Rosmarinic acid, active component of Dansam-Eum attenuates ototoxicity of cochlear hair cells through blockage of caspase-1 activity.

Abstract

Cisplatin causes auditory impairment due to the apoptosis of auditory hair cells. There is no strategy to regulate ototoxicity by cisplatin thus far. Dansam-Eum (DSE) has been used for treating the central nerve system injury including hearing loss in Korea. However, disease-related scientific investigation by DSE has not been elucidated. Here, we demonstrated that DSE and its component rosmarinic acid (RA) were shown to inhibit apoptosis of the primary organ of Corti explants as well as the auditory cells. Administration of DSE and RA reduced the thresholds of the auditory brainstem response in cisplatin-injected mice. A molecular docking simulation and a kinetic assay show that RA controls the activity of caspase-1 by interaction with the active site of caspase-1. Pretreatment of RA inhibited caspase-1 downstream signal pathway, such as the activation of caspase-3 and 9, release of cytochrome c, translocation of apoptosis-inducing factor, up-regulation of Bax, down-regulation of Bcl-2, generation of reactive oxygen species, and activation of nuclear factor-κB. Anticancer activity by cisplatin was not affected by treatment with RA in SNU668, A549, HCT116, and HeLa cells but not B16F10 cells. These findings show that blocking a critical step by RA in apoptosis may be useful strategy to prevent harmful side effects of ototoxicity in patients with having to undergo chemotherapy.

• Authors: Hyun-Ja Jeong, Youngjin Choi, Min-Ho Kim, In-Cheol Kang, Jeong-Han Lee, Channy Park, Raekil Park, Hyung-Min Kim
• Journal: PloS one (PLoS One) Vol. 6 Issue 4 Pg. e18815 (Apr 15 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21526214 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Caspase Inhibitors
• Cinnamates
• Depsides
• NF-kappa B
• Plant Extracts
• Reactive Oxygen Species
• dansam-eum
• Cytochromes c
• Caspase 1

Topics

• Animals
• Apoptosis (drug effects)
• Biomarkers (metabolism)
• Caspase 1 (chemistry, metabolism)
• Caspase Inhibitors
• Cell Line, Tumor
• Cinnamates (chemistry, metabolism, pharmacology)
• Cytochromes c (metabolism)
• Depsides (chemistry, metabolism, pharmacology)
• Enzyme Activation (drug effects)
• Hair Cells, Auditory (drug effects, pathology)
• Humans
• Medicine, Korean Traditional
• Mice
• Mitochondria (drug effects, metabolism)
• Models, Molecular
• NF-kappa B (metabolism)
• Plant Extracts (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Rosmarinic Acid