Pharmaco‐genetic inhibition of pyramidal neurons retards hippocampal kindling‐induced epileptogenesis

Chen, Liying; Liang, Jing; Fan, Fudong; Ruan, Yuanyuan; Cheng, Heming; Wang, Yi; Chen, Zhong; Xu, Cenglin

doi:10.1111/cns.13434

Cited by 10 publications

(11 citation statements)

References 47 publications

(80 reference statements)

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“…Rapid hippocampal kindling was performed following the precise procedure from our previous studies. 19 , 20 , 21 Briefly, the after‐discharge threshold (ADT) of each mouse was determined (monophasic square‐wave pulses, 20 Hz, 1 ms/pulse, 40 pulses) with a constant‐current stimulator (SEN‐7203, SS‐202 J; Nihon kohden) and electroencephalograms (EEGs) were recorded with a Neuroscan system (NuAmps, Neuroscan System). The initial intensity started at 40 μA and was then increased in 20 μA steps with an 1 min interval.…”

Section: Methodsmentioning

confidence: 99%

Long‐term music adjuvant therapy enhances the efficacy of sub‐dose antiepileptic drugs in temporal lobe epilepsy

Nao

Shen

et al. 2021

CNS Neurosci Ther

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Aims Noninvasive music adjuvant therapy shows great potential in improving seizure control when combined with routine antiepileptic drugs. However, the diversity of previous music protocols has resulted in disparate outcomes. The optimized protocol and features for music adjuvant therapy are still not fully understood which limits its feasibility. Methods By applying different regimens of music therapy in various temporal lobe epilepsy models, we evaluated the effect of music in combination with sub‐dose drugs on epileptic seizures to determine the optimized protocol. Results A subgroup of kindled mice that were responsive to music adjuvant therapy was screened. In those mice, sub‐dose drugs which were noneffective on kindled seizures, alleviated seizure severity after 12 h/day Mozart K.448 for 14 days. Shorter durations of music therapy (2 and 6 h/day) were ineffective. Furthermore, only full‐length Mozart K.448, not its episodes or other music varieties, was capable of enhancing the efficacy of sub‐dose drugs. This music therapeutic effect was not due to increasing cerebral drug concentration, but instead was related with the modulation of seizure electroencephalogram (EEG) spectral powers in the hippocampus. Conclusion These results indicate that long‐term full‐length Mozart K.448 could enhance the anti‐seizure efficacy of sub‐dose drugs and may be a promising noninvasive adjuvant therapy for temporal lobe epilepsy.

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Section: Methodsmentioning

confidence: 99%

Long‐term music adjuvant therapy enhances the efficacy of sub‐dose antiepileptic drugs in temporal lobe epilepsy

Nao

Shen

et al. 2021

CNS Neurosci Ther

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“…Subsequently, all mice received 10 kindling stimulations daily (400 μA, 20 Hz, 2‐s trains, 1‐ms monophasic square‐wave pulses). Seizure severity was classified into seizure stages 1–5 according to the Racine scale, among which stages 1–3 were considered as focal seizures (FS) and stages 4–5 as generalized seizures (GS) 33 . The severity of seizure was scored by a trained observer who was unaware of the experimental groupings.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of hyperactivity of the dorsal raphe 5‐HTergic neurons ameliorates hippocampal seizure

Cheng

Lai

et al. 2021

CNS Neurosci Ther

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Aims Epilepsy, frequently comorbid with depression, easily develops drug resistance. Here, we investigated how dorsal raphe (DR) and its 5‐HTergic neurons are implicated in epilepsy. Methods In mouse hippocampal kindling model, using immunochemistry, calcium fiber photometry, and optogenetics, we investigated the causal role of DR 5‐HTergic neurons in seizure of temporal lobe epilepsy (TLE). Further, deep brain stimulation (DBS) of the DR with different frequencies was applied to test its effect on hippocampal seizure and depressive‐like behavior. Results Number of c‐fos+ neurons in the DR and calcium activities of DR 5‐HTergic neurons were both increased during kindling‐induced hippocampal seizures. Optogenetic inhibition, but not activation, of DR 5‐HTergic neurons conspicuously retarded seizure acquisition specially during the late period. For clinical translation, 1‐Hz‐specific, but not 20‐Hz or 100‐Hz, DBS of the DR retarded the acquisition of hippocampal seizure. This therapeutic effect may be mediated by the inhibition of DR 5‐HTergic neurons, as optogenetic activation of DR 5‐HTergic neurons reversed the anti‐seizure effects of 1‐Hz DR DBS. However, DBS treatment had no effect on depressive‐like behavior. Conclusion Inhibition of hyperactivity of DR 5‐HTergic neuron may present promising anti‐seizure effect and the DR may be a potential DBS target for the therapy of TLE.

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“…[14][15][16][17] The effect of DREADDs expressed in the hippocampus in chronic mouse models of epilepsy demonstrated initial success. 13,17,18 In chronic rat models, suppression of acute seizures using chemogenetic modulation of primary motor cortex 14 and midline thalamus 16 have been reported.…”

Section: Introductionmentioning

confidence: 99%

Long‐term chemogenetic suppression of seizures in a multifocal rat model of temporal lobe epilepsy

et al. 2021

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Summary 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.

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Pharmaco‐genetic inhibition of pyramidal neurons retards hippocampal kindling‐induced epileptogenesis

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 10 publications

References 47 publications

Long‐term music adjuvant therapy enhances the efficacy of sub‐dose antiepileptic drugs in temporal lobe epilepsy

Long‐term music adjuvant therapy enhances the efficacy of sub‐dose antiepileptic drugs in temporal lobe epilepsy

Inhibition of hyperactivity of the dorsal raphe 5‐HTergic neurons ameliorates hippocampal seizure

Long‐term chemogenetic suppression of seizures in a multifocal rat model of temporal lobe epilepsy

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