Traditional medicine, memory and neurodegeneration. Cognitive and memory enhancing effects of Polygala and other extracts

    •  
    • Presentation speakers

     

     

     

     

    A projected 66 million people worldwide will be living with dementia by 2030, a figure set to rise to 115 million by 2050. With an escalating global cost of > US$600 billion per year for dealing with dementia, there is a great urgency to discover safe and efficacious treatments for Alzheimer’s Disease (AD).

    In 1992, Hardy and Higgins 1 proposed the Amyloid Cascade Hypothesis of Alzheimer’s Disease. It postulates that build-up of toxic amyloid-β (Aβ) species initiates a series of events that culminates in neurodegeneration and symptoms. The exact sequence of events linking Aβ accumulation to aggregation of hyper-phosphorylated tau in different neuronal compartments, neuronal loss, synaptic dysfunction and symptoms remain incompletely understood. Current treatments include cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonists. Clinical research focuses on targeting amyloid: beta-secretase inhibitors; blocking aggregation; amyloid clearance and immunotherapy. Despite enormous R&D efforts, effective therapies for AD are still lacking.

    Two of the five licensed drugs for AD (galantamine and rivastigmine) are naturally-derived ChEIs, while Huperzine A is a dual ChEI and NMDA receptor antagonist.  Recent studies have provided evidence suggesting that AD is related to chronic inflammation of brain microvasculature and neuronal network. Thus, therapeutic intervention to maintain the functional integrity of brain microvasculature is likely to augment the actions of ChEIs and drugs targeting Aβ-induced pathology.

    Polygala tenuifolia and Acorus calamus are medicinal herbs commonly used in Asia for memory enhancement and neuroprotection. In a randomized, double-blind, placebo-controlled trial, an extract of P. tenuifolia produced significant cognitive improvement in elderly humans 2. Recently, Fan and his Chinese collaborators demonstrated cognitive- and memory-enhancing effects of Polygala extracts in a mouse model of Aβ-induced amnesia 3, and aged mice 4, respectively. The roots of Polygala species contain terpenoids and xanthones as bioactive constituents. Others have shown tenuigenin to promote the proliferation and differentiation of hippocampal neural stem cells, while β-asarone from A. calamus attenuates Aβ-induced neuronal apoptosis.

    Using human cell lines, ‘omics and chemogenomics approaches 5, we are testing the hypothesis that phytochemicals derived from these and other plant extracts alleviate dementia through their vaso- and neuro-protective mechanisms by modulating multiple molecular targets on endothelial and neuronal cells. The optimization of, and drug development from, natural molecules from traditional medicine will improve the quality, safety and efficacy of potential prophylactic and therapeutic agents for AD and other diseases.

    References

    1.    Hardy JA, Higgins GA. (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science. 256(5054):184-5.
    2.    Shin KY, Lee JY, Won BY, Jung HY, Chang KA, Koppula S, Suh YH. (2009) BT-11 is effective for enhancing cognitive functions in the elderly humans. Neurosci Lett. 465(2):157-9. doi: 10.1016/j.neulet.2009.08.033.
    3.    Xu SP, Yang YY, Xue D, Liu JX, Liu XM, Fan TP, le Pan R, Li P. (2011)
    Cognitive-enhancing effects of polygalasaponin hydrolysate in aβ(25-35)-induced amnesic mice. Evid Based Complement Alternat Med. 2011:839720. doi: 10.1155/2011/839720.
    4.    Li Z, Liu Y, Wang L, Liu X, Chang Q, Guo Z, Liao Y, Pan R, Fan TP. (2014) Memory-enhancing effects of the crude extract of Polygala tenuifolia on aged mice. Evid Based Complement Alternat Med. 2014:392324. doi: 10.1155/2014/392324.
    5.    Mohd Fauzi F, Koutsoukas A, Lowe R, Joshi K, Fan TP, Glen RC, Bender A. (2013) Chemogenomics approaches to rationalizing the mode-of-action of traditional Chinese and Ayurvedic medicines. J Chem Inf Model. 53(3):661-73. doi: 10.1021/ci3005513.