The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567) and a natural compound derivative (tanshinone IIA sulfonate) in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ) seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders.

The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567) and a natural compound derivative (tanshinone IIA sulfonate) in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ) seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders.

De nombreuses études expérimentales montrent que les canaux calciques activés par la dépolarisation membranaire, tout particulièrement les canaux calciques de type T (canaux T), jouent un rôle important dans la physiopathologie des épilepsies. Il existe trois isoformes des canaux T, Cav3.1, Cav3.2 et Cav3.3, toutes exprimées au niveau neuronal. De manière classique, c'est dans l'épilepsie absence où les canaux T ont été le plus étudiés. Les canaux T jouent également un rôle dans des modèles d'épilepsie partielle secondairement généralisée, comme le modèle pilocarpine qui mime l'épilepsie du lobe temporal (ELT). Jusqu'à présent ces canaux ne possédaient pas de pharmacologie spécifique, mais plusieurs molécules récemment synthétisées, en particulier le TTA-A2, apparaissent sélectives des canaux T. Le premier objectif de ma thèse était d'étudier l'implication des canaux T dans l'épileptogenèse. Pour cela nous avons traité des souris au TTA-A2 pendant la phase de latence du modèle pilocarpine (modèle ELT). Nos conditions expérimentales ne nous ont pas permis de conclure quant à une action protectrice du TTA-A2 dans ce modèle. Le deuxième objectif était d'étudier l'effet du TTA-A2 sur des modèles murins de convulsions généralisées : le modèle du Maximal Electroshock Seizure (MES) et le modèle pentylènetétrazole (PTZ). Deux lignées de souris inactivées pour les isoformes Cav3.1 ou Cav3.2 (KO Cav3.1 et KO Cav3.2) ont également été caractérisées dans cette étude. Nous montrons que le TTA-A2 réduit l'apparition des crises toniques dans le modèle MES et que les souris KO Cav3.1 sont également protégées, suggérant un rôle prépondérant des canaux Cav3.1 dans le développement des crises toniques. / Numerous experimental studies show that calcium channels activated by membrane depolarization, especially T-type calcium channels (T-channels), play an important role in the physiopathology of epilepsy. There are three T-channels isoforms, Cav3.1, Cav3.2 and Cav3.3, all expressed in neuronal level. Conventionally, T-channels were the most studied in absence epilepsy. T-channels are also involved in partial secondarily generalized epilepsy models, as the pilocarpine model that mimics temporal lobe epilepsy (TLE).Up to now, there was no specific pharmacology for this channels, but several molecules have recently been synthesized, particularly TTA-A2, appearing selective T-channels. The first goal of my thesis was to study the T-channels involvement in epileptogenesis. For this purpose we treated mice with TTA-A2 during the silent phase of the pilocarpine model (TLE model). Our experimental conditions do not allow us to conclude about a possible protective action of TTA-A2 on this model. The second goal was to study TTA-A2 effects on mice models of generalized seizures: the Maximal Electroshock model (MES) and the pentylenetetrazole model (PTZ). Two mice strains knock-out for Cav3.1 or Cav3.2 (KO Cav3.1 and KO Cav3.2) have also been characterized in this study. We show that the TTA-A2 reduces the appearance of tonic seizures in the MES model and the KO Cav3.1 mice are also protected, suggesting a preponderant role of Cav3.1 channels in the development of tonic seizures.

Tidigare forskning visar att ambulanssjuksköterskor upplever bristfällig utbildningsgrund samt känslor av bristande självförtroende och osäkerhet kopplat till vårdsituationer med den vuxna patienten med pågående krampanfall. Den forskning som finns etablerad omkring ambulanssjuksköterskors upplevelser av att möta den vuxna patienten med pågående kramp är dock begränsad. Ambulanssjuksköterskan har i sin yrkesutövning en förväntan på sig att inneha en handlingsberedskap för alla typer av patientärenden, så även för den vuxna patienten med pågående krampanfall. Krampanfall med tonisk-klonisk karaktär innebär ett komplext vårdmöte där ambulanssjuksköterskan måste ta ställning till multipla faktorer, både rörande en kritisk somatik samt patientens omvårdnadsmässiga behov. Studiens syfte är att beskriva ambulanssjuksköterskors upplevelse av att möta vuxna patienter med pågående epileptiskt anfall av tonisk-klonisk karaktär i prehospital miljö. Studien har genomförts som en kvalitativ, semistrukturerad intervjustudie med induktiv ansats. Genomförda intervjuer har analyserats utifrån en kvalitativ innehållsanalys och resulterade slutligen i huvudkategorin Ett vårdande som balanserar mellan trygghet och oförutsägbarhet, med efterföljande kategorier Mångbottnad upplevelse, Vårdrelationen och Prehospitalt vårdande. Resultatet visar på attambulanssjuksköterskor bär på en bred upplevelsegrund när det kommer till vårdmötet med denkrampande patienten, där känslor av osäkerhet och stress är vanlig förekommande. Ambulanssjuksköterskorna upplever även vårdmötet som utmanande i förhållande till faktorer som vårdmiljö, patientomhändertagande samt mötet med anhöriga. Ambulanssjuksköterskorna upplever att det i första hand är yrkeserfarenhet som utgör en trygghetsskapande grund i patientmötet. För att skapa förbättrade grundförutsättningar för vårdandet samt förstärka upplevelsen av trygghet för ambulanssjuksköterskor, bör ämnet lyftas tydligare inom utbildning och arbetsplatsrelaterad fortbildning. / Previous research shows that ambulance nurses experience a deficient educational basis as well as feelings of lack of self-confidence and uncertainty linked to care situations with the adult patient with ongoing seizures. However, the research that has been established about ambulance nurses' experiences of meeting the adult patient with ongoing convulsions is limited. In her professional practice, the ambulance nurse is expected to be ready to act for all types of patient matters, including for the adult patient with an ongoing seizure. Seizures with a tonic-clonic character involve a complex care encounter where the ambulance nurse must take a position on multiple factors, both concerning a critical somatic condition and the patient's nursing needs. The purpose of the study is to describe ambulance nurses' experience of meeting adult patients with ongoing epileptic seizures of tonic-clonic character in a prehospital environment. The study has been conducted as a qualitative, semi-structured interview study with an inductive approach. Conducted interviews have been analyzed based on a qualitative content analysis and finally resulted in the main category Care that balances between safety and unpredictability, with subsequent categories Multi-rooted experience, Care relationship and Pre-hospital care. The results show that ambulance nurses have a broad base of experience when it comes to the care meeting with the convulsing patient, where feelings of uncertainty and stress are common occurrences. The ambulance nurses also experience the care meeting as challenging in relation to factors such as the care environment, patient care and the meeting with relatives. The ambulance nurses feel that it is primarily professional experience that constitutes a security-creating basis in the patient encounter. In order to create improved basic conditions for care and strengthen the experience of security for ambulance nurses, the topic should be highlighted more clearly in education and workplace related continuing education.