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Pharmacological characterization of new neuroprotectants in Parkinson's disease models

English Abstract

Parkinson’s disease (PD) ranks second in the prevalence of neurodegenerative disorders among the elderly. Current therapies to PD mainly focus on relieving symptoms, and there is no effective drug to prevent, halt or slow the progression of the disease. Earlier studies highlight the multi-pathological factors involved in PD. It is thus interesting to investigate the potential treatment of PD with the multi-target approach of Traditional Chinese medicine (TCM) that bases on a holistic and integrated theory for disease treatment. TCMs particularly ameliorate the ageing-related symptoms, and hence are likely to be beneficial for chronic diseases such as PD. Chinese medicinal herbs which contain multiple chemical components are rich sources of bioactive compounds for the multi-target strategy in improving the treatment of PD. In an attempt to identify effective neuroprotectants for the prevention/treatment of PD, a panel of herbal extracts and a list of pure compounds with anti-inflammation, anti-oxidant, anti-ageing and tonificating activities were selected for screening in neurotoxin-induced PD model. Data from preliminary screening showed that the ethanolic extract of Fructus Alpiniae oxyphyllae (AOE) and pure compounds including quercetin and SU4312 exhibited promising neuroprotective effects. They were then systematically evaluated in established PD experimental cellular and zebrafish models, and the mechanisms underlying the neuroprotective activities were addressed. Major achievements of this study are summarized as follows: (1) AOE was demonstrated for the first time to prevent and restore 6-OHDA-induced DA neuron loss in zebrafish. Pre-incubation with AOE increased Abstract iv the viability of 6-OHDA-treated PC12 cells in vitro by attenuating cellular apoptosis. The mechanism underlying its neuroprotective effect involved anti-inflammation, anti-oxidant and activation of neuronal survival related phosphatidylinositol 3-kinase (PI3K)/Akt pathway. (2) Two polyphenols present in AOE, namely PCA and chrysin, exhibited enhanced protective effect against 6-OHDA-induced damage in PC12 cells in vitro and DA neuron in zebrafish through activation of Nrf2/ARE signaling pathway. These two compounds might partially contribute to the neuroprotective action of AOE. (3) The present study showed that quercetin could prevent (< 3 day post fertilization (dpf) zebrafish embryos) but not rescue (> 3 dpf zebrafish embryos) the zebrafish DA neuron loss induced by 6-OHDA when quercetin was administered at different maturation stages of the BBB in zebrafish. This provides indirect evidence of the presence of a functional BBB at 3dpf zebrafish larvae and an important role of BBB permeability in determining the beneficial effect of quercetin in PD in vivo. (4) SU4312, a potent and selective inhibitor of vascular endothelial growth factor receptor-2, for the first time, was demonstrated to exhibit significantly neuroprotective effect against MPP+ -induced damage of rat cerebella granule neurons, and ameliorated the loss of DA neurons and the impairment of swimming behavior of zebrafish caused by MPTP. The neuroprotective effect of SU4312 did not correlate with its anti-angiogenic activities, but via off-target inhibition of neuronal nitric oxide synthase. In summary, the present study provided scientific rationale for the use of Alpinia Oxyphyllae and its active ingredients, as well as SU4312, in the prevention/treatment of PD and may lead to development of potential preventive agents for PD.

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Zhang, Zai Jun


Institute of Chinese Medical Sciences




Parkinson's disease

Parkinson's disease -- Treatment

Medicine, Chinese

Herbs -- Therapeutic use

Pharmacology -- China


Lee, Ming-Yuen

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