IMM-H004, A NOVEL COUMARIN DERIVATIVE COMPOUND, PROTECTS AGAINST AMYLOID BETA-INDUCED NEUROTOXICITY THROUGH A MITOCHONDRIAL-DEPENDENT PATHWAY

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 (A beta)-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 A beta(25-35) or A beta(1-42), determined by MTT, TUNEL staining and Flow cytometry. Further study indicated that IMM-H004 significantly inhibited An-induced cytotoxicity and apoptosis by reversing An-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 BcI-2, decreased levels of p53 and active caspase-3 protein induced by A beta(25-35). Furthermore, IMM-H004 also reduced translocation of AIF (apoptosis-inducing factor) induced by A beta(25-35). These results demonstrated that IMM-H004 was capable of protecting neuronal cells from A beta-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 A beta, and holds the potential to protect neuronal mitochondrial function in Alzheimer's disease. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.