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Planta Med 2017; 83(17): 1342-1350
DOI: 10.1055/s-0043-111896
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Treatment with Mountain-Cultivated Ginseng Alleviates Trimethyltin-Induced Cognitive Impairments in Mice via IL-6-Dependent JAK2/STAT3/ERK Signaling

Thu-Hien Thi Tu   *
1   Neuropsychopharmacology and Toxicology Program, BK21 PLUS Project, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea
,
Naveen Sharma   *
1   Neuropsychopharmacology and Toxicology Program, BK21 PLUS Project, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea
,
Eun-Joo Shin
1   Neuropsychopharmacology and Toxicology Program, BK21 PLUS Project, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea
,
Hai-Quyen Tran
1   Neuropsychopharmacology and Toxicology Program, BK21 PLUS Project, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea
,
Yu Jeung Lee
2   Clinical Pharmacy, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea
,
Seung-Yeol Nah
3   Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea
,
Hoang-Yen Phi Tran
4   Physical Chemistry Department, University of Medicine and Pharmacy, Ho Chi Minh City, Viet Nam
,
Ji Hoon Jeong
5   Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
,
Jung Hwan Jeong
6   Headquarters of Forestry Support, Korea Forestry Promotion Institute, Seoul, Republic of Korea
,
Sung Kwon Ko
7   Department of Oriental Medical Food & Nutrition, Semyung University, Jecheon, Republic of Korea
,
Jae Kyung Byun
8   Korean society of forest environment research, Namyangju, Republic of Korea
,
Hyoung-Chun Kim
1   Neuropsychopharmacology and Toxicology Program, BK21 PLUS Project, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea
› Author Affiliations
Further Information

Publication History

received 21 December 2016
revised 02 May 2017

accepted 13 May 2017

Publication Date:
30 May 2017 (online)

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Abstract

Panax ginseng is the most widely used herbal medicine for improving cognitive functions. The pharmacological activity and underlying mechanisms of mountain-cultivated ginseng, however, have yet to be clearly elucidated, in particular, against trimethyltin-induced cognitive dysfunction. We previously reported that interleukin-6 plays a protective role against trimethyltin-induced cognitive dysfunction. Because of this, we have implemented a study system that uses interleukin-6 null (−/−) and wild-type mice. Interestingly, mountain-cultivated ginseng significantly upregulated interleukin-6 expression. With this study, we sought to determine whether the interleukin-6-dependent modulation of the Janus kinase 2/signal transducer activator of transcription 3 and extracellular signal-regulated kinase signaling network is also associated with the pharmacological activity of mountain-cultivated ginseng against trimethyltin-induced cognitive dysfunction. Trimethyltin treatment (2.4 mg/kg, intraperitoneal) causes the downregulation of Janus kinase 2/signal transducer activator of transcription 3, extracellular signal-regulated kinase signaling, and impairment of the cholinergic system. We found that mountain-cultivated ginseng treatment (50 mg/kg, intraperitoneal) significantly attenuated cognitive impairment normally induced by trimethyltin by upregulating p-Janus kinase 2/signal transducer activator of transcription 3, p-extracellular signal-regulated kinase signaling, and the cholinergic system. Trimethyltin-induced cognitive impairments were more pronounced in interleukin-6 (−/−) mice than wild-type mice, and they were markedly reduced by treatment with either mountain-cultivated ginseng or recombinant interleukin-6 protein (6 ng, intracerebroventricular). Additionally, treatment with either AG490 (20 mg/kg, intraperitoneal), a Janus kinase 2/signal transducer activator of transcription 3 inhibitor, or U0126 (2 µg/head, intracerebroventricular), an extracellular signal-regulated kinase inhibitor, reversed the effects of mountain-cultivated ginseng treatment. The effects of mountain-cultivated ginseng treatment were comparable to those of recombinant interleukin-6 protein in interleukin-6 (−/−) mice. Our results, therefore, suggest that mountain-cultivated ginseng acts through interleukin-6-dependent activation of Janus kinase 2/signal transducer activator of transcription 3/extracellular signal-regulated kinase signaling in order to reverse cognitive impairment caused by trimethyltin treatment.

Key words

cognitive dysfunction - IL-6 knockout mice - JAK2/STAT3/ERK signaling - cholinergic system - Panax ginseng - Araliaceae - trimethyltin

* Thu-Hien Thi Tu and Naveen Sharma contributed equally to this work.


Supporting Information

    The content and representative HPLC chromatogram for each ginsenoside in the MCG extract (Table 1S and Fig. 1S, respectively) as well as details of the HPLC analysis are available as Supporting Information.

  • Supporting Information
 

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