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. 2021 Sep;42(9):1409-1421.
doi: 10.1038/s41401-020-00558-4. Epub 2020 Nov 19.

Ginsenoside Rg1 exerts neuroprotective effects in 3-nitropronpionic acid-induced mouse model of Huntington's disease via suppressing MAPKs and NF-κB pathways in the striatum

Xiong Yang  1 , Shi-Feng Chu  1 , Zhen-Zhen Wang  1 , Fang-Fang Li  1 , Yu-He Yuan  1 , Nai-Hong Chen  2
Affiliations

Ginsenoside Rg1 exerts neuroprotective effects in 3-nitropronpionic acid-induced mouse model of Huntington's disease via suppressing MAPKs and NF-κB pathways in the striatum

Xiong Yang et al. Acta Pharmacol Sin. 2021 Sep.

Abstract

Huntington's disease (HD) is one of main neurodegenerative diseases, characterized by striatal atrophy, involuntary movements, and motor incoordination. Ginsenoside Rg1 (Rg1), an active ingredient in ginseng, possesses a variety of neuroprotective effects with low toxicity and side effects. In this study, we investigated the potential therapeutic effects of Rg1 in a mouse model of HD and explored the underlying mechanisms. HD was induced in mice by injection of 3-nitropropionic acid (3-NP, i.p.) for 4 days. From the first day of 3-NP injection, the mice were administered Rg1 (10, 20, 40 mg·kg-1, p.o.) for 5 days. We showed that oral pretreatment with Rg1 alleviated 3-NP-induced body weight loss and behavioral defects. Furthermore, pretreatment with Rg1 ameliorated 3-NP-induced neuronal loss and ultrastructural morphological damage in the striatum. Moreover, pretreatment with Rg1 reduced 3-NP-induced apoptosis and inhibited the activation of microglia, inflammatory mediators in the striatum. We revealed that Rg1 exerted neuroprotective effects by suppressing 3-NP-induced activation of the MAPKs and NF-κΒ signaling pathways in the striatum. Thus, our results suggest that Rg1 exerts therapeutic effects on 3-NP-induced HD mouse model via suppressing MAPKs and NF-κΒ signaling pathways. Rg1 may be served as a novel therapeutic option for HD.

Keywords: 3-nitropropionic acid; Huntington’s disease; MAPKs; NF-κB; ginsenoside Rg1; neuroprotective effects; striatum.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Scheme of the experimental procedure.
After a week of acclimatization, HD was induced in mice by injection of 3-NP twice daily for four days. The dose of 3-NP was 60 mg/kg on the first day, and 80 mg/kg 3-NP was administered from the second day to the fourth day. Half an hour before 3-NP injection, Rg1 was administered at doses of 10, 20, 40 mg/kg. The open field test and neurological scoring were carried out on the fifth day. All mice were sacrificed for further study.
Fig. 2
Fig. 2. Rg1 alleviated body weight loss and behavioral defects induced by 3-NP.
a The chemical structure of Rg1. b Changes of body weight across groups over 4 experimental days. c Neurological scores across groups on day 5. d Total distance traveled in the open field test across groups. Data are expressed as the mean ± SEM, n = 8. ###P < 0.001 vs control group; *P < 0.05, **P < 0.01 vs model group.
Fig. 3
Fig. 3. Rg1 ameliorated striatal neuronal loss induced by 3-NP.
a–g, a’-g’ Nissl staining of striatal neurons across groups. h The counting results of Nissl staining-positive cells in the striatum. i, j The representative blots and densitometry data for DARPP-32 in the striatum across groups. Data are expressed as the mean ± SEM, n = 3. ###P < 0.001 vs control group; *P < 0.05, **P < 0.01 vs model group. Scale bars, (a–g) 500 μm; (a’-g’) 50 μm.
Fig. 4
Fig. 4. Rg1 alleviated the striatal ultrastructural morphological damage induced by 3-NP.
a–d The representative photomicrographs of striatal neurons across the groups. e–h The representative TEM images of subcellular structures in the striatum across groups. i–l The representative photomicrographs of myelination in the striatum. m–p The ultrastructural morphology of the BBB across groups. Scale bars, (a–d) 5 μm; (e–p) 2 μm.
Fig. 5
Fig. 5. Rg1 reduced the striatal apoptosis induced by 3-NP.
a and c The representative blots and densitometry data for cleaved caspase-3 protein in the striatum across groups. b The activity of SDH in the striatum across groups. Data are expressed as the mean ± SEM, n = 3. ##P < 0.01 vs control group; *P < 0.05, **P < 0.01 vs model group.
Fig. 6
Fig. 6. Rg1 inhibited the striatal microglial activation induced by 3-NP.
a–g, a’–g’ The representative photomicrographs of immunofluorescence histochemical staining of Iba-1 in the striatum. i Quantitative analysis of Iba-1-positive cells in the striatum. h, j The representative blots and densitometry data for Iba-1 in the striatum across groups. Data are expressed as the mean ± SEM, n = 3. ##P < 0.01 vs control group; *P < 0.05, **P < 0.01 vs model group. Scale bars, (a–g, a’–g’) 25 μm.
Fig. 7
Fig. 7. Rg1 decreased the productions of proinflammatory cytokines induced by 3-NP.
a–g, a’–g’ The representative photomicrographs of IHC staining for TNF-α and IL-1β in the striatum across groups. h, h’ Quantitative analysis of TNF-α- and IL-1β-positive cells in the striatum across groups. Data are expressed as the mean ± SEM, n = 3. ###P < 0.001 vs control group; **P < 0.01 vs model group. Scale bars, (a–g, a’–g’) 100 μm.
Fig. 8
Fig. 8. Rg1 suppressed activations of the MAPKs and NF-κB pathways induced by 3-NP.
a–e The representative blots and densitometry data for p-p38, p-ERK, p-JNK, p-NF-κB p65 in the striatum across groups. Data are expressed as the mean ± SEM, n = 3. ###P < 0.001 vs control group; *P < 0.05, **P < 0.01 vs model group.
Fig. 9
Fig. 9. The schematic diagram for possible mechanisms of Rg1’s neuroprotective effects in 3-NP induced HD mouse model.
3-NP inhibits the activity of SDH in striatal cells, leading to mitochondrial dysfunction and the death of neurons in the striatum, and it also induces BBB disruption, which leads to the leakage of more peripheral proinflammatory cells and microglia into the CNS. In microglia, 3-NP induces the activation of the MAPK and NF-κB signaling pathways. Rg1 alleviates 3-NP-induced mitochondrial dysfunction and BBB breakdown, and it also contributes to the survival of striatal neurons by inhibiting striatal microglial activation, apoptosis, and the expression of proinflammatory cytokines induced by 3-NP. Moreover, Rg1 protects against striatal neuronal death by suppressing the activation of proteins in the MAPK and NF-κB signaling pathways.
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