Panax ginseng is neuroprotective in a novel progressive model of Parkinson's disease
Introduction
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the progressive loss of dopaminergic nigrostriatal neurons and the resultant depletion of dopamine in the terminal fields of the caudate-putamen. Key features of PD include, though are not limited to, tremor, rigidity and akinesia/bradykinesia. Dopamine replacement therapy in the form of its precursor, levodopa, remains the primary mode of treatment. However, over time, responsiveness to levodopa declines and dyskinesias develop, which may be due, in part, to ongoing cell loss. To date, only symptomatic treatment is available for PD patients, with no effective means of slowing or stopping the progression of the disease.
While several putative neuroprotective compounds have been described in animal studies, no drug has yet been identified that can definitively slow or stop the progression of PD. This may be due to the multi-factorial nature of the disease, which is characterized by a self-perpetuating cascade involving a myriad of deleterious events at various stages, including mitochondrial dysfunction, short-term and long-term oxidative stress, energy crisis, excitotoxicity, neuroinflammation, and protein aggregation. Not only are multiple factors involved, they appear to impinge upon each other to further promote cell death. In addition, PD cases are highly varied and the relative significance of each event in the disease process may vary among individuals. Unfortunately, putative neuroprotective agents often only target one aspect of the disease process. This may help to explain why many neuroprotective candidates have failed in the clinic despite showing promise in preclinical models.
Ginseng is unique, in comparison to other proposed neuroprotective agents, in that it is not one single compound but a collection of various compounds, called ginsenosides. Indeed, there are more than 60 known ginsenosides (Huang and Williams, 1999), each with unique actions. Ginseng has been demonstrated to modulate several putative biochemical markers shown to be important to the initiation and progression of PD. Various reports have shown the beneficial effects of ginseng or its ginsenoside components in the blockade of toxin uptake (Nah et al., 2009, Tsang et al., 1985a, Tsang et al., 1985b), reductions in excitotoxicity (Gu et al., 2009, Kim et al., 2007, Zhang et al., 2012), antioxidant effects (Chen et al., 2003), both through alterations in nitric oxide production as well as antioxidant enzyme activities required to eliminate free radicals, anti-inflammatory actions (Lee et al., 2012a, Lin et al., 2007, Yu and Li, 2000), and altered expression of neurotrophic factors (Liang et al., 2010, Wang et al., 2013). Ginseng has demonstrated neuroprotective capabilities in a variety of paradigms including stroke (He et al., 2012, Lee et al., 2011, Ye et al., 2013), Alzheimer's disease (Fang et al., 2012), Huntington's disease (Wu et al., 2009), ALS (Jiang et al., 2000), and PD (Chen et al., 2005a, Luo et al., 2011, Van Kampen et al., 2003). Indeed, we have previously demonstrated that the ginseng extract, G115, provides protection against the neurotoxic effects of MPTP and its neurotoxic metabolite, MPP+, in rodent models of PD (Van Kampen et al., 2003).
One other reason why neuroprotective candidates do so poorly in the clinic may involve the models used for preclinical screening. The vast majority of PD animal models fail to mimic the progressive nature of the disease, which may be critical for the proper identification of neuroprotective therapies. In order to effectively screen therapies designed to slow or halt disease progression, it may be necessary to replicate such progression. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic (Khabazian et al., 2002, Schulz et al., 2006, Tabata et al., 2008, Wilson et al., 2002). When fed to rats, β-sitosterol β-d-glucoside (BSSG) triggers the progressive development of neurological deficits, with behavioral and cellular features that closely approximate those observed in Parkinson's patients. These include motor abnormalities, striatal dopamine loss, loss of dopaminergic neurons of the SNc, and the appearance of Lewy body-like α-synuclein aggregates (Shen et al., 2010, Van Kampen et al., 2013). Clinical signs and histopathology continue to develop for several months following cessation of exposure to the neurotoxic insult.
Here, we examine the neuroprotective effects of the ginseng extract, G115, using this novel progressive rodent model of PD, assessing locomotor function, nigrostriatal cell loss, inflammation, and accumulation of protein aggregates.
Section snippets
Animals
All studies used female Sprague Dawley rats (Charles River), approximately 3 months of age. Animals were housed in a temperature-controlled environment with a 12 h light/dark cycle and 24 hour ad libitum access to standard chow and water, except during staircase step test training, when ad libitum access was limited to 4 h each day. All animal experimentation was conducted in accordance with the CCAC guidelines for the care and use of laboratory animals and was approved by the University of Prince
The ginseng extract, G115, prevents the development of locomotor impairments
Eighteen, twenty six and thirty four weeks following the initiation of BSSG intoxication, animals underwent assessments for locomotor impairments. Locomotor activity was measured for 1 h using a home cage video tracking system (MED Associates Inc.). Using this measure of akinesia/bradykinesia, BSSG was found to have no effect on locomotor function at 18 weeks, when toxin exposure was complete. However, BSSG significantly reduced locomotor activity, as compared to flour-treated controls, at the 26
Discussion
Collectively, these data suggest a possible role for ginseng extract as a neuroprotective therapy for PD. Here, we have demonstrated its ability to prevent BSSG-induced apoptosis and loss of SNc dopaminergic neurons, a key characteristic feature of PD pathology. This preservation of nigral neurons was reflected by the relative absence of locomotor abnormalities, as open field assessments revealed no reductions in locomotor activity. Fine motor control in the skilled reaching task was also
Conclusions
The ginseng extract, G115, provided near-complete protection against dopaminergic cell loss in the BSSG model of PD. This was accompanied by a reduction in indices of inflammation, apoptosis and cell stress. Further, locomotor deficits, characteristic of this and many other models of PD, failed to develop in those animals treated with G115. These data suggest that ginseng extract may be an effective neuroprotective therapy for the treatment of PD and may represent a safe means of early
Conflict of interest
Dr.s Van Kampen, Baranowski, and Kay were employed by Neurodyn Inc.
Acknowledgments
This work was supported, in part, by the Atlantic Canada Opportunities Agency. Special thanks to Dr. Harold Robertson for his assistance in reviewing this work.
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