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 (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.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (179 K)Download as PowerPoint slideHighlights► IMM-H004 exhibits significant protection against Aβ-induced apoptosis. ► IMM-H004 reverses the damage of mitochondria. ► IMM-H004 protects neurons through a caspase-dependent pathway. ► IMM-H004 protects neurons also by the AIF-dependent pathway. ► IMM-H004 is a potential compound to therapy AD-like degeneration.