title: Pravastatin attenuates noise-induced cochlear injury in mice.
abstract: Noise-induced hearing loss (NIHL) is one of the most common forms of sensorineural hearing loss and a well-known contributor to presbycusis. Based on the generation of reactive oxygen species (ROS) in the pathogenesis of NIHL, augmentation of the antioxidative defense system is a major target for pharmacological prevention. In this study, we assessed whether administration of pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which is a rate-limiting enzyme of cholesterol synthesis, before noise exposure protects against cochlear injury in BALB/c mice. Noise exposure produced both compound threshold shift (CTS) and permanent threshold shift (PTS) over 40 dB at 16 and 32 kHz. Pretreatment with pravastatin (25 mg/kg) for 5 days significantly decreased both CTS and PTS. Pravastatin also reduced hair cell death after noise exposure in the cochlea, which was identified by surface preparation and scanning electron microscopy (SEM). It also reduced the formation of noise-induced 4-hydroxynonenal (4-HNE), a byproduct of lipid peroxidation. Activation of Rac1, one of the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which is a major superoxide generator in the cell membrane, was inhibited by the administration of pravastatin. These findings suggest that pravastatin can protect against cochlear acoustic injury by lowering ROS generation via inhibition of the formation of the NADPH oxidase complex. This study will be helpful for the development of new therapeutic strategies for NIHL and other hearing loss-related diseases caused by ROS overproduction.
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon 443-721, South Korea. sangmyun@ajou.ac.kr
authors.forename: J S
authors.initials: JS
authors.lastname: Park
authors.forename: S W
authors.initials: SW
authors.lastname: Kim
authors.forename: K
authors.initials: K
authors.lastname: Park
authors.forename: Y H
authors.initials: YH
authors.lastname: Choung
authors.forename: I
authors.initials: I
authors.lastname: Jou
authors.forename: S M
authors.initials: SM
authors.lastname: Park
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D003051:Cochlea / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D006199:Hair Cells, Auditory, Inner / Q000473:pathology; D006317:Hearing Loss, Noise-Induced / Q000188:drug therapy* / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008855:Microscopy, Electron, Scanning; D019255:NADPH Oxidases / Q000378:metabolism; D017035:Pravastatin / Q000627:therapeutic use*; D011304:Presbycusis / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000447:Aldehydes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017382:Reactive Oxygen Species; D002784:Cholesterol; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; C027576:4-hydroxy-2-nonenal; D017035:Pravastatin