KISEP Information Korean J Otolaryngol 2006;49:962-7 노인성난청의환경위험요소들에대한고찰 건국대학교의과대학이비인후과학교실 Presbycusis:Review for its Environmental Risk Factors Bo-Hyung Kim, MD Department of Otolaryngology, Kon-Kuk University Medical School, Chungju, Korea 서론 노인성난청 (Presbycusis) 은연령증가에따른가장흔한감각신경성기능저하의한질환으로서 60대의 35% 이상, 70대에서는 50% 이상이일상생활의어려움을호소하고있으며이또한고령화사회, 환경인자등으로인하여빈도가점점증가하고있는추세이다. 1) 노인성난청의전형적소견으로는고음영역에서상칭적인감각신경성난청의형태로나타나며, 남성이여성보다더심하게영향을받는것으로알려지고있다. 2) 비록연령증가에따른청력역치의저하가일정한변화곡선을지니더라도노인성난청의시작연령대와진행형태, 그리고중증도등은매우심한편차를보이고있음을알수있다. 60대남성의고음영역의청력검사에서최하위 10% 에서는 55~75 db의청력역치를보이며, 최상위 10% 에서는 10 db보다더좋은결과를보이기도하는데이러한수치는연령의증가에따라서고음영역에서더큰변화를초래하는것으로알려지고있다. 소리의인지능력은매우복잡한경로를통하여발생되는데이경로의구성요소들또한연령의증가에따라서기능의변화가발생하여청력의저하를초래한다. 노인성난청은청각유모세포, 청신경세포그리고혈관선조의변성과연관이되지만변성과정의정확한기전은아직명확하지는않다. Schuknecht 등은인간의측두골병리조직분석과청력소견을종합하여노인성난청은크게네종류의형태를지니며조직소견에따라서청력검사의형태도다르게나타난다고보고하였다. 3) 이분류에따르면순음청력검사에서고음영역에서청력역치의저하를보이는경우와우기저부의유모세포의손상에의한것으로이를 sensory presbycusis 라고하였으며청력이편평하거나완만하게하강곡선을보일경우는대개혈관선조의위축변화에의한것으로이를 strial presbycusis 로명명하였다. 세번째형태는와우전체의와우신경세포의결손을보이는 neural presbycusis 로여기서는점진적인어음분별력의감소를보인다. 네번째는청력검사에서하강곡선이특징인 cochlear conductive presbycusis 로병리소견과특별한연관이없는것으로알려졌다. 최근의연구에서는유모세포의손상, 혈관선조의퇴화, 그리고신경세포의손상들이노인성난청에서나타나고는있지만이러한변화가독특한청력검사결과의형태를가지는것이아니라는보고도있다. 4) 저자는현재까지알려진노인성난청의분류및원인등을토대로하여환경위험인자및최근보고되고있는예방치료에대하여알아보고자한다. 본론 Age-related changes in the auditory system 노령인구의 15% 정도에서신경과적질환에관계없이감각운동성장애를지니고있다고알려지고있다. 조직학적으로노령자의귀의변화는유모세포의결손, 조직의변성, 그리고와우측벽의 apoptosis 등이관찰된다. 5) 이러한청각기의해부학적변화는청력기능에영향을미치는생리적변화에의해서도초래할수있다. 노화현상은대사작용과생리작용의점진적변화에의한부산물의생체축적에의해질병의감수성의증가를초래하는것으로알려지고있다. 생체기전의부전에의하여노화현상을초래하는요소는 4가지로요약할수있다. 962
Gene repression 체계적으로프로그래밍된나이에따른유전자변형과정으로이과정을통하여 RNA 합성의연속적인쇠퇴로 chromatin 의축적으로세포내의 potassium 의증가를초래하여 homeostsis 의부전을초래한다. 6) Intercellular communication 정상적인세포정렬에서는서로급속히분자이동을할수있는공간적배열을하고있는데노화과정에서이러한정렬의파괴가올수있으며이것은주로 gap junction protein과 connexin-26의변이에의해서발생한다고알려졌으며노인성난청의기전과비슷한것으로보인다. Waste accumulation 세포내부산물의자정작용의저하로체내결손부위의확대를초래하는것으로혈관내막의비후와 lipofuscin 의축적, 그리고 collagen의손상을야기시킨다. Age-related depletional defects 연령증가에따른세포작용의점진적파괴로생체기관의작용이급속히저하되는현상을말한다. 7) 위의사항을종합하여보면청각기의노화는신체모든장기의복합적조절작용의파괴에의하여나타나는인체노화과정의일부임을알수있으며노화에의한노인병자체가하나의특정질환으로만이루어진것이아닌신체장기의복합적장애를동반한질환으로이해하여야할것으로보인다. 최근보고되고있는 telomerase 이론에의하면 DNA 의반복적 sequencing 이일어나는 telosomere 가노화에의해 telomerase 의활동저하로변이를초래하여체내노화과정에의한부작용을유발한다고알려졌으며이또한 presbycusis 의기전의설명에서도부합되는것으로알려졌다. 8-12) Causes of presbycusis:environmental risk factors Presbycusis 는이미알려진여러환경적요소의복합적작용에의하여발생되는것으로알려졌다. 하지만이러한요소들이어떤기전으로귀의기능적변화를증폭시키는지, 그리고어떤생리적변화를초래하는지는분명하지는않다. 13) 소음폭로는난청을초래하는환경적요소중제일많이알려져있다. 14) 과도한소음은와우의대사성기능과기계적기능의손상을야기시키는데기계적손상은고음강도의 소음에의해야기되며, 반면대사성와우기능손상은저음영역의소음에서야기되는것으로알려지고있다. 그리고이러한변화의과정에 free radicals 과다른 reactive endogenous substances 가중요한역할을하고있다고알려졌다. 15) 소음성난청의초기변화는와우의외유모세포의소실이며장기간폭로시내유모세포의소실을유발하게된다. 16) 하지만궁극적으로는일상에서의소음폭로에의한난청과 presbycusis 는청력측정과조직소견으로는구별을하기가힘들다고알려졌다. 17-19) 이독성약제의사용, 특히노년층, 또한난청을초래하는중요한원인으로써간기능과신장기능의저하에따라서혈중농도의증가를가져온다. 20) Aminoglycoside계항생제는소음성난청과비슷한형태의난청을초래하는것으로고음영역에서비가역적난청을발생시키며소음과동반시그부작용이증폭되는것으로알려졌다. 21) 정상적으로는 aminoglycoside계항생제의이독성은약물의용량과관계되지만사람에따라서는약제의감수성에의해결정되는것으로알려지고있다. 이러한환자들에서는 mitochondrial 12S ribosomal RNA gene(1555a G) 의변이가있는것으로 aminoglycoside-induced 난청의 17~ 33% 에서관찰된다고알려졌다. 22)23) 항암제인 cisplatin 은초기에외유모세포의변성을초래하지만계속투여시내유모세포의변성도초래하며이또한고음영역에서비가역적난청을유발하는것으로보고되고있다. 24) Salicylate 는외유모세포의세포막전도를증가시켜 cochlear amplfier 의 gain 을감소시켜가역적난청과이명을야기시키는것으로알려졌다. 25) Furosemide, ethacrynic acid 같은 loop diuretics 는혈관선조의 ion balance 의변화로가역성난청을초래하지만 aminoglycoside계약물과병용투여시이독성작용이증폭되어비가역성난청을초래하는것으로알려졌다. 21) 그외흡연과음주가난청을초래한다는보고가있지만그기전과효과에대해서는아직논란의여지가있는것으로알려지고있다. 26-29) Causes of presbycusis:medical risk factors 의학적조건들도난청의선행원인이될수있다. 순환기계질환은노년층에서유병률이높은것으로이또한난청과관련될수있다. 순환기계질환 (stroke, coronary heart disease, intermittent claudication) 들은저음영역의난청과관련된다고한다. 저음영역의난청은혈관선조의위축을야기시키는미세혈행장애질환과관련된다고한다. 28) 963
노인성난청의환경위험요소들에대한고찰 고혈압과수축기혈압은청력역치에영향을미친다는보고가있다. 27) 그외고지혈증과당뇨병에서도고음영역의감각신경성난청을초래한다고한다. 28)30) 당뇨에서의난청을초래하는기전에대하여두가지의가능성을제시하는데첫째는내이로흘러가는혈행장애로인하여와우자체의손상에의한난청기전과둘째는청신경의신경염에의한후미로성난청이온다는기전이다. 최근에는 mitochondrial DNA 변이가성인성당뇨병환자의감각신경성남청과관련된다는보고도있다. 31) 신부전증환자에서는고음영역의난청을초래하는것으로알려졌는데이는주로치료와병자체의진행양상에의해좌우되는것으로전자의예로는만성투석, 신장이식과이독성약제사용을들수있으며후자의경우는 uremic neuropathy, electrolyte imbalance, premature cardiovascular disease, shared angiotenicity between kidney and cochlea 등이다. 32) Cause of presbycusis:genetic study 노인성난청의유전학적위험요소에대한연구의선행조건으로는 phenotype에대한분명한정의가필요하다. 연구는주로환자의 DNA 변이에대하여이루어지고있으며, 연령대별, 성별과각각의음역별청력역치가달라지기때문에 Z-score로 median hearing threshold를구하여 ISO 7079(threshold of hearing by air conduction as a function of age and sex for otologically normal persons;international Organization for Standardization, 1984) 로기술하였다. 33) Cause of presbycusis:oxidative imbalance Oxidative imbalance는 aged cochlea의생리기전설명에적합한모델로알려져있다. 이러한현상으로인하여 reactive oxygen species 의부산물의증가와방어기전의쇠퇴를야기시키는것으로알려지고있다. Oxidant stress 의표식자인 lipid peroxidation, glutathionylation 그리고 nitrosylation of protein 의축적이증가하며, 반면 antioxidant defenses 인 AIF, SOD2 등은연령이증가함에따라감소하는것으로보고되고있다. 이미알려진것처럼노화에의해서야기된내이의미토콘드리아쇠퇴는이러한 oxidative stress 의작용으로이루어지리라고본다. 34)35) 미토콘드리아효소인 SOD2 는정상적으로 superoxide radical의형성을억제시키는작용이있으나연령증가에따라서이러한 antioxidant reaction 이떨어지게된다. 하지만 SOD2 의 mrna 는변화가없는것으로알려져이것은 gene expression 의감소와는관련이없는것으로보아서미토콘드리아의단백물질의비활성이이반응과관계되는것으로사료된다. 36) AIF는 DNA의 transcription 역할을하는부위와결합하는작용과 oxido-reductase activity를수행하는부위와결합을통하여 antioxidant reaction 을수행하는것으로알려지고있다. 37)38) Aged ear에서는이러한 antioxidant reaction 이감소하여와우조직내에서 oxidative stress 가외유모세포로부터점차혈관선조까지진행되어난청의정도가증가함을알수있다. 39) 그리고 oxidative sress는 supporting cell보다외유모세포에서초기에 apoptosis를유발시키는것으로알려지고있다. 40) Treatment 모든형태의난청은의사전달과정뿐만아니라삶의질에도영향을미친다. 대개의노인성난청의치료는개개인의삶의질향상에목적을두고서보청기를사용한청음의증폭에역점을두고있다. 41) 그러므로치료의효과는원활한의사전달과정이상의목적을이루는데있다. 즉현재의치료는소실된청력의회복에있는것이아니라는것이다. 청력회복에대한연구는아직은과학적난제로남아있다. Prevention 비록어느정도의 sensory presbycusis 는피할수없는것이지만이러한노인성청력저하현상은생활중해로운소음을회피하거나혹은적합한귀마개를사용함으로써충분히감소시킬수가있다. 귀마개 (ear plug) 의착용으로대략 15~25 db의소음감소효과를보게되므로다소시끄러운환경에서도작업을원활히수행할수있도록해주는것으로알려지고있다. 총소리나시끄러운음악소리등일상생활에서접하는소음누적은결국나이가듦으로인하여의사전달과정의어려움으로남게된다. 심혈관계질환, 예를들면 stroke, myocardial infarction, hyperlipidemia, 그리고 diabetes mellitus 같은경우노인연령에서심각한난청을초래하는것으로알려져있다. 그러므로건강한육체와몸매를유지하는것이모든질병의예방효과와마찬가지로노인성난청의빈도를낮추리라고본다. 고지방다이어트는필수적으로난청과연관된다고한다. 42) 964 Korean J Otolaryngol 2006;49:962-7
하지만동물실험을통하여평소의 low-carolic diet 는수명연장과노인성난청의빈도를낮춘다고보기는힘들다는보고도있다. 43) 노화현상의예방과인간수명의연장을위해그효과에대해아직의문의여지는있지만 antioxidant agent 의효과에대한연구가많이시행되고있다. Prevention of cell death 환경인자중이독성과소음에의한유모세포의손상을예방하는세가지물질에대한연구와보고가증가하고있다. 이러한물질들로는 neurotrophic factor계와 anti-oxidants, 그리고 anti-apoptotic agent 같은분자물질들이속한다. 이분자물질들은임상적으로손상에적절하게반응하는능력을가지고있다고한다. 하지만이러한물질에의한치료효과는예방적인입장에서의고려대상이지기존의질환에대한치료효과는없는것으로알려지고있다. Neutrophic factors Neutrophic factor(nf) 는주로신경단위뿐만아니라청각기의상피층같은비신경단위조직 (non-neuronal tissue) 에많은영향을미치는것으로알려져있다. 정상적인청각신경단위발생과정의중요한 factor 로는 brain derived neurotrophic factor(bdnf) 와 neurotrophin 3(NT-3) 을들수있다. 44) NT-3 는청각기의감각상피의발생에도중요한역할을한다고한다. 45) BDNF와 NT-3 는 glial cellline derived neurotrophic factor(gdnf) 와비슷하게성숙된청각유모세포의손상으로부터의방어인자역할을수행하는것으로알려지고있다. 46-48) 하지만이러한방어기전도정상적인생체내에서초기에일어나다가자극의정도가지속할때는그능력의한계를접하게된다. 그러므로앞으로의예방치료는 anti-oxidant와 NF, NMDA 형태의 glutamate receptor antagonist, nitric oxide(no)blocker와 anti-apoptotic agent 의병합치료에목표를두는것이좋을것으로사료된다. 49) Anti-oxidants ROS(reactive oxygen substance) 는 cell death, 세포치환같은변화를가져와조직내의손상을가져오는것으로 anti-oxidants 의사용은조직내의 free radical 제거에이론적으로적합한방어인자로작용할것으로본다. 실제로 deferoxamine, dihydroxylbenzoate와같은 iron chelator 는 aminoglycoside 계의내이독성작용의방어에 탁월하다는보고가있다. 50) 현재안전하면서저비용의약제로아스피린의유용성에대한보고가증가하고있다. 51) Anti-apoptotic agents 일반적으로 cell death cascade 는비교적제한된과정과분자물질에의하여급속히진행되는것으로알려지고있다. 이러한 cascade 에서분자물질의 signaling 동정은 cell death 의예방에상당한도움을주는것으로본다. 예를들면겐타마이신의이독성에의한유모세포의 cell death 와 apoptosis에 JNK가관여하는것으로알려졌는데이과정은 CEP-134731의주입으로상당히통제할수있음을알수있다. 52)53) 그외 organ of Cori의 apoptosis에영향을미치는 caspase의 inhibitor로는 Z-VAD-FMK 를들수있는데주로 caspase-3 dependent apoptosis 에효과적인 inhibitor 로작용한다고알려져있다. 54) 최근에는 caspase inhibitor 가내이의손상방어작용에중요한역할을하는것으로밝혀져이에대한임상적연구가활발히진행되고있는실정이다. 결 론 노인성난청은우리사회가점점노령화시대로접어듦으로인하여그수도증가추세이며이비인후과영역에서장애진단서발부의상당한부분을차지하고있음을주지하고있다. 이러한노인성난청의경우그질환단독으로치료및예방에궁극적목표를두는것보다는전신적노화에대한근본적인식의변화가필요하리라본다. 최근에는 C57B6/J mice에항산화제의투여, gene therapy, stem cell 국소주입등의많은연구가진행되고있으며, 향후이에대한체계적연구가더욱더필요하리라고본다. REFERENCES 1) Fransen E, Lemkens N, Van Laer L, Van Camp G. Age-related hearing impairment (ARHI): Environmental risk factors and genetic prospects. Exp Gerontol 2003;38(4):353-9. 2) Davis A. Prevalence of hearing impairment. In: Davis A, editor. Hearing in Adults. Whurr Publishers Ltd. London:1994. p.43-321. 3) Schuknecht HF, Gacek MR. Cochlear apthology in presbycusis. An Otol Rhinol Laryngol 1993;102(1 pt 2):1-16. 4) Saitoh Y, Hosokawa M, Shimada A, Watanabe Y, Yasuda N, Murakami Y, et al. Age-related cochlear degeneration in senescence-accelerated mouse. Neurobiol Aging 1995;16(2):129-36. 5) Cohn ES. Hearing loss with aging: Presbycusis. Clin Geritar Med 1999;15(1):145-61. 6) Semsei I, Szeszak F, Nagy I. In vivo studies of age dependent de- 965
노인성난청의환경위험요소들에대한고찰 crease of the rates of total and mrna synthesis in the brain cortex in the rats. Arch Gerontol Geriatr 1982;1(1):29-42. 7) Strehler BL. Aging: A challenge to science, society and the individual. Clin Geriatr Med 1985;1(1):5-13. 8) Pommier JP, Lebeau J, Ducray C. Chromosomal instability and alteration of telomere repeat sequences. Biochimie 1995;77(10):817-25. 9) Shay JW, Wright WE. Telomerase activity in human cancer. Curr Opin Oncol 1996;8(1):66-71. 10) Hiyama K, Hirai Y, Kyoizumi S, Akiyama M, Hiyama E, Piatyszek MA, et al. Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol 1995;155(8):3711-5. 11) Kane DJ, Sarafian TA, Anton R, Hahn H, Gralla EB, Valentine JS, et al. Bcl-2 inhibition of neural cell death: Decreased generation of the reactive oxygen species. Science 1993;262(5137):1274-7. 12) Korsmeyer SJ, Yin XM, Oltvai ZN, Veis-Novack DJ, Linette GP. Reactive oxygen species and regulation of cell death by the Bcl-2 gene family. Biochim Biophys Acta 1995;1271(1):63-6. 13) Wright A, Davis A, Bredberg G, Ulehlova L, Spencer H. Hair cell distributions in the normal human cochlea. Acta Otolaryngol Suppl 1987;444:1-48. 14) Mulroy MJ, Henry WR, McNeil PL. Nose-induced transient microlesions in the cell membrane of auditory hair cells. Hear Res 1998; 115(1-2):93-100. 15) Yamasoba T, Nuttall AL, Harris C, Raphael Y, Miller JM. Role of lutathione in protection against noise-induced hearing loss. Brain Res 1998;784(1-2):82-90. 16) Emmerich E, Richter F, Reinhold U, Linss V, Linss W. Effects of industrial noise exposure on distortion product otoacoustic emissions (DPOAEs) and hair cell loss of the cochlea-long term experiments in awake guinea pig. Hear Res 2000;148(1-2):9-17. 17) Corso JF. Support for Corso s hearing loss model. Relating aging and noise exposure. Audiology 1992;31(3):162-7. 18) Passchier-Vermeer W. Measurement and rating of impulse noise in relation to noise-induced hearing loss. In: Rossi G, editor. Noise as apublic health problem. Milano;1983. p.143. 19) Henderson D, Subramanian M, Boettcher FA. Individual susceptibility to noise-induced hearing loss: An old topic revisited. Ear Hear 1993;14:152-68. 20) Clark WW. Noise exposure from leisure activities: A review. J Acoust Soc Am 1991;90:175-81. 21) Aran JM, Hiel H, Hayashida T. Noise, aminoglycosides, diuretics. In: Dancer A, Henderson D, Salvi R, Hmernik R, editors. Noise induced hearing loss. Mosby. St Louis;1992. p.188-95. 22) Prezant TR, Agapian JV, Bohlman MC, Bu X, Oztas S, Qiu WQ, et al. Mitochondrial ribosomal RNA mutation associated with both antibiotic-indced and non-syndromic deafness. Nat Genet 1993;4(3): 289-94. 23) Usami S, Abe S, Akita J, Shinkawa H, Kimberling WJ. Sensorineural hearing loss associated with mitochondrial mutations. Adv Otorinolaryngol 2000;56:203-11. 24) Boettcher FA, Gratton MA, Bancroft BR, Spongr V. Interaction of noise and other agents: Recent advances. In: Dancer A, Henderson D, Salvi R, Hmernik R, editors. Noise induced hearing loss. Mosby. St Louis;1992. p.175-87. 25) Stypulkowski PH. Mechanisms of salicylate ototocity. Ear Rs 1990; 46(1-2):113-45. 26) Rosenhall U, Sixt E, Sundh V, Svanborg A. Correlations between presbycusis and extrinsic noxious factors Audiology 1993;32(4): 234-43. 27) Brant LJ, Gordon-Salant S, Pearson JD, Klein LL, Morrell CH, Metter EJ, et al. Risk facors related to age associated hearing loss in the speech frequencies. J Am Acad Audiol 1996;7(3):152-60. 28) Gates GA, Cobb JL, D Agostino RB, Wolf PA. The relation of hearing in the elderly to the presence of cardiovascular risk factors. Arch Otolaryngol Head Neck Surg 1993;119(2):156-61. 29) Fuortes LJ, Tang S, Pomrehn P, Anderson C. Prospective evaluation of association between hearing sensitivity and selected cardiovascular risk factors. Am J Ind Med 1995;28(2):275-80. 30) Kurien M, Thomas K, Bhanu TS. Hearing threshold in patients with diabetes mellitus. J Laryngol Otol 1989;103(2):164-8. 31) Janssen GM, Maassen JA, van Den Ouweland JM. The diabetesassociated 3243 mutation in the mitochondrial trna (Leu(UUR)) gene causes severe mitochondrial dysfunction without a strong decrese in protein synthesis rate. J Biol Chem 1999;274(42):29744-8. 32) Antonelli AR, Bonfioli F, Garrubba V, Ghisellini M, Lamoretti MP, Nicolai P, et al. Audiological findings in eiderly patients with chronic renal failure. Acta Otolaryngol Sppl 1990;476:54-68. 33) Page GP, Amos CI. Comparison f linkage-dequilrium meths for localization of gene influencing quantitative traits in humans. Am J Hum Gent 1999;64(4):1194-205. 34) Pickles JO. Mutation in mitochondrial DNA as a cause of presbycusis. Audiol Neurootol 2004;9(1):23-33. 35) Seidman MD, Bai U, Khan MJ, Quirk WS. Mitochondrial DNA deletion associated with aging and presbycusis. Arch Otolaryngol Head Neck Surg 1997;123(10):1039-45. 36) Basoah A, Matthews PM, Morten KJ. Rapid rates of newly synthesized mitochondrial protein degradation are significantly affected by the generation of mitochondrial free radicals. FEBS Lett 2005;579 (28): 6511-7. 37) Mate MJ, Ortiz-Lombardia M, Boitel B, Haouz A, Tello D, Susin SA, et al. The crystal structure of the mouse apoptosis-inducing factor AIF. Nat Struct Biol 2002;9(6):442-6. 38) Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S, Larochette N, et al. DNA bindind is required for the apoptogenic action of apoptosis inducing factor. Nat Strut Biol 2002;9(9):680-4. 39) Schuknecht HF. Pathology of the ear. Cambridge:Harvard University Press;1974. p.388-409. 40) Sha SH, Taylor R, Forge A, Schacht J. Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals. Hear Res 2001;155(1-2):1-8. 41) Mulrow CD, Aguilar C, Endicott JE. Quality of life changes and hearing impairment: A randomized trial. Ann Intern Med 1990;113 (3): 188-94. 42) Rosen S, Olin P, Rosen HV. Dietary prevention of hearing loss. Acta Otolaryngol 1970;70(4):242-7. 43) Willott JF, Erway LC, Archer JR, Harison DE. Genetics of agerelated hearing loss in mice II. Strain differences and effects of caloric restrictionon cochlear pathology and evoked response thresholds. Hear Res 1995;88(1-2):143-55. 44) Fritzsch B, Farunas I, Reichardt LF. Lack of neurotrophin 3 causes losses of both classes of spiral ganglion neurons in the cochlea in a region-specific fashion. J Neurosci 1997;1(16):6213-25. 45) Fritzsch B, Barbacid M, Silos-Santiago I. Nerve dependency of developing and mature sensory receptors cells. Ann NY Acad Sci 1998;855:14-27. 46) Gao WQ. Therapeutic potential of neurotrophins for treatment of hearing loss. Mol Neurobiol 1998;17(1-3):17-31. 47) Marzella PL, Gillespie LN, Clark GM, Bartlett PF, Kilpatrick TJ. The neurotrophins act synergistically with LIF and members of the TGFbeta superfamily to promote the survival of spiral ganglia neurons in vitro. Hear Res 1999;138(1-2):73-80. 48) Keithley EM, Ma CL, Ryan AF, Louis JC, Magal E. GDNF protects 966 Korean J Otolaryngol 2006;49:962-7
the cochlea against noise damage. Neuroreport 1998;9(10):2183-7. 49) Seidman MD. Effects of dietary restriction and antioxidants on presbycusis. Laryngoscope 2000;110(5 pt 1):727-38. 50) Song BB, Anderson DJ, Schacht J. Protection from gentamicin ototoxicity by iron chelators in guinea pig in vivo. J Pharmacol Exp Ther 1997;282(1):369-77. 51) Sha SH, Schacht J. Antioxidants attenuate gentamicin-induced free radical formation in vitro and ototoxicity in vivo: D-methionine is a potential protectant. Hear Res 2000;142(1-2):34-40. 52) Liu W, Staecher H, Stupak H, Malgrange B, Lefebvre P, Van De Water TR. Caspase inhibitors prevent cisplatin-induced apoptosis of auditory sensory cells. Neuroreport 1998;9(11):2609-14. 53) Rybak LP, Husain K, Morris C, Whitworth C, Somani S. Effect of protective agents against cisplatin ototoxicity. Am J Otol 2000;21 (4):513-20. 54) Takahashi K, Kamiya K, Uraser K, Suga M, Takizawa T, Mori H, et al. Caspase-3-deficiency induces hyperplasia of supporting cells and degeneration of sensory cells resulting in the hearing loss. Brain Res 2001;894(2):359-67. 967