Overview: Recent Advances in the Study of (-)Clausenamide on Chemistry, Biological Activities and Mechanism of Action
The Synthesis of Clausenamide Family Natural Products and Analogues
Pharmacological Activity of Clausenamide as A Chiral Drug
Neuroprotection of (-)Clausenamide via Inhibiting Tau Hyperphosphorylation and Preserving Microtubule Structure
Synaptic Pharmacology of Clausenamide
Two Forms of Long-term Potentiation Induced by (-)Clausenamide and Rgl
The Nootropic Mechanism of (-)Clausenamide
Mechanism of (-)Clausenamide Induced Calcium Transient in Primary Culture of Rat Cortical Neurons
(-)Clausenamide Enhances the Synaptic Plasticity through Gasotransmitters
Antiapoptotic Effect of (-)Clausenamide and its Mechanisms of Action
The Signal Transduction Pathway of (-)Clausenamide on Activation of Learning and Memory
Pharmacokinetics and Metabolism of Clausenamide Enantiomers
Metabolic Transformation of Clausenamide
Preclinical Safety Evaluation and General Pharmacology of (-)Clausenamide
Optical Separation and Quality Research of Clausenamide Enantiomers
Abstracts in English and Chinese
Clausenamide is a novel compound isolated from Clausena lansium (Lour) Skeels, which is a species of fruit tree commonly seen in southern China. As the content contained in the plant is very low, many scientists try to synthesize it. After long term of effort, this compound has now been chemically synthesized by our institute and the production art has reached semi-industry scale that satisfies the demand for clinical trail and hereafter therapeutic use.
Clausenamide research received extensive attention, the reasons for this are as follows: it is the first chiral compound having anti-dementia effect; clausenamide contains 4 chiral centers having 16 enantiomers. According to the biogenetic hypothesis proposed by Prof. Huang, synthesis of 16 enantiomers and optical active clausenamide as well as asymmetric synthesis of (-) and (+) clausenamide were achieved.
For pharmacology, (-)clausenamide shows multi-target effects which benefit complicate diseases including Alzheimer's disease and other neuro- degenerative disorders. According to the new theory "synaptic loss=AD", a good anti-dementia drug must be able to improve synaptic plasticity and promote synaptogenesis. Fortunately, (-)clausenamide happened to be such compound. As proved in our study that (-)clausenamide increased synaptic plasticity both in efficacy and structure. For latter, (-)clausenamide increased synaptic density (synaptogenesis) and expression of growth associate protein (GAP-43) in the brain significantly.
This book is aimed to review the recent advances and new discoveries in chemistry, pharmacology and anti-dementia mechanism of (-)clausenamide. Hope that readers will enjoy and get benefit from many stories and new findings written in this book.
All invited authors are engaged in clausenamide research for many years and have rich theoretical knowledge and practice experience. They contribute a lot to develop (-)clausenamide to Ⅱ phase of clinical trail. I also appreciate their articles which are full of new ideas and new thoughts. Some new findings are especially interesting. In addition, we have cooperated with Norkong Scientific Company for about 8 years, they give us many support including economic support. Let us express our many thanks. We also extend our thanks to Chemical Industry Press for their patience in organizing and editing this book which is my third book in English version.
of the tau protein. Thus, revealing the protein kinases and phosphatases involved in abnormal phosphorylation of tau is critical for our understanding the pathogenesis of AD. Hyperphosphorylation of tau decreases the stability of microtubules affecting the assembly of microtubules, destroys neuron functions including the transfer function of axoplasm, and eventually leads to neuron death.Furthermore, abnormal hyperphosphorylation of tau also reduces glycogenesis and PDH phosphorylation, thus affecting the synthesis of acetylcholine in neurons and function of cholinergic transmission, which plays an important role in learning and memory[19-23].
Many protein kinases can phosphorylate tau protein, or augment phosphorylating activity through a reciprocally concerted mechanism. Among them GSK-3 and CDK-5 have been well studied. GSK-3 can phosphorylate tau protein through many action sites, including the Ser199/202 site. GSK-3 has been shown to induce Alzheimer's disease via phosphorylation of tau following transfection of cells with the enzyme, suggesting that GSK-3 is crucially involved in PHF-tau hyperphosphorylation. Moreover, GSK-3 has also been shown to be preferentially localized in NFT-bearing neurons. As an upstream kinase of GSK-3,CDK-5 regulates the activity of GSK-3[24-27].
In addition to overactive kinases, it has been suggested that hyperphosphorylation of PHF-tau could be a result of decreased protein phosphatase in Alzheimer's disease since phosphatase activities are reported to be reduced in Alzheimer's disease brain. Furthermore, protein phosphatases PP-1, PP-2A and PP-2B have been shown to revert kinase-induced hyperphosphorylated tau to its normal-like state.
Okadaic acid (OA) is an inhibitor of PP-2A and PP-1. By disturbing the balance the phosphorylation and dephosphorylation, OA induces hyperphosphorylation of tau and disorganization of microtubules and thus may lead to blockage of axonal and dendrite transport. In this scenario, the anterograde transport of mitochondria and synaptic vesicles from the neuronal cell bodies to the synaptic endings, as well as the retrograde transport of neurotrophic factors from synaptic terminals to neuronal cell bodies, may be hampered, thus resulting in synapse degeneration and neuronal apoptosis. Our study showed that (-)clausenamide and lithium inhibited the neurotoxicity of OA, indicated by the maintained activity of mitochondria and the integrity of cell membrane[29,30].