Pharmacological and genetic modulation of the endocannabinoid system

Rüden, Eva-Lotta von (2015): Pharmacological and genetic modulation of the endocannabinoid system: Evaluation of preventive strategies in the amygdala kindling model of temporal lobe epilepsy. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Epilepsy is one of the most common chronic neurological diseases worldwide and the prevention of epileptogenesis is so far unmet. A major challenge in epilepsy research is the development of new therapeutic approaches for patients with therapy-resistant epilepsies, for epilepsy prevention and for disease modification. The endocannabinoid system serves as a retrograde negative feedback mechanism and one of its key functions is regulating neuronal activity within the central nervous system. Thus, the endocannabinoid system can be considered a putative target for central nervous system diseases including epilepsies. The purpose of this thesis was to evaluate the impact of the endocannabinoid and endovanilloid systems on both epileptogenesis and ictogenesis. Therefore, I modulated the systems pharmacologically and genetically and analyzed the impact on the generation of a hyperexcitable neuronal network as well as on ictogenesis in the kindling model of temporal lobe epilepsy. In addition, the impact of seizures on associated cellular alterations, like CB1-receptor (CB1R) expression and neurogenesis, was evaluated. I established that the endocannabinoid system affects seizure and afterdischarge duration dependent on the neuronal subpopulation being modulated. Genetic deletion of CB1Rs from GABAergic forebrain neurons caused shorter seizure duration. Deletion of CB1R from principal neurons of the forebrain and pharmacological antagonism with rimonabant (5 mg/kg) resulted in the opposite effect. Along with these findings, the CB1R density was increased in mice with recurrent induced seizures. However, neither genetic knockout nor pharmacological antagonism had any impact on the development of generalized seizures. In contrast to genetic deletion or pharmacological blockade of CB1Rs, modulation of transient receptor potential vanilloid receptor 1 (TRPV1) neither genetically nor pharmacologically with SB366791 (1 mg/kg) had an effect on the duration of behavioral or electrographic seizure activity. Pharmacological blockade of the 2-arachidonoylglycerol degrading enzyme, monoacylglycerol lipase (MAGL) with JZL184 (8 mg/kg), delayed the development of generalized seizures and decreased seizure and afterdischarge durations whereas in fully-kindled mice JZL184 (4, 8 and 16 mg/kg) had no relevant effects on associated seizure parameters. In addition, I confirmed by the use of conditional CB1R knockout mice that these effects are CB1R mediated. In conclusion, my findings support the concept that the endocannabinoid system may be a therapeutic target for decreasing seizure duration and that it is involved in terminating seizures as an endogenous mechanism. Moreover, targeting MAGL may be a promising strategy for an antiepileptogenic approach. Respective strategies are of particular interest for the management of long-lasting refractory status epilepticus and cluster seizures as well as for the prevention of the development of symptomatic epilepsies after an initial insult.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: epileptogenesis, seizure, ictogenesis, CB1, hyperexcitable network
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 30. Januar 2015
• 1. Bericht­erstatter:in: Potschka, Heidrun