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P3‐432: An inhibitor of kynurenine 3‐monooxygenase is neuroprotective in a mouse model of Alzheimer's disease
Author(s) -
Zwilling Daniel,
Truong Jennifer,
Andrews-Zwilling Yaisa,
Hsieh Eric,
Louie Jamie,
Huang Yadong,
Muchowski Joseph M.,
Masliah Eliezer,
Schwarcz Robert,
Muchowski Paul J.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1975
Subject(s) - kynurenine , kynurenine pathway , dentate gyrus , neuroprotection , kynurenic acid , genetically modified mouse , neuroscience , hippocampus , amyloid precursor protein , transgene , pharmacology , chemistry , psychology , medicine , biology , alzheimer's disease , disease , glutamate receptor , biochemistry , tryptophan , receptor , amino acid , gene
cytokines were measured by biochemical assays. Results: (1) In APP transgenic mice, TSG decreased amyloid plaques, Ab and presenelin-1 in hippocampus. (2) In Ab1-40 brain ventricle injection mouse model, TSG decreased IL-1 and malondialdehyde (MDA), and protected ultrastructure of mitochondria and neurons in hippocampus. (3) In cholinergic damage rats induced by forebrain injection of IBO, TSG increased the ChAT activity and M-cholinergic receptor in hippocampus and cerebral cortex. (4) In aged rats, TSG decreased loss of cholinergic neurons and synapses, protected synaptic ultrastructure, enhanced expression of synaptophysin, NGF and TrkA, and promoted signal transduction for neuron survival including IRS-1, p-CREB and p70S6K in hippocampus. (5) In brain aging mouse model induced by D-galactose injection, TSG decreased MDA, increased glutathion and SOD, and enhanced NGF and TrkA in hippocampus and cerebral cortex. (6) In dementia rat model induced by hypercholesterolemia, TSG decreased Ab in hippocampus, and declined cholesterol and LDL in serum. (7) In dementia rat model induced by chronic cerebral ischemia, TSG decreased neuron death and MDA content, increased glutathion peroxidase activity and expression of PP2A and MAP-2 in hippocampus. (8) TSG improved learning-memory impairment in all above model animals. Conclusions: TSG improves learning-memory ability in 7 kinds of AD-like animal models. Its mechanisms are involved in antagonizing multiple targets in AD pathogenesis. TSG may have strong potentials for treating AD. This natural product has finished Phase I clinical trial and started Phase II clinical trial to treat AD in China.