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

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

Publication date: Mar 07, 2019

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-_705B (NF-_705B) 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.

Jang, M., Choi, J.H., Chang, Y., Lee, S.J., Nah, S.Y., and Cho, I.H. Gintonin, a ginseng-derived ingredient, as a novel therapeutic strategy for Huntington’s disease: Activation of the Nrf2 pathway through lysophosphatidic acid receptors. 06394. 2019 Brain Behav Immun.

Concepts Keywords
Acid Apoptosis
Antagonist Neuroprotection
Antioxidant Striatum
Apoptosis LPAR1
DJ NFE2L2
Erythroid Lysophosphatidic acid receptor
Ginseng Gintonin
Huntingtin Cell biology
Huntington G protein-coupled receptors
IL 1 Branches of biology
Inflammation Mitochondrial dysfunction
Inflammatory Mediators
INOS
Intoxication
Ligand
Lysophosphatidic Acid
Mitochondrial
Mitogen
MRNA
Mutant
N171
Neurodegenerative Diseases
Neurological
Neuroprotective
Nrf2
Receptor
Receptors
Serotype
Striatal
Striatum
Succinate Dehydrogenase
TNF
Toxicity
Vector
Viral

Semantics

Type Source Name
gene UNIPROT IL1B
pathway BSID Apoptosis
drug DRUGBANK Succinic acid
pathway BSID Neurodegenerative Diseases
disease MESH neurodegenerative diseases
disease MESH inflammation
drug DRUGBANK Ginseng
pathway BSID NRF2 pathway
disease MESH syndromes
gene UNIPROT LPA
gene UNIPROT SLC6A4
gene UNIPROT HTT
gene UNIPROT LPAR1
gene UNIPROT GABPA
gene UNIPROT NFE2L2
gene UNIPROT NOS2
gene UNIPROT ISYNA1
gene UNIPROT PTGS2
gene UNIPROT IL6
gene UNIPROT TNF

Original Article

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