title: IMM-H004, a novel coumarin derivative compound, protects against amyloid beta-induced neurotoxicity through a mitochondrial-dependent pathway.
abstract: We have investigated the effect of IMM-H004 (7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-2H-chromen-2-one), a coumarin derivative, on the amyloid beta (Aβ)-induced neurotoxicity in primary culture cortical neurons and pheochromocytoma (PC12) cells. Our results showed that treatment with IMM-H004 markedly reduced the number of apoptotic cells after exposure to Aβ25-35 or Aβ1-42, determined by MTT, TUNEL staining and Flow cytometry. Further study indicated that IMM-H004 significantly inhibited Aβ-induced cytotoxicity and apoptosis by reversing Aβ-induced mitochondrial dysfunction, including MMP (mitochondrial membrane potential) decrease, reactive oxygen species production, and mitochondrial release of cytochrome c. IMM-H004 can regulate the interaction between Bax and Bcl-2, decreased levels of p53 and active caspase-3 protein induced by Aβ25-35. Furthermore, IMM-H004 also reduced translocation of AIF (apoptosis-inducing factor) induced by Aβ25-35. These results demonstrated that IMM-H004 was capable of protecting neuronal cells from Aβ-induced degeneration through a mitochondrial-dependent apoptotic pathway. The results of this study lend further credence to the notion that IMM-H004 is a 'multipotent therapeutic agrent' that reduces toxic levels of brain Aβ, and holds the potential to protect neuronal mitochondrial function in Alzheimer's disease.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China.
authors.forename: X Y
authors.initials: XY
authors.lastname: Song
authors.forename: J F
authors.initials: JF
authors.lastname: Hu
authors.forename: M N
authors.initials: MN
authors.lastname: Sun
authors.forename: Z P
authors.initials: ZP
authors.lastname: Li
authors.forename: D H
authors.initials: DH
authors.lastname: Wu
authors.forename: H J
authors.initials: HJ
authors.lastname: Ji
authors.forename: Y H
authors.initials: YH
authors.lastname: Yuan
authors.forename: Z X
authors.initials: ZX
authors.lastname: Zhu
authors.forename: N
authors.initials: N
authors.lastname: Han
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: N H
authors.initials: NH
authors.lastname: Chen
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D003374:Coumarins / Q000737:chemistry*; D045304:Cytochromes c / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D061251:Primary Cell Culture; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D051033:Apoptosis Inducing Factor; D003374:Coumarins; C588372:IMM-H004; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D045304:Cytochromes c