Ginsenoside Re protects against kainate-induced neurotoxicity in mice by attenuating mitochondrial dysfunction through activation of the signal transducers and activators of transcription 3 signaling
- Authors
- Nguyen, YenNhiDoan; Jeong, JiHoon; Sharma, Naveen; Tran, Ngoc KimCuong; Tran, Hoang-Yen Phi; Dang, Duy-Khanh; Park, JungHoon; Byun, Jae Kyung; Ko, Sung Kwon; Nah, Seung-Yeol; Kim, Hyoung-Chun; Shin, Eun-Joo
- Issue Date
- Apr-2024
- Publisher
- TAYLOR & FRANCIS LTD
- Keywords
- Hippocampus; IL-6 knockout mice; Kainate seizures; Mitochondrial dysfunction; Oxidative stress; STAT3 signaling
- Citation
- Free radical research, v.58, no.4, pp 276 - 292
- Pages
- 17
- Journal Title
- Free radical research
- Volume
- 58
- Number
- 4
- Start Page
- 276
- End Page
- 292
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/73495
- DOI
- 10.1080/10715762.2024.2341885
- ISSN
- 1071-5762
1029-2470
- Abstract
- It was demonstrated that ginsenosides exert anti-convulsive potentials and interleukin-6 (IL-6) is protective from excitotoxicity induced by kainate (KA), a model of temporal lobe epilepsy. Ginsenosides-mediated mitochondrial recovery is essential for attenuating KA-induced neurotoxicity, however, little is known about the effects of ginsenoside Re (GRe), one of the major ginsenosides. In this study, GRe significantly attenuated KA-induced seizures in mice. KA-induced redox changes were more evident in mitochondrial fraction than in cytosolic fraction in the hippocampus of mice. GRe significantly attenuated KA-induced mitochondrial oxidative stress (i.e., increases in reactive oxygen species, 4-hydroxynonenal, and protein carbonyl) and mitochondrial dysfunction (i.e., the increase in intra-mitochondrial Ca2+ and the decrease in mitochondrial membrane potential). GRe or mitochondrial protectant cyclosporin A restored phospho-signal transducers and activators of transcription 3 (STAT3) and IL-6 levels reduced by KA, and the effects of GRe were reversed by the JAK2 inhibitor AG490 and the mitochondrial toxin 3-nitropropionic acid (3-NP). Thus, we used IL-6 knockout (KO) mice to investigate whether the interaction between STAT3 and IL-6 is involved in the GRe effects. Importantly, KA-induced reduction of manganese superoxide dismutase (SOD-2) levels and neurodegeneration (i.e., astroglial inhibition, microglial activation, and neuronal loss) were more prominent in IL-6 KO than in wild-type (WT) mice. These KA-induced detrimental effects were attenuated by GRe in WT and, unexpectedly, IL-6 KO mice, which were counteracted by AG490 and 3-NP. Our results suggest that GRe attenuates KA-induced neurodegeneration via modulating mitochondrial oxidative burden, mitochondrial dysfunction, and STAT3 signaling in mice.
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