Author: Xu, Daping
Title: The potent neuroprotective activities and underlying molecular mechanisms by T-006 : a novel anti-alzheimer's agent derived from Chinese medicine
Advisors: Han, Yifan (ABCT)
Degree: Ph.D.
Year: 2017
Subject: Hong Kong Polytechnic University -- Dissertations
Neuroprotective agents
Alzheimer's disease -- Treatment
Department: Department of Applied Biology and Chemical Technology
Pages: xx, 111 pages : color illustrations
Language: English
Abstract: Backgrounds: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, featured by progressive impairment of memory and cognitive function. The explicit pathogenesis mechanism underlies AD still remain unclear. Nevertheless, it is well accepted that increased oxidative stress, inappropriate neuronal apoptosis and impairment in neurogenesis and neuronal differentiation is intimately related with the occurrence and progression of AD. Current single target drugs exert only limited therapeutic effect to patients and the new paradigm of multi-functional compound development may open up new horizon on our way of defeating AD. Here in this research, we jointly synthesized a Chinese medicinal component tetramethylpyrazine with J147, another multi-potent compound, and yield a novel agent with potential anti-AD activity named T-006. Methodology: Various assessments and experiments were undertaken to investigate the pharmacological activity of T-006. In in vitro models, MTT and LDH assay were used to determine cell viability and FDA/PI/Hoechst staining were used to exhibit apoptosis and necrosis. Intracellular ROS, RNS and calcium were detected by fluorescent probes. Immunostaining is conducted to manifest neuronal differentiation. Various chemical inhibitors and western blot were employed to interrogate the signaling pathways underlying T-006's protection. In in vivo model, APP/PS1 transgenic mice were used to probe the anti-AD effects of T-006.
Results: T-006 firstly showed free radical scavenging ability by suppressing the overproduction of intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS). Then, T-006 protected rat cerebellar granule neurons (CGNs) against glutamate-induced excitotoxicity with a EC50 value of 59.4nM, which was much more potent than the clinical available NMDA receptor blocker memantine. Further study indicates that T-006 blocked the over-activation of NMDA receptor and ensued calcium influx. The protection of T-006 is also achieved through the concurrent regulation of ERK and PI3-K/Akt/GSK-3ß pathway. The anti-AD effects of T-006 were then confirmed in huAPPswe/PS1.E9 transgenic AD mice model. Summary and prospects: T-006 shows radical scavenging activity as well as excitotoxicity inhibition effect. The amelioration of learning and memory are also found in T-006-treated in vivo AD model. Above results offer deeper understanding of the anti-neurodegenerative activity of T-006 and provide insight into its possible therapeutic potential for AD treatment in light of the multipotent nature of T-006. To develop T-006 into an anti-AD candidate, further researches are needed to determine its bioavailability and pharmacodynamic features as well as the more detailed mechanisms underlying its neuroprotection.
Rights: All rights reserved
Access: open access

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