Abstracts

Comparative analysis of clozapine and JHU37160 in chemogenetic seizure suppression in a mouse model for drug-resistant temporal lobe epilepsy

Abstract number : 237
Submission category : 2. Translational Research / 2B. Devices, Technologies, Stem Cells
Year : 2020
Submission ID : 2422583
Source : www.aesnet.org
Presentation date : 12/6/2020 12:00:00 PM
Published date : Nov 21, 2020, 02:24 AM

Authors :
Jana Desloovere, Ghent University; Paul Boon - Ghent University; Lars Emil Larsen - Ghent University; Marie-Gabrielle Goossens - Ghent University; Jean Delbeke - Ghent University; Evelien Carrette - Ghent University; Kristl Vonck - Ghent University; Alfre


Rationale:
More than one third of patients with epilepsy continue to have seizures despite treatment with anti-epileptic drugs (AEDs). In this study we evaluate whether selective silencing of excitatory hippocampal neurons using the inhibitory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) hM4Di leads to suppression of spontaneous hippocampal seizures in the intrahippocampal kainic acid (IHKA) mouse model for TLE using clozapine and the novel DREADD ligand JHU37160.
Method:
Mice (n=10) were unilaterally injected with kainic acid (0.2 µg/50 nl) in the right hippocampus. Ten weeks later, the KA-lesioned hippocampus was injected with 500nl adeno-associated viral vector carrying genes encoding hM4Di-HA protein (DREADD group, n=8) or control AAV (non-DREADD group, n=2) under transcriptional control of CamKIIalpha promotor, specific for excitatory neurons. Bipolar recording electrodes were implanted at the injection site. Mice were treated with DREADD-activators clozapine (0.1mg/kg) and JHU37160 (0.1mg/kg) or AED levetiracetam (800mg/kg).
Results:
In DREADD animals systemic administration of both clozapine and JHU37160 reduced the fraction of time in seizures (FTS). However, effects of JHU37160 were less potent compared to clozapine (p=0.051) and seizure suppression lasted shorter (22h and 34h suppression after JHU37160 and clozapine treatment resp., interaction drug*time p< 0.0001). In non-DREADD animals neither clozapine nor JHU37160 affected FTS. Effects of clozapine were much more potent compared to levetiracetam, which did not reduce FTS in DREADD nor control mice (p< 0.0001).
Conclusion:
These results show that a chemogenetic treatment can be used to efficiently suppress spontaneous seizures in the IHKA mouse model.  JHU37160 is a suitable chemogenetic agonist, however seizure suppressive effects lasted shorter compared to clozapine. Levetiracetam did not suppress seizures in this study. Chemogenetic treatment outstands the use of a very high dose of levetiracetam, indicating its potency to suppress drug-resistant seizures.
Funding:
:Fonds Wetenschappelijk Onderzoek. Grant Number 1S74519N
Translational Research