1. Long-term chemogenetic suppression of seizures in a multifocal rat model of temporal lobe epilepsy.
- Author
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Goossens MG, Boon P, Wadman W, Van den Haute C, Baekelandt V, Verstraete AG, Vonck K, Larsen LE, Sprengers M, Carrette E, Desloovere J, Meurs A, Delbeke J, Vanhove C, and Raedt R
- 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
- 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., 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., 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., 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., (© 2021 International League Against Epilepsy.)
- Published
- 2021
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