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. 2009 Oct;158(3):738-48.
doi: 10.1111/j.1476-5381.2009.00361.x. Epub 2009 Aug 24.

Ginsenoside Rg1 protects dopaminergic neurons in a rat model of Parkinson's disease through the IGF-I receptor signalling pathway

Li Xu  1 , Wen-Fang Chen, Man-Sau Wong
Affiliations

Ginsenoside Rg1 protects dopaminergic neurons in a rat model of Parkinson's disease through the IGF-I receptor signalling pathway

Li Xu et al. Br J Pharmacol. 2009 Oct.

Abstract

Background and purpose: We have shown that ginsenoside Rg1 is a novel class of potent phytoestrogen and activates insulin-like growth factor-I receptor (IGF-IR) signalling pathway in human breast cancer MCF-7 cells. The present study tested the hypothesis that the neuroprotective actions of Rg1 involved activation of the IGF-IR signalling pathway in a rat model of Parkinson's disease, induced by 6-hydroxydopamine (6-OHDA).

Experimental approach: Ovariectomized rats were infused unilaterally with 6-OHDA into the medial forebrain bundle to lesion the nigrostriatal dopamine pathway and treated with Rg1 (1.5 h after 6-OHDA injections) in the absence or presence of the IGF-IR antagonist JB-1 (1 h before Rg1 injections). The rotational behaviour induced by apomorphine and the dopamine content in the striatum were studied. Protein and gene expression of tyrosine hydroxylase, dopamine transporter and Bcl-2 in the substantia nigra were also determined.

Key results: Rg1 treatment ameliorated the rotational behaviour induced by apomorphine in our model of nigrostriatal injury. This effect was partly blocked by JB-1. 6-OHDA significantly decreased the dopamine content of the striatum and treatment with Rg1 reversed this decrease. Treatment with Rg1 of 6-OHDA-lesioned rats reduced neurotoxicity, as measured by tyrosine hydroxylase, dopamine transporter and Bcl-2 protein and gene level in the substantia nigra. These effects were abolished by JB-1.

Conclusions and implications: These data provide the first evidence that Rg1 has neuroprotective effects on dopaminergic neurons in the 6-OHDA model of nigrostriatal injury and its actions might involve activation of the IGF-IR signalling pathway.

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Figures

Figure 1
Figure 1
Apomorphine-induced rotation behaviour. Rotational behaviour was counted for 30 min after i.p. injection of 0.05 mg·kg−1 apomorphine in the 6-hydroxydopamine (6-OHDA) group, Rg1 + 6-OHDA group, Rg1 + JB-1 + 6-OHDA group and JB-1 + 6-OHDA group. All values are expressed as mean ± SEM. n= 12. **P < 0.01, ***P < 0.001 versus the 6-OHDA group, ##P < 0.01 versus the Rg1 + 6-OHDA group.
Figure 2
Figure 2
Effect of Rg1 on the dopamine (DA) content of the striatum of rats with 6-hydroxydopamine (6-OHDA) induced Parkinson's disease and the blocking effect of JB-1 (ng·mg−1 wet weight of brain tissue). The unlesioned and lesioned side of striatum were used to determine the content of dopamine by HPLC. All values are expressed as mean ± SEM. n= 6. ***P < 0.001 versus the control group, ###P < 0.001 versus the lesioned side of 6-OHDA group.
Figure 3
Figure 3
Effect of Rg1 on the tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantia nigra pars compacta (SNpc) of the rat model of 6-hydroxydopamine (6-OHDA) induced Parkinson's disease and the blocking effect of JB-1. (A) Representative microphotographs of coronal sections immunostained for TH-IR neurons in the unlesioned side of the SNpc in the control (sham) group (a) and the lesioned side of the SNpc in the control (sham) group (b), 6-OHDA group (c), Rg1 + 6-OHDA group (d), Rg1 + JB-1 + 6-OHDA group (e) and JB-1 + 6-OHDA group (f). Bar = 30 µm. (B) Quantitative analysis of TH-IR neurons in the unlesioned and lesioned side of the SNpc. All values are expressed as mean ± SEM. n= 6. ***P < 0.001 versus the control group, ###P < 0.001 versus the lesioned side of 6-OHDA group.
Figure 4
Figure 4
Effect of Rg1 on the dopamine transporter-immunoreactivity (DAT-IR) neurons in the substantia nigra pars compacta (SNpc) of the rat model of Parkinson's disease induced by 6-hydroxydopamine (6-OHDA) and the blocking effect of JB-1. (A) Representative microphotographs of coronal sections immunostained for DAT-IR neurons the unlesioned side of the SNpc in the control (sham) group (a) and the lesioned side of the SNpc in the control (sham) group (b), 6-OHDA group (c), Rg1 + 6-OHDA group (d), Rg1 + JB-1 + 6-OHDA group (e) and JB-1 + 6-OHDA group (f). Bar = 30 µm. (B) Quantitative analysis of DAT-IR neurons in the unlesioned and lesioned side of the SNpc. All values are expressed as mean ± SEM. n= 6. ***P < 0.001 versus the control group, ###P < 0.001 versus the lesioned side of 6-OHDA group.
Figure 5
Figure 5
Effect of Rg1 on tyrosine hydroxylase (TH) gene expression in the substantia nigra (SN) of the rat model of Parkinson's disease induced by 6-hydroxydopamine (6-OHDA) and the blocking effect of JB-1. Total RNA was isolated from the unlesioned and lesioned side of SN and subjected to semi-quantitative RT-PCR analysis of TH and GAPDH mRNA expression. The TH mRNA expression level was expressed as a ratio of the expression of GAPDH. Summary results shown are expressed as mean ± SEM. n= 6. *P < 0.05, ***P < 0.001 versus the control group, ##P < 0.01 versus the lesioned side of 6-OHDA group.
Figure 6
Figure 6
Effect of Rg1 on dopamine transporter (DAT) gene expression in the substantia nigra (SN) of the rat model of Parkinson's disease induced by 6-hydroxydopamine (6-OHDA) and the blocking effect of JB-1. Total RNA was isolated from the unlesioned and lesioned side of the SN and subjected to semi-quantitative RT-PCR analysis of DAT and GAPDH mRNA expression. The DAT mRNA expression level was expressed as a ratio of the expression of GAPDH. Summary results shown are expressed as mean ± SEM. n= 6. ***P < 0.01 versus the control group, ###P < 0.01 versus the lesioned side of 6-OHDA group.
Figure 7
Figure 7
Effect of Rg1 on the Bcl-2 protein expression in the substantia nigra pars compacta (SNpc) of the rat model of Parkinson's disease induced by 6-hydroxydopamine (6-OHDA) and the blocking effect of JB-1. (A) Representative microphotographs of coronal sections immunostained for Bcl-2 protein expression in the unlesioned side of the SNpc in the control (sham) group (a) and the lesioned side of the SNpc in the control (sham) group (b), 6-OHDA group (c), Rg1 + 6-OHDA group (d), Rg1 + JB-1 + 6-OHDA group (e) and JB-1 + 6-OHDA group (f). Bar = 30µm. (B) Quantitative analysis of Bcl-2 protein expression in the unlesioned and lesioned side of the SNpc. All values are expressed as mean ± SEM. n= 6. ***P < 0.001 versus the control group, ###P < 0.001 versus the lesioned side of 6-OHDA group.
None
Effect of Rg1 on Bcl-2 gene expression in the substantia nigra (SN) of the rat model of Parkinson's disease induced by 6-hydroxydopamine (6-OHDA) and the blocking effect of JB-1. Total RNA was isolated from the unlesioned and lesioned side of SN and subjected to semi-quantitative RT-PCR analysis of Bcl-2 and GAPDH mRNA expression. The Bcl-2 mRNA expression level was expressed as a ratio of the expression of GAPDH. Summary results shown are expressed as mean ± SEM. n= 6. **P < 0.01, ***P < 0.001 versus the control group, ###P < 0.001 versus the lesioned side of 6-OHDA group.
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