Neuroprotective Effects Of Ginsenoside Rg1 On Nigrostriatal System In The Ovariectomized Rat Model Of Pakinson's Disease And Its Mechanism

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by selectively dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and the depletion of dopamine (DA) content in the striatum. Epidemiologic studys revealed that the prevalence of Parkinson disease is higher in males than in females. Estrogens may be involved the reason for the gender difference. Women treated with estrogen replacement therapy exhibit a reduced severity of PD. Although data suggest beneficial effects of estrogen in PD and the other senile diseases, many women turn to phtoestrogens as an alternative to hormone replacement therapy because of the undesirable side effects, such as increased risk of breast and endometrial cancer. Phytoestrogens are plant-derived compounds that structurally or functional mimic mammalian estrogens. Ginsenosides Rg1, the principal active components of ginseng, has neurotropic and neuroprotective effects on the nervous system either in vivo or in vitro, but the detail mechanism is not very clear. Our present study aims at investigating the neuroprotective effects and the possible mechanisms involved in mediating ginsenoside Rg1 actions in 6-OHDA-lesioned ovariectomized rat model of Parkinson's disease. The contents of DA and its metabolites dihydroxy-phenylacetic acid (DOPAC) and homovanillic (HVA) in the striatum were determined by using high performance liquid chromatography-electrical chemical detection (HPLC-ECD). Results were as follows:1. Rg1 can ameliorate the rat's rotation behavior induced by apomorphine. This effect could be partly blocked by IGF-1R antagonist JB-1 or ER antagonist ICI182,780.2. The DA, DOPAC and HVA levels in the Str of the injured side of PD rats were significantly decreased compared with the intact side (P<0.01). Rg1 treatment could reverse the decrease of DA, DOPAC and HVA induced by 6-OHDA and this effect could be completely blocked by JB-1 or ICI182,780 (P<0.01).3. The numbers of TH immunoreactive neurons and gene expressions decreased in the injured side of SN compared with that of uninjured side of SN (P<0.01), Rg1 treatment could increase TH immunoreactive neurons and gene expressions in the injured side of SN compared to the 6-OHDA group. This effect could be blocked by IGF-1R antagonist JB-1 or ER antagonist IC1182,780 (P<0.01).4. 6-OHDA -challenge with Rg1 treatment demonstrated reduced neurotoxicity with DAT protein and gene level in the substantial nigra. Cotreatment with JB-1 or ICI182,780 completely abolished the neuroprotective effects of Rg1 on the DAT protein and gene expressions.5. 6-OHDA -challenge with Rg1 treatment demonstrated reduced neurotoxicity with Bcl-2 protein and gene level in the substantial nigra. Cotreatment with JB-1 or 1CI182,780 completely abolished the neuroprotective effects of Rg1 on the Bcl-2 protein and gene expressions.These results demonstrated that ginsenoside Rg1 has neuroprotective effects on the dopaminergic neurons in the 6-OHDA induced OVX rat model of PD and its actions might involve activation of IGF-IR and ER signaling pathway. These results provide experimental evidence for the clinical application of ginsenoside Rg1 for prevention and treatment of PD.