7‰ la prévalence de l’utilisation des antiépileptiques pendant la grossesse et de montrer une baisse de l’utilisation des antiépileptiques de première génération, en particulier de l’acide valproïque, au bénéfice des antiépileptiques de deuxième génération entre 2007 et 2014. Dans le deuxième volet de cette thèse, l’exposition in utero à l’acide valproïque a été retrouvée associée à une augmentation du risque d’un grand nombre des malformations congénitales majeures (MCM) étudiées, avec une relation dose-effet pour les MCM les plus fréquentes, et l’exposition in utero au topiramate à une augmentation du risque de fentes oro-faciales. Des signaux relatifs à la prégabaline, au clonazépam et au phénobarbital ont aussi été identifiés. Dans le troisième volet de cette thèse, l’exposition in utero à l’acide valproïque a été retrouvée associée à une augmentation du risque de chacun des événements neuro-développementaux précoces étudiés versus lamotrigine, avec une relation dose-effet, à l’inverse des autres antiépileptiques. La réalisation d’études pharmaco-épidémiologiques à partir des BDMA françaises a permis aux autorités sanitaires de fournir rapidement des données sur l’utilisation des antiépileptiques pendant la grossesse en France. La réalisation de ces études a aussi permis de participer à l’enrichissement de la littérature observationnelle internationale sur les conséquences de l’exposition in utero aux antiépileptiques pour l’enfant à naitre. / The works of this thesis have been carried out within a programme of pharmacoepidemiological studies initiated by the National Agency of Medicine and Health Product Safety (ANSM) and the National Health Insurance fund (Cnam) in order to evaluate the public health situation in relation to prenatal exposure to valproic acid in France on the basis of the French health care databases. The objective of this thesis was to study antiepileptic drug (AED) use during pregnancy and the risks of congenital malformations and neurodevelopmental disorders associated with prenatal exposure to these drugs. In a first study, we developed an algorithm to identify pregnancy episodes and related outcomes using the French health care claims databases and applied it to study AED use during pregnancy between 2007 and 2014. Over the study period, 6.7 per 1000 pregnancies were exposed to an AED. The use of newer AEDs increased concomitantly with the decreased use of valproic acid and the other older AEDs. In a second study, prenatal exposure to valproic acid was found to be associated with a wide range of malformations among those investigated, with a dose-response relationship for half of them, and prenatal exposure to topiramate with an increased risk of cleft lip with or without cleft palate. Signals concerning pregabalin, clonazepam and phenobarbital have also been identified. In a third study, prenatal exposure to valproic acid was found to be associated with increased risks of all early neurodevelopmental outcomes investigated compared with lamotrigine, with a dose-response relationship. Prenatal exposure to the other AEDs was not associated with an increased risk of any of these neurodevelopmental outcomes versus lamotrigine. Conducting pharmacoepidemiological studies based on the French health care databases enabled the health authorities to rapidly provide data on the use of AED during pregnancy in France. It also brought additional evidence to the international observational literature on the consequences of prenatal exposure to AEDs for the unborn child.