Cimicifuga racemosa Extract Ze 450 Re-Balances Energy Metabolism and Promotes Longevity.

Malena Rabenau,Veronika Butterweck,Sylvia Krippner,Madeline Günther,Gunter P Eckert,Carsten Culmsee,Jürgen Drewe,Benjamin Dillberger,Georg Boonen

doi:10.3390/antiox10091432

Abstract

Recently, we reported that the Cimicifuga racemosa extract Ze 450 mediated protection from oxidative cell damage through a metabolic shift from oxidative phosphorylation to glycolysis. Here, we investigated the molecular mechanisms underlying the effects of Ze 450 against ferroptosis in neuronal cells, with a particular focus on mitochondria. The effects of Ze 450 on respiratory complex activity and hallmarks of ferroptosis were studied in isolated mitochondria and in cultured neuronal cells, respectively. In addition, Caenorhabditis elegans served as a model organism to study mitochondrial damage and longevity in vivo. We found that Ze 450 directly inhibited complex I activity in mitochondria and enhanced the metabolic shift towards glycolysis via cMyc and HIF1α regulation. The protective effects against ferroptosis were mediated independently of estrogen receptor activation and were distinct from effects exerted by metformin. In vivo, Ze 450 protected C. elegans from the mitochondrial toxin paraquat and promoted longevity in a dose-dependent manner. In conclusion, Ze 450 mediated a metabolic shift to glycolysis via direct effects on mitochondria and altered cell signaling, thereby promoting sustained cellular resilience to oxidative stress in vitro and in vivo.

Highlights

Cimicifuga racemosa (L.) Nutt. (Ranunculaceae) extracts have obtained a “well-established use” status in the treatment of menopausal complaints in the Committee of Herbal Medicinal Products conclusions included in the Monograph “Black Cohosh” of the European Medicines Agency (EMA/265439/2018)
HT22 neuronal cells were challenged with erastin in the presence of the glycolysis inhibitor 2-deoxyglucose; 2-NDBG, (2-(N-(7Nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxyglucose (2-DG)
The results clearly show that Ze 450 is protective against erastin-mediated oxidative insult, but in the presence of

Summary

Introduction

Cimicifuga racemosa (L.) Nutt. (Ranunculaceae) (synonym of the accepted nameActaea racemosa L.) extracts have obtained a “well-established use” status in the treatment of menopausal complaints in the Committee of Herbal Medicinal Products conclusions included in the Monograph “Black Cohosh” of the European Medicines Agency (EMA/265439/2018). Climacteric symptoms include sweating, insomnia, mood changes, headache, vaginal dryness, and, most frequently, hot flushes [4]. It is well-known that during menopausal transition, the fluctuation of estrogen levels leads to alterations in central nervous system gene expression, neurotransmitter synthesis, and to an impairment of hypothalamic neuronal activity, including mitochondrial dysfunction and imbalanced redox homeostasis [5]. These alterations promote inflammatory processes and oxidative stress [6].

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