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Ginsenoside Re Protects Trimethyltin-Induced Neurotoxicity via Activation of IL-6-Mediated Phosphoinositol 3-Kinase/Akt Signaling in Mice

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Abstract

Ginseng (Panax ginseng), an herbal medicine, has been used to prevent neurodegenerative disorders. Ginsenosides (e.g., Re, Rb1, or Rg1) were obtained from Korean mountain cultivated ginseng. The anticonvulsant activity of ginsenoside Re (20 mg/kg/day × 3) against trimethyltin (TMT) insult was the most pronounced out of ginsenosides (e.g., Re, Rb1, and Rg1). Re itself did not significantly alter tumor necrosis factor-α (TNF-α), interferon-ϒ (IFN-ϒ), and interleukin-1β (IL-1β) expression, however, it significantly increases the interleukin-6 (IL-6) expression. In addition, Re attenuated the TMT-induced decreases in IL-6 protein level. Therefore, IL-6 knockout (−/−) mice were employed to investigate whether Re requires IL-6-dependent neuroprotective activity against TMT toxicity. Re significantly attenuated TMT-induced lipid peroxidation, protein peroxidation, and reactive oxygen species in the hippocampus. Re-mediated antioxidant effects were more pronounced in IL-6 (−/−) mice than in WT mice. Consistently, TMT-induced increase in c-Fos-immunoreactivity (c-Fos-IR), TUNEL-positive cells, and nuclear chromatin clumping in the dentate gyrus of the hippocampus were significantly attenuated by Re. Furthermore, Re attenuated TMT-induced proapoptotic changes. Protective potentials by Re were comparable to those by recombinant IL-6 protein (rIL-6) against TMT-insult in IL-6 (−/−) mice. Moreover, treatment with a phosphoinositol 3-kinase (PI3K) inhibitor, LY294002 (1.6 µg, i.c.v) counteracted the protective potential mediated by Re or rIL-6 against TMT insult. The results suggest that ginsenoside Re requires IL-6-dependent PI3K/Akt signaling for its protective potential against TMT-induced neurotoxicity.

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Acknowledgements

This study was supported by a grant (Project No. S111415L020100) of the ‘‘Forestry Technology Projects’’ provided by the Korea Forest Service, and by the Basic Science Program through the National Research Foundation of Korea (NRF) funded by the ministry of Science, ICT & Future Planning (#NRF-2013R1A1A2060894 and #NRF-2016R1A1A1A050055201), Republic of Korea. Thu-Hien Thi Tu, Naveen Sharma, and Hai-Quyen Tran were supported by the BK21 PLUS program.

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    1. Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea

      Thu-Hien Thi Tu, Naveen Sharma, Eun-Joo Shin, Hai-Quyen Tran & Hyoung-Chun Kim

    2. Clinical Pharmacy, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea

      Yu Jeung Lee

    3. Pharmacology, College of Medicine, Chug-Ang University, Seoul, Republic of Korea

      Ji Hoon Jeong

    4. Headquarters of Forestry Support, Korea Forestry Promotion Institute, Seoul, 07570, Republic of Korea

      Jung Hwan Jeong

    5. Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea

      Seung Yeol Nah

    6. Physical Chemistry Department, University of Medicine and Pharmacy, Ho Chi Minh City, 760000, Vietnam

      Hoang-Yen Phi Tran

    7. Korean Society of Forest Environment Research, Namyangju, 12014, Republic of Korea

      Jae Kyung Byun

    8. Department of Oriental Medical Food & Nutrition, Semyung University, Jecheon, 27136, Republic of Korea

      Sung Kwon Ko

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    Tu, TH.T., Sharma, N., Shin, EJ. et al. Ginsenoside Re Protects Trimethyltin-Induced Neurotoxicity via Activation of IL-6-Mediated Phosphoinositol 3-Kinase/Akt Signaling in Mice. Neurochem Res 42, 3125–3139 (2017). https://doi.org/10.1007/s11064-017-2349-y

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