Novel anti-Alzheimer's dimer Bis(7)-cognitin: cellular and molecular mechanisms of neuroprotection through multiple targets.
Alzheimer's disease (AD) is a progressive and degenerative brain disorder that has emerged as one of the major public health problems in adults. Unfortunately, its molecular pathology and therapeutic strategies remain elusive. Because there are multiple factors closely indicated in the pathogenesis of AD, multiple drug therapy will be required to address the varied pathological aspects of this disease. Existing pharmacological approaches with one-molecule-one-target are limited in their ability to modify the pathology of AD. Novel therapeutics strategies comprise multifunctional compounds specifically designed to target concurrently on different sites at multifactorial etiopathogenesis of AD, thereby providing greater therapeutic efficacy. Over the past decade, our group has developed several series of dimeric acetylcholinesterase (AChE) inhibitors derived from tacrine and huperzine A, a unique anti-Alzheimer's drug originally discovered from a traditional Chinese medicinal plant. Bis(7)-Cognitin, one of our novel dimers, through inhibition of AChE, N-methyl-D-aspartate receptor, nitric oxide synthase, and amyloid precursor protein/beta-amyloid cascade concurrently, possesses remarkable neuroprotective activities. More importantly, the synergism between these targets might serve as one of the most effective therapeutic strategies to arrest/modify pathological process of AD in addition to improving the cognitive functions for AD.
Li
Wenming
W
Department of Applied Biology & Chemical Technology, Institute of Modern Chinese Medicine, the Hong Kong Polytechnic University, Hong Kong SAR, China.
Mak
Marvin
M
Jiang
Hualiang
H
Wang
Qinwen
Q
Pang
Yuanping
Y
Chen
Kaixian
K
Han
Yifan
Y
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use
C122128:1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine; D016229:Amyloid beta-Peptides; D020746:Calcium Channels, L-Type; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D013619:Tacrine; D019001:Nitric Oxide Synthase; D000110:Acetylcholinesterase