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

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 (ΔΨ_m), 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_m level with JC-1, a fluorescence ΔΨ_m indicator. We further examined the depolarization of ΔΨ_m 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 ΔΨ_m value as the ATP synthesis index (ASI). The level of ΔΨ_m increased significantly by 24-h pretreatment with TND1128 (10 mg/kg), and significantly higher depolarization of the ΔΨ_m 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 ΔΨ_m and activate on-demand ATP synthesis. TND1128 might rescue neurons in various brain diseases caused by energy defects. (198)