In vitro and in vivo characterization of Lu AA41178: A novel, brain penetrant, pan-selective Kv7 potassium channel opener with efficacy in preclinical models of epileptic seizures and psychiatric disorders
| Autor: | Mario Rottländer, Morten Grupe, Vibeke Nielsen, Anette Graven Sams, Anne-Marie Jacobsen, Henrik Sindal Jensen, Morten Grunnet, Jesper F. Bastlund, Kristen Frederiksen, Tau Benned-Jensen, Lasse Skibsbye, Bo Hjorth Bentzen |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty medicine.medical_treatment 03 medical and health sciences chemistry.chemical_compound Epilepsy Mice Xenopus laevis 0302 clinical medicine In vivo Seizures Medicine Animals Humans KCNQ2 Potassium Channel Rats Wistar Psychiatry Pharmacology Psychotropic Drugs Seizure threshold Dose-Response Relationship Drug business.industry GABAA receptor Retigabine Mental Disorders Brain medicine.disease Rats Mice Inbred C57BL Disease Models Animal 030104 developmental biology Anticonvulsant Treatment Outcome chemistry Antidepressant Potassium channel opener Anticonvulsants Female business 030217 neurology & neurosurgery |
| Zdroj: | European journal of pharmacology. 887 |
| ISSN: | 1879-0712 |
| Popis: | Activation of the voltage-gated Kv7 channels holds therapeutic promise in several neurological and psychiatric disorders, including epilepsy, schizophrenia, and depression. Here, we present a pharmacological characterization of Lu AA41178, a novel, pan-selective Kv7.2–7.5 opener, using both in vitro assays and a broad range of in vivo assays with relevance to epilepsy, schizophrenia, and depression. Electrophysiological characterization in Xenopus oocytes expressing human Kv7.2-Kv7.5 confirmed Lu AA41178 as a pan-selective opener of Kv7 channels by significantly left-shifting the activation threshold. Additionally, Lu AA41178 was tested in vitro for off-target effects, demonstrating a clean Kv7-selective profile, with no impact on common cardiac ion channels, and no potentiating activity on GABAA channels. Lu AA41178 was evaluated across preclinical in vivo assays with relevance to neurological and psychiatric disorders. In the maximum electroshock seizure threshold test and PTZ seizure threshold test, Lu AA41178 significantly increased the seizure thresholds in mice, demonstrating anticonvulsant efficacy. Lu AA41178 demonstrated antipsychotic-like activity by reducing amphetamine-induced hyperlocomotion in mice as well as lowering conditioned avoidance responses in rats. In the mouse forced swim test, a model with antidepressant predictivity, Lu AA41178 significantly reduced immobility. Additionally, behavioral effects typically observed with Kv7 openers was also characterized. In vivo assays were accompanied by plasma and brain exposures, revealing minimum effective plasma levels Lu AA41178, a potent opener of neuronal Kv7 channels demonstrate efficacy in assays of epilepsy, schizophrenia and depression and might serve as a valuable tool for exploring the role of Kv7 channels in both neurological and psychiatric disorders. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect