TND1128, a 5-deazaflavin derivative with auto-redox ability, facilitates polarization of mitochondrial membrane potential (ΔΨm) and on-demand ATP synthesis in mice brain slices
{"title":"TND1128, a 5-deazaflavin derivative with auto-redox ability, facilitates polarization of mitochondrial membrane potential (ΔΨm) and on-demand ATP synthesis in mice brain slices","authors":"Nanae Takahashi , Tomohisa Nagamatsu , Norio Akaike , Yoshihisa Kudo","doi":"10.1016/j.jphs.2024.10.001","DOIUrl":null,"url":null,"abstract":"<div><div>TND1128, a 5-deazaflavin derivative, is a drug with self-redox ability. We examined the effect of TND1128 on the level of mitochondrial membrane potential (ΔΨ<sub>m</sub>), which is the most critical motive power for the biosynthesis of ATP. We prepared brain slices from mice pretreated with TND1128 (0.1–10 mg/kg, intraperitoneally) and detected ΔΨ<sub>m</sub> level with JC-1, a fluorescence ΔΨ<sub>m</sub> indicator. We further examined the depolarization of ΔΨ<sub>m</sub> under 5-min exposure to 25 mM KCl-ACSF (25K-ACSF), which activated neuronal voltage-dependent Ca<sup>2+</sup> channels. We evaluated the effect of TND1128 by using the inverse number of the ΔΨ<sub>m</sub> value as the ATP synthesis index (ASI). The level of ΔΨ<sub>m</sub> increased significantly by 24-h pretreatment with TND1128 (10 mg/kg), and significantly higher depolarization of the ΔΨ<sub>m</sub> was observed with 25K-ACSF exposure than in non-treated control. We found a significant decrease in 25K-ACSF induced [Ca<sup>2+</sup>]<sub>c</sub> and [Ca<sup>2+</sup>]<sub>m</sub> levels in the TND1128-pretreated preparations. We confirmed the dose and time-dependent facilitatory effects of TND1128 on the ASI. This study suggested that TND1128 could be incorporated into the TCA cycle and electron transfer chains to facilitate the polarization of ΔΨ<sub>m</sub> and activate on-demand ATP synthesis. TND1128 might rescue neurons in various brain diseases caused by energy defects. (198)</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 4","pages":"Pages 218-229"},"PeriodicalIF":3.0000,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of pharmacological sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1347861324000677","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
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Abstract
TND1128, a 5-deazaflavin derivative, is a drug with self-redox ability. We examined the effect of TND1128 on the level of mitochondrial membrane potential (ΔΨm), which is the most critical motive power for the biosynthesis of ATP. We prepared brain slices from mice pretreated with TND1128 (0.1–10 mg/kg, intraperitoneally) and detected ΔΨm level with JC-1, a fluorescence ΔΨm indicator. We further examined the depolarization of ΔΨm under 5-min exposure to 25 mM KCl-ACSF (25K-ACSF), which activated neuronal voltage-dependent Ca2+ channels. We evaluated the effect of TND1128 by using the inverse number of the ΔΨm value as the ATP synthesis index (ASI). The level of ΔΨm increased significantly by 24-h pretreatment with TND1128 (10 mg/kg), and significantly higher depolarization of the ΔΨm was observed with 25K-ACSF exposure than in non-treated control. We found a significant decrease in 25K-ACSF induced [Ca2+]c and [Ca2+]m levels in the TND1128-pretreated preparations. We confirmed the dose and time-dependent facilitatory effects of TND1128 on the ASI. This study suggested that TND1128 could be incorporated into the TCA cycle and electron transfer chains to facilitate the polarization of ΔΨm and activate on-demand ATP synthesis. TND1128 might rescue neurons in various brain diseases caused by energy defects. (198)
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