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Brain Behav Immun. 2019 Mar 7. pii: S0889-1591(18)30392-1. doi: 10.1016/j.bbi.2019.03.001. [Epub ahead of print]

Gintonin, a ginseng-derived ingredient, as a novel therapeutic strategy for Huntington's disease: Activation of the Nrf2 pathway through lysophosphatidic acid receptors.

Author information

1
Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
2
Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Science in Korean Medicine and Brain Korea 21 Plus Program, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.
3
Department of Neuroscience and Physiology, School of Dentistry, Seoul National University, Seoul 08826, Republic of Korea.
4
Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 05029, Republic of Korea.
5
Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Science in Korean Medicine and Brain Korea 21 Plus Program, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; Institute of Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: ihcho@khu.ac.kr.

Abstract

Gintonin (GT), a ginseng-derived lysophosphatidic acid receptor ligand, regulates various cellular effects and represses inflammation. However, little is known about the potential value of GT regarding inflammation in the neurodegenerative diseases, such as Huntington's disease (HD). In this study, we investigated whether GT could ameliorate the neurological impairment and striatal toxicity in cellular or animal model of HD. Pre-, co-, and onset-treatment with GT (25, 50, or 100 mg/kg/day, p.o.) alleviated the severity of neurological impairment and lethality following 3-nitropropionic acid (3-NPA). Pretreatment with GT also attenuated mitochondrial dysfunction i.e. succinate dehydrogenase and MitoSOX activities, apoptosis, microglial activation, and mRNA expression of inflammatory mediators i.e. IL-1β, IL-6, TNF-α, COX-2, and iNOS in the striatum after 3-NPA-intoxication. Its action mechanism was associated with lysophosphatidic acid receptors (LPARs) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway activations and the inhibition of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signaling pathways. These beneficial effects of GT were neutralized by pre-inhibiting LPARs with Ki16425 (a LPAR1/3 antagonist). Interestingly, GT reduced cell death and mutant huntingtin (HTT) aggregates in STHdh cells. It also mitigated neurological impairment in mice with adeno-associated viral (AAV) vector serotype DJ-mediated overexpression of N171-82Q-mutant HTT in the striatum. Taken together, our findings firstly suggested that GT has beneficial effects with a wide therapeutic time-window in 3-NPA-induced striatal toxicity by antioxidant and anti-inflammatory activities through LPA. In addition, GT exerts neuroprotective effects in STHdh cells and AAV vector-infected model of HD. Thus GT might be an innovative therapeutic candidate to treat HD-like syndromes.

KEYWORDS:

3-Nitropropionic acid; Adeno-associated viral vector; Gintonin; Huntington’s disease; Lysophosphatidic acid receptor; Nuclear factor erythroid 2-related factor 2

PMID:
30853569
DOI:
10.1016/j.bbi.2019.03.001

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