Targeting the prostaglandin E2 EP1 receptor and cyclooxygenase-2 in the amygdala kindling model in mice.
The prostaglandin E2 EP1 receptor as well as the inflammatory enzyme cyclooxygenase-2 have been suggested as targets for disease modulation, improvement of therapeutic response, and restoration of pharmacosensitivity in epilepsies. Translational development of respective add-on approaches requires careful analysis of putative effects on ictogenesis. Therefore we evaluated the impact of the EP1 receptor antagonist SC-51089, the EP1 receptor agonist misoprostol and the COX-2 inhibitors celecoxib and NS-398 in the mouse amygdala kindling model of temporal lobe epilepsy. Neither celecoxib nor NS-398 affected the generation, spread and termination of seizure activity. Whereas SC-51089 did not affect the seizure threshold, the highest dose (30mg/kg) significantly decreased the seizure severity when administered 60min before stimulation. Moreover, SC-51089 significantly prolonged seizure duration at the highest dose. The EP1 receptor agonist misoprostol exerted contrasting effects on seizure duration with a significant decrease in the duration of motor seizure activity. The data suggest that doses of COX-2 inhibitors and EP1 receptor antagonists which exert disease modulating or antiepileptic drug potentiating effects do not negatively affect seizure control in temporal lobe epilepsy. The contrasting impact of the EP1 receptor antagonist and agonist suggests that EP1 receptors can influence endogenous mechanisms involved in termination of seizure activity.
Fischborn
Sarah Verena
SV
Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilian-University, Koeniginstr. 16, D-80539 Munich, Germany. potschka@pharmtox.vetmed.uni-muenchen.de
Soerensen
Jonna
J
Potschka
Heidrun
H
D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism* / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D006834:Hydrazines / Q000008:administration & dosage; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D010077:Oxazepines / Q000008:administration & dosage; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors* / Q000502:physiology
D052246:Cyclooxygenase 2 Inhibitors; D006834:Hydrazines; D010077:Oxazepines; D058306:Receptors, Prostaglandin E, EP1 Subtype; C086836:SC 51089; D051546:Cyclooxygenase 2; D015232:Dinoprostone