Neuroprotective Effects Of Medicinal Herbal Polysaccharides With Antioxidant Activity

As the aging population becomes the world's growing medical and social problems, the late-onset neurodegenerative diseases have become one of the biggest public health challenges for humanity. A common feature of neurodegenerative diseases is the aggregation of pathogenic proteins, e.g., amyloid-? peptide (A?) in Alzheimer's disease (AD) and polyglutamine (polyQ) in Huntington's disease (HD). Studies show that, a variety of stresses and body's responses have interplayed complicatedly following the growth and development of neurodegenerative diseases. And among the stressors, oxidative damage, proteostasis disorder and aging have been considered to play the important role. Effective reduce of the stresses and associated influences represent one of the efficient strategies for the treatment of neurodegenerative diseases.Traditional Chinese medicine have provided a rich theory and medicinal resources for the treatment of neurodegenerative diseases, and polysaccharides from traditional Chinese medicine have drawn more and more public attentions because of its huge potential activities. So, we choose 10 kinds of Chinese herbs which have been reported to be benefit for the health care, and extracted 10 kinds of acidic polysaccharides through ethanol purification, ion-exchange and dialysis purification methods. We firstly screened the antioxidant polysaccharides based on the oxidative survival assays in wild type N2 nematodes, and studied its antioxidant mechanism. Then, we examined the neuroprotective effect of the antioxidant polysaccharides using the chemosensory behavior assay in the HD and AD like nematodes models following by further examination of neuroprotective mechanism through proteostasis regulation and anti-aging effects.Results showed that:polysaccharides from Dictyophora indusiata (DiPS), Acanthopanax senticosus (AsPS) and Panax ginseng (PgPS) significantly increased the survival rate of wild type C. elegans N2 under paraquat (PQ) stress, and reduced the oxidative stress levels in CL2166 nematodes, exerting a prominently antioxidant activities against PQ stress. Further examinations demonstrated that, the antioxidant polysaccharides are able not only to decrease reactive oxygen species (ROS) and malonaldehyde (MDA) levels, increased superoxide dismutase (SOD) activity, but also to restore the functional parameters of mitochondria, including membrane potential and ATP content in PQ-stressed nematodes. In addition to this, the antioxidant activity of DiPS is demonstrated to dependent on the activation and regulation of the stress-response transcription factor DAF-16/FOXO.In consideration of the correlation between oxidative stress and neurodegenerative diseases, we further show that the antioxidant polysaccharides DiPS, AsPS and PgPS are also capable of reducing ROS levels, increasing oxidative survival and alleviating chemosensory behavior dysfunction in polyglutamine and amyloid-? mediated neurodegenerative nematode models. Together, these findings provide an insight into the potential of antioxidant polysaccharides in neuroprotection.In order to reveal the neuroprotective mechanism of the antioxidant polysaccharides, we took Acanthopanax senticosus polysaccharide (AsPS) as an example to study the proteostasis regulation activity. We found that AsPS not only protected the ASH neuron survival from polyQ toxicity, but also partly inhibited the polyQ aggregation in vivo. Examinations revealed the neuroprotective effect of AsPS was related to the regulation of intracellular protein balance system which was contributed by the activation of molecular chaperons on HSP16.2 to maintain protein-folding homeostasis and the activation of ubiquitin-proteasome system (UPS) to eliminate protein aggregation especially on the regulatory RPN subunits of 19S proteasome. Further studies revealed that AsPS could effectively inhibit the key kinases activities of MAPK pathways which may also contribute to its neuroprotection.In addition to this, the antioxidant polysaccharides also exhibited a potential of senescence delaying activity especially the Panax ginseng polysaccharide (PgPS). Results showed that:although PgPS did not directly influence the lifespan of HD like nematode model, PgPS significantly extended the average and median lifespan of wild type C. elegans N2 and alleviated the chemosensory behavior dysfunction in HD and AD like nematode models, indicating an indirect correlation between neuroprotection and anti-aging.In conclusion, the antioxidant polysaccharides from traditional Chinese medicine could effectively inhibit neurotoxicity and exhibit neuroprotection in the neurodegenerative diseases through the inhibition of oxidative stress, regulation of proteostasis and delay of senescence pathways. This study not only promotes the development of polysaccharids in the prevention of neurodegenerative diseases, but also provides a theoretical foundation to the application of herbal polysaccharides in the area of health care products.