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소음에 의한 와우 손상의 약리학적 치료
- Author(s)
- 박정섭
- Advisor
- 박상면
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2014-02
- Language
- eng
- Keyword
- Noise; Hearing loss; Reactive oxygen species; NADPH oxidase; Mitochondria; Cysteinyl leukotriene; Pravastatin; Methylene blue; Montelukast
- Alternative Abstract
- Noise-induced hearing loss (NIHL) has become one of the most common occupational disease in both developing and developed countries and is also the major contributing factor of age-related hearing loss. NIHL is uniquely preventable sensorineural hearing loss and researchers have investigated additional preventive strategy based on the discovered pathogenesis of NIHL. The pathogenetic mechanisms of NIHL are considered as multifactorial such as glutamate excitotoxicity, ischemia-reperfusion injury, ATP depletion and reactive oxygen species (ROS) formation. Among them, I determined that blockade of ROS formation is one of the most efficient targets of prevention using an animal model of NIHL. Firstly I reported that noise exposure induced superoxide formation through the activation of NADPH oxidase complex and inhibition of complex formation by pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which is a rate-limiting enzyme of cholesterol synthesis, before noise exposure protected 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 NADPH oxidase complex was inhibited by the administration of pravastatin due to its pleiotropic effect. Secondly, I also showed that methylene blue (MB) pretreatment for 4 consecutive days significantly decreased both CTS and PTS after exposure to intense broad band noise for 3 h. MB reduced outer hair cell (OHC) death in the cochlea that was identified by surface preparation and SEM, and it also reduced ROS and RNS formation after noise exposure. MB significantly protected against rotenone- and antimycin A-induced cell death, and also reversed ATP generation in vitro. Furthermore, MB effectively attenuated noise-induced impairment of complex IV activity. MB also increased the neurotrophin-3 (NT-3) level which could affect synaptic connections between hair cells and spiral ganglion neurons in the noise-exposed cochlea. MB promoted the conservation of both efferent and afferent nerve terminals on the OHC and inner hair cells. Finally, I found the expression of cysteinyl leukotriene type 1 receptor (CysLT1) were increased at 3 days after noise exposure, but not in control mice. Enhanced CysLT1 expression was mainly occurred in the spiral ligament and the organ of Corti. Expression pattern of upstream enzyme 5-lipoxygenase was similar to CysLT1. Consistent with these results, elevated cysteinyl leukotrienes (CysLTs) concentration was also accompanied, as compared to control mice. Posttreatment of leukotriene receptor antagonist (LTRA), montelukast (10 mg/kg) for 4 consecutive days significantly decreased not CTS but PTS. Montelukast also reduced hair cell death after noise exposure in the cochlea which was identified by surface preparation and SEM. Taken together, pharmacological management using pravastatin, MB and montelukast will be helpful for providing novel strategies for the prevention of NIHL and other hearing loss-related diseases possibly related to oxidative stress or leukotriene signaling.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 4. Theses(Ph.D)
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