WEKO3
アイテム
Chemogenetic suppression of pharmacologically induced frontal lobe epilepsy in a macaque monkey
https://repo.qst.go.jp/records/84373
https://repo.qst.go.jp/records/8437339bec995-f6f4-499b-bb32-8f83f50f66f4
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2021-12-23 | |||||
| タイトル | ||||||
| タイトル | Chemogenetic suppression of pharmacologically induced frontal lobe epilepsy in a macaque monkey | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Naohisa, Miyakawa
× Naohisa, Miyakawa× Yuji, Nagai× Kawasaki, Keisuke× Yukiko, Hori× Kei, Oyama× Asumi, Orihara× Matsuo, Takeshi× Ken-ichi, Inoue× Takada, Masahiko× Tetsuya, Suhara× Makoto, Higuchi× Takafumi, Minamimoto× Naohisa, Miyakawa× Yuji, Nagai× Yukiko, Hori× Kei, Oyama× Asumi, Orihara× Tetsuya, Suhara× Makoto, Higuchi× Takafumi, Minamimoto |
|||||
| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Rationale: Medical treatments and surgical lesions of epilepsy sometimes lead to unexpected side effects by affecting the surrounding normal tissues, and therefore, a more focused and on-demand approach is desirable. DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) is a recently developed “chemogenetics” tool that combines genetically introduced functional proteins (artificial receptors) and pharmacologically introduced chemicals (actuator drugs), offering focused and on-demand control of neuronal activities. We have recently developed a potent and selective actuator drug, Deschloroclozapine (DCZ), whose radiolabeled form can be used as a PET tracer to monitor DREADD expression in vivo. This study examined the utility of DREADDs on epilepsy treatment using a pharmacological model of epilepsy in a non-human primate (NHP). Methods: We injected virus vectors carrying hM4Di, an inhibitory DREADD gene (AAV2.1-hSyn-FLAG-hM4Di-IRES-AcGFP) to the putative hand/arm-region of the motor cortex in a cynomolgus macaque. Five weeks after the vector injection, hM4Di expression was confirmed using PET imaging with [11C]DCZ. We performed additional surgery to open a cranial window and placed an epidural electrocorticogram (ECoG) electrode array and a chronic chamber to approach the target region. Acute injections of bicuculline methiodide (6~12 µg) into the hM4Di-expressing region were conducted to start artificial epilepsy. DCZ (100~200 µg/kg) or control vehicle (2% DMSO in saline) were injected intramuscularly while we monitored the ECoG and video for seizure and body responses. Nissl and anti-GFP antibody staining were performed after the animal was euthanized, and cardially fixated. Results: Bicuculline injection caused paroxysmal cortical discharges with twitching and stiffening of the right arm. Recurrent cortical discharges (status epilepticus) spreading over a wider area of the cortex soon followed coinciding with hemi- and whole-body convulsions. Intramuscular injection of DCZ (100~200 µg/kg), but not the control vehicle (2% DMSO in saline), attenuated the body convulsions and spreading of recurrent seizures. Post-mortem histology confirmed the preserved cell condition of the DCZ-expressing cortex, but with some reduction of the layer 5 large pyramidal cells in the bicuculline-injected subregion. Conclusions: Although further study is needed, these preliminary results are the first to demonstrate in an NHP model that epilepsy can be suppressed using the DREADD system, suggesting its promising utility for future clinical applications. |
|||||
| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | AES 2021 | |||||
| 発表年月日 | ||||||
| 日付 | 2021-12-09 | |||||
| 日付タイプ | Issued | |||||
