title: The IDO inhibitor coptisine ameliorates cognitive impairment in a mouse model of Alzheimer's disease.
abstract: Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in the kynurenine pathway (KP) of tryptophan catabolism, was recently established as one of the potential players involved in the pathogenesis of Alzheimer's disease (AD). Coptisine is a main pharmacological active constituent of the traditional Chinese medicinal prescription Oren-gedoku-to (OGT) which has therapeutic potential for the treatment of AD. Our recent studies have demonstrated that OGT significantly inhibited recombinant human IDO activity, which shed light on the possible mechanism of OGT's action on AD. Here, we characterized the effects of coptisine in an AD mouse model on the basis of its IDO inhibitory ability. Coptisine was found to be an efficient uncompetitive IDO inhibitor with a Ki value of 5.8 μM and an IC50 value of 6.3 μM. In AβPP/PS1 transgenic mice, oral administration of coptisine inhibited IDO in the blood and decreased the activation of microglia and astrocytes, consequently prevented neuron loss, reduced amyloid plaque formation, and ameliorated impaired cognition. Neuronal pheochromocytoma (PC12) cells induced with amyloid-β peptide 1-42 and interferon-γ showed reduction of cell viability and enhancement of IDO activity, while coptisine treatment increased cell viability based on its reversal effect on the enhanced activity of IDO. In conclusion, our present findings provide further evidence supporting the critical links between IDO, KP, and AD, and demonstrate coptisine, a novel IDO inhibitor, as a potential new class of drugs for AD treatment.
authors: State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai, China.
authors: Dan
authors: D
authors: Yu
authors: Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors: Bang-Bao
authors: BB
authors: Tao
authors: State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai, China.
authors: Yun-Yun
authors: YY
authors: Yang
authors: State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai, China.
authors: Li-Sha
authors: LS
authors: Du
authors: State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai, China.
authors: Shuang-Shuang
authors: SS
authors: Yang
authors: State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai, China.
authors: Xiao-Jie
authors: XJ
authors: He
authors: State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai, China.
authors: Yu-Wen
authors: YW
authors: Zhu
authors: State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai, China.
authors: Jun-Kai
authors: JK
authors: Yan
authors: State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai, China.
authors: Qing
authors: Q
authors: Yang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D000077265:Donepezil; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007189:Indans / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D018697:Nootropic Agents / Q000494:pharmacology*; D016716:PC12 Cells; D010880:Piperidines / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D007189:Indans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018697:Nootropic Agents; C508853:PSEN1 protein, human; D010880:Piperidines; D053764:Presenilin-1; C034384:coptisine; D001599:Berberine; D000077265:Donepezil
keywords: Alzheimer's disease; coptisine; indoleamine 2, 3-dioxygenase; indoleamine 2, 3-dioxygenase inhibitor; kynurenine pathway