Back to Search
Start Over
Long-term chemogenetic suppression of seizures in a multifocal rat model of temporal lobe epilepsy.
- Source :
-
Epilepsia [Epilepsia] 2021 Mar; Vol. 62 (3), pp. 659-670. Date of Electronic Publication: 2021 Feb 11. - Publication Year :
- 2021
-
Abstract
- Objective: One third of epilepsy patients do not become seizure-free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long-term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons.<br />Methods: Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno-associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell-specific promotor targeting excitatory neurons. The effect of clozapine-mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long-term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction.<br />Results: In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD-expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long-term treatment with clozapine and olanzapine both resulted in significant seizure-suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection.<br />Significance: This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure-suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy.<br /> (© 2021 International League Against Epilepsy.)
- Subjects :
- Animals
Dentate Gyrus drug effects
Dentate Gyrus physiopathology
Disease Models, Animal
Evoked Potentials physiology
G-Protein-Coupled Receptor Kinases drug effects
G-Protein-Coupled Receptor Kinases genetics
Gene Editing methods
Hippocampus drug effects
Hippocampus physiopathology
Male
Rats
Rats, Sprague-Dawley
Receptors, Neurotransmitter drug effects
Seizures prevention & control
Anticonvulsants therapeutic use
Clozapine therapeutic use
Epilepsy, Temporal Lobe drug therapy
Olanzapine therapeutic use
Receptors, Neurotransmitter genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-1167
- Volume :
- 62
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Epilepsia
- Publication Type :
- Academic Journal
- Accession number :
- 33570167
- Full Text :
- https://doi.org/10.1111/epi.16840