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Audiological Medicine Publication details, including instructions for authors and subscription information: http://www.informaworld.com/smpp/title~content=t713782286 Pharmacological approaches to the prevention and treatment of cochlear injury due to noise

To cite this Article: , 'Pharmacological approaches to the prevention and treatment of cochlear injury due to noise', Audiological Medicine, 5:1, 66 - 80 To link to this article: DOI: 10.1080/16513860601181046 URL: http://dx.doi.org/10.1080/16513860601181046

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© Taylor and Francis 2007 Downloaded By: [informa internal users] At: 08:00 11 May 2007 -al [email protected] E-mail: SN15-8XpitIS 6133 online 1651-3835 print/ISSN 1651-386X ISSN 56 N.W. 3400 Institute, Ear science. Hough Kopke, D. basic R. Correspondence: of realm the in are data date, To the be studies. of to preclinical most of known proven variety a and these in explored successful of been most have Therapeutic mechanisms to issue). this corresponding in article strategies (see Schacht processes and death Talaska cell by as oxida- well as and stress, fluxes tive calcium excitotoxicity, reperfusion, glutamate ischemia now include have These mole- described. processes other been cellular of and number biochemical, a cular, documented, consis- been has and tently that macro- the damage ameliorate to cochlear addition micro-mechanical to In hazard. help phar- common this that might suggested approaches noise- have of macological injury basis molecular cochlear and induced da- cellular numerous the noise decade of past treat the studies Over and cochlea. the prevent to mage to pharma- adjunctive approach an cological towards research to driving that limitations are and inherent devices, some have hazardous protection approaches hearing these noise personal less better develop workplaces approaches make engineering in Although to made loss. being hearing are preven- sensorineural advances common of most cause the table be loss to hearing continues hearing for (NIHL) noise-induced need programs, the of conservation awareness growing Despite Introduction Clinical robust. quite are molecular effects and these that of cellular compounds words: Some therapeutic the Key injury. of elucidating number of a to mechanisms emerge. of known decade documentation to on the last beginning based to are the led hearing remain studies has in to to This devices damage time noise. next noise protection to much a SNHL, due attenuate hearing from devoted injury of researchers personal cochlear have Therefore cause of limitations. and worldwide leading mechanisms inherent hearing solutions have laboratories of second they implementation engineering of loss, the the hearing While despite number is noise-induced SNHL preventing II. noise preventable to War of approaches of World cause important effects leading after the damaging is programs It the conservation world. to industrialized the due in (SNHL) presbyacusis, loss hearing Sensorineural Abstract USA City, Oklahoma Institute, Ear Hough KOPKE D. RICHARD noise of to treatment due and injury prevention cochlear the to approaches Pharmacological Medicine Audiological O:10.1080/16513860601181046 DOI: os-nue ern os rvnin ramn,hi el,oiaiesrs,aueaosi trauma acoustic acute stress, oxidative cells, hair treatment, prevention, loss, hearing noise-induced 07 :66 5: 2007; . # 80 07Tyo Francis & Taylor 2007 th tet kaoaCt,O 31,UA Tel: USA. 73112, OK City, Oklahoma Street, 6 fautdsbighaigls sdet noise to due is loss that hearing are disabling estimates adult worldwide of and 16% (3), NIHL of risk as such to exposures, due (2). intensity explosions damage high permanent unexpected anticipated to short be leads always frequently cannot this noise and damaging (1), HPD 6) an wearing precludes need communicate overriding to the both applications device in civilian often the and 5) military of maintained; be fitting always precise cannot which on HPD relies protec- 3) their capability 4) the tive cochlea; dependent; the frequency by-passing is damage skull, attenuation trans- to be the device the can through protective of energy directly capability acoustic mitted protective injurious 2) the devices noise device; exceed 1) can because effective protection levels partially only are hearing (HPDs) Currently-available be strategy useful? pharmacological a might Why and available some of data. by clinical made induced emerging be the will injury of Mention many cochlear noise. on of based mechanisms of cochlea ap- known treatment the pharmacological and to damage prevention the noise the at review aimed will proaches article This ntewrpae3 o4 ilo mrcn r at are Americans million 40 to 30 workplace the In / 0 1 20 Fax: 1270. 917 405 1 / 0 4 6226. 947 405 1 Downloaded By: [informa internal users] At: 08:00 11 May 2007 htccla nuywsas eaoial induced but metabolically nature, also NIHL in was (12 that physical injury found or cochlear was mechanical that it just ago, not decade was a effectiveness. than conservation More hearing solu- improve additional to require tions factors aforementioned the (10,11). transporta- construction and and include, farming (8,9), tion (7), overexposure mining have acoustic others, that among of occupations active risks conservation are Civilian significant HPDs (5,6). hearing of ongoing use and though the emphasizing even programs rising (4) expenditures NIHL annually disability (VA) with military, problem Affairs expensive the and Veterans acute an In be to employment. continues in exposure nuisdsrbdicuehi elseeclainjury stereocilia repair cell (22 (19 hair intrinsic include an exist described injuries that does indicating capability thought threshold (TTS), lesions. are temporary injuries shifts pharmacologically noise-induced destructive to milder to contribute less these to of these possible some of Indeed, be repair might described, enhance be been it may has and that micromechanical damage considered However, pharmacolo- with approaches. induce treatable to be mechanical gical likely not is would gross that (18), Corti injury membrane of organ causes basilar the the of from that separation the as noise such damage, level High damage Micromechanical the to damage noise cochlea treat and prevent to strategies pharmacological Mechanism-based co- acutely-injured intervention. the pharmacological treating to through resistant chlea or more injury cochlea conserva- acoustic the hearing hearing making for preventing namely, strategies in tion, other compounds suggests of loss acoustic number of the a success with The of variety (16,17). reducing associated models animal a in loss in overexposure defined hearing effective has permanent therapeutics models potential animal in research using role (15), significant injury cochlear a acoustically-generated plays stress oxidative metabolic igefcso oi roiaieiblnesecond- imbalance oxidative or ionic of dama- the effects ameliorating ging or processes, enhancing repair states, (27). intrinsic might energy reticular cellular mechanisms perturbations optimizing the these include ionic and to in toxic approaches cells holes to Treatment hair and leading (25), (26), lamina between cells cells junctions pillar supporting of cell loss ruptured (19), membrane tectorial hs hl P opinei lasa issue, an always is compliance HPD while Thus, 4.Snetedsoeyta noise-induced that discovery the Since 14). 4,dsoncino troii isfo the from tips stereocilia of disconnection 24), 1.Micromechanical 21). ramn fccla nuyb hraooia methods pharmacological by injury cochlear of Treatment in samr motn atrta CO than factor important cochlear-oxygena- more a (i.e. is oxygen tion) that concluded It shifts. was threshold a noise-induced in in resulted decrease oxygen marked 100% and controls to compared hfsi otfeuniswietemxueo 5% of mixture the while threshold frequencies CO reduced most in in shifts resulted carbogen exposure, a tde sa gn opeetnoise-induced prevent cochlear to maintained Pentoxifylline agent flow, shifts. an xanthine blood threshold as bed a studied capillary was Pentoxifyllin, promotes that (32). derivative noise- damage from cochlea the induced of protection in vasodilator) %CO 5% l hfscmaigcroe 9%O (95% carbogen thresh- (31). comparing noise-induced shifts frequencies cochlear old on lower study the another preserved In at noise- and sensitivity prevented ischemia auditory exposure antagonist microcirculatory noise receptor induced of during angiotensin Pretreatment the sarthran others. with and animals carbo- glucocorticoids been pentoxifylline, gen, have sartharan, changes including noise-induced studied, from flow is blood compounds these of the (30). effects in vasoconstriction the locally-induced isoprostanes of of One formation to cochlea. intense the leading that induces found (ROS), study noise recent species A oxygen damage. forma- oxidative reactive by the of enhance article can tion Re-oxygenation reperfusion (see issue). with this cochlea ischemic occurring in the Schacht an and to Talaska induces thought injury is overexposure it reperfusion flow however, acoustic blood general, cochlear In that on varied. sound more loud have are of effect observations exposure the reported sound on investigators’ loud reported, to been due anatomy cochlear physiology in and changes consistent fairly While injury Ischemic steady (28). (28) both noise for impulse loss effective and cell state was ears. KX1-004, control hair agent, pretreated and One solution-only hearing to Treated in less compared exposure. noise inhibitors showed level window Src ears high to round specific prior several solution the were with through ears membrane Src Chinchilla topically death involving (29). pathway can pretreated cell kinase a matrix tyrosine programmed of protein extracellular activation of the their initiation through and the cells induce between or connections been of recently cells Disruption has (28). death described cell programmed to induced recovery. order and in repair for injuries conditions micromechanical the optimize these to ary ait fcmonsfrpoetn cochlear protecting for compounds of variety A mechanically- to approach therapeutic novel A 2 aryeddn ifrnei hehl shifts threshold in difference no yielded /air 2 arad10 xgngvndrn noise during given oxygen 100% and /air 2 5 CO /5% 2 ie sa as (i.e. 67 2 ), Downloaded By: [informa internal users] At: 08:00 11 May 2007 ihterdxmdltr ieo h N-methyl-D- the of site glutamate modulatory redox noise-induced interact the to with to thought is due Carbamathione excitotoxicity. injury decrease to reported cochlear been have number strategies A different (40). (OHCs) of precursor cells interfering hair (GSH) outer by glutathione the in the or cystine of (39), uptake (NO) the oxide with nitric to (36 related neu- fluxes ionic auditory inducing over- primary by rons acoustic afferent injure during may exposure release glutamate Excessive excitotoxicity Glutamate less significantly potentials. evoked reduction were auditory noise-induced of improve therapies not did or other effective All or prednisolone HES. with predniso- monotherapy and by HBO followed of lone, combination was a loss with hearing achieved noise-induced on effect therapeutic 68 ohericei a civdol yHES, by only achieved noise-induced on was HBO effect ischemia therapeutic (35). cochlear isotonic HES) sustained or of A prednisolone, and without infusion pentoxifylline, saline, and (IBO); (simultaneous with supplements (HBO) oxygenation H1-receptor oxygenation hyperbaric histamine isobaric sodium, antagonist); diclofenac (predniso- biloba, lone, agents Gingko anti-inflammatory betahistine, drugs naftidrofuryl); promoting the pentoxifylline, iso- flow blood (HES, after of in (placebo); infusion studied and saline tonic intravenous were during treatments: ABRs pigs following and guinea CAPs, noise-exposed CMs, as as oxygen, of study well pressure blood partial this cochlear perilymphatic in study, and complex measures flow very ABRs. these another on and In effect (34). naftidro- CAPs no and had of biloba (HES furyl recovery Gingko full 200) pentoxifylline, even Saline, HES or and (betahistine) of 70 recovery partial partial and in HES CMs, resulting 70, betahistine, HES and action after 200 significantly measures steady improved brainstem compound evoked (ABRs) and and (CMs), Co- (CAPs), the unexposed pigs. potentials microphonics guinea of in noise-exposed chlear studied broad-band combinations state and was (HES), various starch naftidrofuryl drugs, and hydroxyethyl biloba, betahistine, as Gingko such promot- pentoxifylline, flow blood drugs, of effect ing the blood example, cochlear For on flow. effects potential reduce with compounds did drug not this (33). TTS with did noise-induced per- Treatment vascular but increased meability. capillaries, or vasoconstriction through prevent movement blood red cell continuous by assessed as microcirculation ame l aesuidawd ait of variety wide a studied have al. et Lamm ..Kopke R.D. / E,adpnoiyln.Hwvr h best the However, pentoxifylline. and HES, 8 rfe radicals free or 38) rteteto rgt h on window round occur the that to drug side-effects topical and a of (46,47), of MK-801 issue as pretreatment such NIHL the agents prevent with be to antagonist may glutamate model. spectrum this in loss hearing in and effective cell most hair in was NAC reducing NAC by Overall, and regions. core, three modiolar all and wall L-NAME by lateral core, the modiolar in and Corti of 174494 organ PD the in and MK-801 was by cochlea but the attenuated in significantly elevation kHz 8-isoprostane peroxide Noise-induced lipid 2 kHz. the in 20 at at shifts them increased threshold L- partially. cell attenuated so hair did NAME 174494 and PD MK-801 shifts while effectively, (45). threshold loss model attenuated pig NAC guinea and a lipid cochlear in and peroxidation loss HC cochlear NIHL, reduce to effectiveness their L-N(omega)- anti- in (NAC) the inhibitor N-acetylcysteine and oxidant (L-NAME) synthase ester NO methyl Nitroarginine the com- to were 174494) pared PD antagonist receptor NR1/2B NMDA (selective antagonist NMDA specific and more MK-801 a study, comparison a hearing In potential (44). evoked thresholds noise-induced by Caroverine measured h. as against loss 1 hearing function for cochlear exposure steady noise protected by level followed round high rodents, the state of onto applied membrane was window (AMPA)), acid pionic and an (NMDA receptors Caroverine, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepro- glutamate (43). two of TTS antagonist protected guinea noise-induced and the noise state against of steady level membrane high to window prior pig solu- round as the to applied broad-spectrum tion was a antagonist, acid, receptor prevent potential Kynurenic glutamate not (41). did action loss but intraperitoneal OHC shifts compound by threshold mg/kg noise-induced reduced (1 study, another rats injection) after In of (42). dendrites exposure pretreatment and neuron noise intraperitoneal ganglion state loss by steady spiral hearing of mg/kg temporary swelling (1 prevented guinea MK-801 of injection) pretreatment with study, one pigs In calcium channels. receptor-linked ion NMDA blocking glutamate by (41,42). of effects loss inhibition complete hearing produces MK-801 noise-induced in reduction permanent utilized demonstrate of to been experiments has NMDA science basic The MK-801 chinchilla. antagonist in and receptor loss OHC hearing band attenuated mg/kg) octave permanent significantly level high (5.6 exposure, 6-h Carba- a noise systemically after (1). and before given receptor shortly NMDA when the mathione, of selective partial postulated antagonism by and excitotoxicity cochlea gluta- glutamate inhibit the several to in of found receptors one mate receptor, (NMDA) aspartate n ifclypeldn h s fabroad- a of use the precluding difficulty One Downloaded By: [informa internal users] At: 08:00 11 May 2007 nue arcl osi oetmdl (59,60). models rodent noise- in decrease loss the to cell reported hair of induced been cochlear infusion has the tympani into The scala leupeptin inhibitor death. calpain calpain cell potent of onset programmed use calpain-induced the the of blocking through thus noise inhibitors, loss excessive Yet hearing (58). to attenuate exposure to due been noise has state approach steady another where intense prior mice an intraperitoneally and to injected pigs noise-induced were guinea inhibitors in in these reduce confirmed study were subsequent and data a These to (57). loss shifts prior threshold significantly pigs OHC to reported guinea decrease was in exposure noise cyclosporin intense inhibitors and calcineurin the calci- FK506 pathways. of of apoptotic application expression topical activates The the turn calcium in induce which OHC to neurin, known influx. is calcium influx noise- excessive of effects induced the modulating by achieved been has (54 family Bcl-2 proteins the of death in (Bcl-2-associated proteins BAD proapoptotic the promoter) as involving well those activa- as including calpains ROS, pathways death more cell produce of several tion stimulation to the mitochondria including have the cochlea in can of the overstimulation overload in acoustic calcium consequences of This one effects cochlea. is OHCs the of cytoplasm of the into calcium of Influx imbalance homeostasis Calcium (53). humans noise- in and (52) TTS rodents induced in impulse loss permanent hearing oxygenation not noise-related but and temporary flow prevent Additional supplementation blood (51), cochlear magnesium (50). improve that may membranes suggest glutamate studies of presynaptic glutamate release the excessive block from to act by may and induced toxic release glutamate the influxes reducing reduce and calcium to countering thought by excitotoxicity is shifts Magnesium exposure threshold (48). noise noise-related reduce weapons to reported and was training basic cell trainees during basic hair (48,49). Israeli in overexposure supplementation to and acoustic Magnesium with reported hearing associated and loss is noise-induced shifts, supplementation ameliorate ion threshold magnesium noise-induced gluta- preventing other than agent (1). oral antagonists an mate appli- as potential more clinically have cation might FDA-approved it the disulfiram, of metabolite drug active antago- an receptor is NMDA and nist partial Because a is impractical. carbamathione clinically be would membrane ansu a ensuidi h otx of context the in studied been has Magnesium 6.Eprmnal,sm success some Experimentally, 56). ramn fccla nuyb hraooia methods pharmacological by injury cochlear of Treatment DO hltsio ntsusadpeet free reaction prevents Fenton and the iron inhibiting (the tissues by in formation mesylate radical iron Deferoxamine chelates (64). (DFO) radicals XO damaging an generate superoxide as actually role can reduce threshold its allopurinol in inhibitor permanent to Interestingly, (63). not found (PTS) shifts but was TTS allopurinol and noise-induced state microphonic steady noise, level higher impulse with cochlear model using pig study guinea and another a In noise. partially CAP that by damaged rats thresholds in reported the noise and state (62) preserved steady before prolonged al. given a after allopurinol et oxidase free injected xanthine Seidman reduce systemically inhibiting (61). can by (XO) radicals, formation free production. radical some of radical scavenger free Preventing GSH scavenging, radical etc.). inhibition, free death (e.g. cell mechan- production, multiple action have of them of isms many mechan- action, primary of a ism of have compounds many listed While above the (LA)). (acetyl-L-carnitine acid R-alpha-lipoic mitochondria ALCAR, 2-oxothiazolidine- repairing and protect- ester, and ing GSH (4-OH- D-methionine), GSH (OTC), with 4-carboxylate 4-hydroxy-PBN homeostasis (NAC, GSH prodrugs PBN, enhancing PBN)), ebselen, lipoic superoxide (SOD-PEG), acid, alpha-tocopherol, glycol antioxi- dismutase-polyethylene (resveratrol, extrinsic with dants treatment (R-PIA)), (R-phenylisopropylade- nosine activity up-regulating enzyme antioxidant (PBN)), free edaravone, mannitol, phenyl-N-tert-butylnitrone with (salicylate, scavengers production treatment radical radical deferoxamine), free have prevent (allopurinol, Investigations to agents homeostasis. included been redox has cochlea the restoring to in AAT treating approach and oxidative successful preventing very additional one impaired to Accordingly, with stress. leading coupled production, species radical energy increased free to to leads of probably levels oxidants addition of production levels in ongoing high of by noise caused injury high-level mitochondrial the of by overdriving antioxidants Metabolic mitochondria intracellular GSH. deranged reduced key as of further such depletion is the Addi- homeostasis with peroxides. oxidant lipid reactive and tionally, ROS, of (RNS), variety species that a nitrogen documented generates well noise acute level is with high It cochlea (AAT). the trauma to in acoustic stress contribute oxidative probably excessive all excitotoxicity glutamate and reperfusion, ischemia damage, Micromechanical stress Oxidative e eoie eeaigtehgl reactive highly the generating peroxide, gen atdpnetdcmoiinof decomposition salt-dependent louio,a Allopurinol, hydroxyl dihydro- 69 Downloaded By: [informa internal users] At: 08:00 11 May 2007 rprto) h opud4O-B sthe is in al., 4-OH-PBN et compound (Choi manner state The dependent steady dose preparation). 6-h a high-level in a noise after when itself h PTS AAT-induced 4 reducing exposure found administered in was noise effective 4-OH-PBN, be the to compound, related by A the caused (73). reduce not auditory loss to did noise-induced hearing but prior significantly reduced rats shifts toxicant noise, threshold to industrial and given common hearing ACN PBN, additional the (ACN). the by acrylonitrile NIHL, reduce induced of to a loss potentiator found In the was another (72). reduce PBN alone of noise significantly study by follow-on not induced noise, shifts low did level threshold to high PBN rats the the during although of monoxide carbon co-exposure of level by potentiation a the induced the In reduced NIHL reduce PBN toxicants. systemic of to that by administration demonstrated investigators reported caused model, NIHL rat been of has potentiation and exposure. radicals post h 21 the loss, in to seen up hearing were even less peroxidation ear lipid an treated and and noise, by loss 3- cell 130dB the ear hair after to h right 33 exposure to up the h or before into pigs. either pump guinea osmotic infused in of was trauma effects Edaravone the acoustic given investigated against (71) when edaravone al. ineffective et relatively Tanaka or be orally. intravenously to stroke given appears is with and It associated (70). radical infarction ische- injury myocardial free reduce reperfusion to potent, clinically mia novel, used currently a in scavenger (3-methyl-1-phenyl-2- is exposure Edaravone protection pyrazolin-5-one) noise (66). partial state provide AAT to from steady shown was level pigs high guinea and scavenger a before hydroxyl systemically after given a chelator Mannitol, iron weak (69). and and loss PTS cell reducing on hair effects model limited pig showed guinea AAT a of Salicy- in systemically (68). as administered scavenger act late radical can hydroxyl Salicylate effective models. an animal to in NIHL degree attenuate to some shown been all have edaravone scavengers. radical Free (67). ototoxicity display to reported has DFO been loss however, OHC circumstances, ml some and noise Under hearing 5 (66). (treatment) reduced after DFO/kg of partially mg in h injection resulting 100 or an 5 hour (control), received saline/kg One and h). subjects after, 5 exposure, SPL, immediately 115dB band, before, octave noise agents, to kHz exposed other were (4 with pigs along guinea DFO intermediate) female of pigmented (IV) study one oxoiron In an (65). via possibly radical, 70 B sasi-rpaetta cvne free scavenges that agent spin-trap a is PBN ..Kopke R.D. aiyae antl B and PBN mannitol, Salicylate, ann eue lttin.Acrigy another vascularis main- Accordingly, in noise- stria glutathione. involved from enzymes reduced increasing and taining protected catalase in by were of cells activity Corti hair damage that of induced conditioning and organ noise sound level the with high cysteine by associated attenuating followed in loss role gamma-glutamyl a hearing played glu- catalase in and reductase, synthetase changes conditions that suggested exposure tathione data antioxidant noise The several enzyme of enzymes. activity the the antioxidant in changes of cochlear induced and on Each conditioning noise activity. of level combination a high and high noise noise, conditioning level of effects et the conditioning Jacono studied of cochlea. (77) al. up-regulation sound the in the the activity to enzyme due antioxidant of be may part effect protective least exposures At sound to (75,76). resistant damaging more of potentially be method a subsequent to as cochlea described the been preconditioning has noise level low to activity. enzyme NAC antioxidant of with Up-regulation or itself by given exposure noise noise- when 1). (Figure after reducing shifts h in threshold 4 results permanent promising derivativeinduced PBN shown This to iNOS. has of as appears activation well as the It (74) inhibit PBN. stress oxidative of mitochondrial reduce metabolite hepatic natural obnto erycmltl lmntdtepraethearing (* permanent two-drug loss the The eliminated Note: completely then one- analysis. nearly was hoc and combination analysis post Statistical exposure, Scheffe days. with two noise ANOVA additional way an after for given h h were 12 4 group) every injection (control solution intraperitoneal carrier by or Drugs mg/kg. 100 oprdt aeiepenietrsod t246ad8kHz. post-noise 8 and days 2,4,6 21 at levels thresholds SPL) pre-noise n hearing 105dB baseline at of to brainstem noise compared shift auditory band average threshold the octave represents response kHz bar 4 Each loss. to hearing exposure (6- noise-induced noise on NAC (4-hydroxy h plus 4-OH-PBN 4-OH-PBN and alone of tylnitrone) Effects 1. Figure

Threshold Shift in dB (2-8 kHz Average) / 10 20 30 40 50 hnhla o ahgop -HPN 0m/g NAC, mg/kg; 50 4-OH-PBN, group. each for chinchillas 6 0 p B Sa / 0.05). u c c e s w s C i f t u o h n l 4 t T r - o r O e l H a t - m P B e n N 4 t - O a o n H f d - A P * 4 c B - u N O t e H A - 4 P - c O B o H N phenyl-N-tert-bu- u - + s P t N B i c N * A + T C Exposure N r A a u C m Downloaded By: [informa internal users] At: 08:00 11 May 2007 1 gk r5 gk al yintraperitoneal by daily mg/kg 50 or mg/kg Alpha-tocopherol days. SPL) (10 consecutive 100dB three band, for octave were h/day kHz 8 (4 pigs noise guinea a to Pigmented exposed AAT. for prophylaxis (83). attenuated shifts of partially threshold gavage administration noise-induced by rats Chronic to rodents. compound has this loss to wine, hearing given red noise-induced when reduce and to grapes reported in been found com- mainly (antioxidant pound) polyphenol naturally-occurring ohertsusta aaye h imtto reac- dismutation 2O the tion, catalyzes that mammalian tissues in cochlear found enzyme antioxidant expressed water-soluble the (6-hydroxy-2,5,7,8-tetra- acid). and Trolox chroman-2-carboxylic methyl analog C), E SOD-PEG, vitamin (vitamin ebselen, include E), ascorbate (vitamin antioxidants the alpha-tocopherol these neutralize resveratrol, substances’. of other can and radicals Some that free of effect nutrients, oxidant and body natural products certain numerous of including any substances, oxidation; chemical inhibits antioxidant that agent defines ‘an PTS. as Dictionary reducing of to, Medical goal prior the Stedman’s with either AAT antioxidants after, shortly delivery extrinsic or of been variety has a studies of preclinical in strategy antioxidants. tive extrinsic with Prevention noise-induced impulse and (79). loss state protection hearing steady both significant in from R-PIA demonstrated and monoethylester combination glutathione appli- the of exposure assessing cation pre-noise study product membrane additional window An well distortion round loss. as OHC and less thresholds showed as (DPOAE) ears ABR Treated emission of h. otoacoustic 4 band recovery octave for kHz SPL better 4 105dB The a chinchillas. at to of noise exposed ears then the right were to the animals applied of topically window was round levels, antioxidant activity up-regulates enzyme which non-hydrolysable analogue stable a adenosine R-PIA, study, activity of this enzyme purpose In (78). the antioxidant for cochlear drug up-regulating a of window application round membrane the utilizing designed was experiment fetv omo hscmon a rv ob a be available, to prove orally may an challenge. compound therapeutic this of of Delivery in form TTS effective (82). noise-induced mice pigs reducing in in guinea protective enzymes be found SOD also to was PTS the SOD noise-induced Intraperitoneally-injected to of (81). susceptibility one their for increased gene the o ta.(4 eotdteefcso iai as E vitamin of effects the reported (84) al. et Hou ueoiedsuae(O)i constitutively- a is (SOD) dismutase Superoxide evrto (trans-3,4 Resveratrol 2 × / / 2H / 0 / H 2 O ? 5tiyrxsibn) a ,5-trihydroxystilbene), 2 / O 2 8) ncotof Knockout (80). nte effec- Another ramn fccla nuyb hraooia methods pharmacological by injury cochlear of Treatment enrpre opeetATi eea studies several also in has AAT prevent mimic, (85 to peroxidase reported glutathione been a alpha- one), receiving not groups of of tocopherol. those shifts than threshold significantly smaller were ABR alpha-tocopherol frequencies receiving most tested, groups At time-points exposure. noise and three the through before after days days three given was injection) n eai n ea oiiisudrcrancon- certain under toxicities (90 renal ditions and hepatic necrosis ebselen apoptosis, and some induce of and under doses reserves GSH higher thiols deplete possibly cellular so (90), deplete has conditions to Ebselen an shown ebselen. be of One been may effect effect (85). biological response noise dose interesting the loud for from explanation confer (88,89). not protection did trials ebselen additional of clinical dose treatment higher in a stroke used Interestingly, in been has past well and the be side-effects to few reported repeated with is tolerated and Ebselen (86). single also exposures both noise Ebselen cells from (87). hair protection noise inner afforded after the immediately beneath evident of dendrites swelling afferent reduced and the eliminated TTS Ebselen documented h. ABR- or 3 SPL an vehicle for 115dB to noise the study, exposure octaveband of before 4-kHz one h dose 1 antioxidant In ebselen oral mg/kg an its 10 RNS. received in to and pigs due PTS ROS guinea probably against and is of have properties TTS AAT mechanism pigs in both The guinea action and models. reduce rats overexposure to in acoustic range shown kg been per mg 10 0dy fe h ct os xoue investigators exposure, noise to acute 7 days the occurring after several burst days to stress 10 treatment oxidative to delayed of a up length cover the or extending the By study, exposure afterwards. before this either noise In given (94). damaging was model compounds pig hearing of guinea attenuate combination a could given AAT in Trolox after loss and or salicylate before of either doses high relatively (93). intake normal C with vitamin those the dietary to on reduced less compared animals or was diet in C There damage at vitamin PTS. cell high noise induce hair and band to loss h octave hearing 6 kHz for with 4 ascor- SPL diet to 114dB of a exposed levels on then deficient days bate, or 35 albino for supplemented study the one raised normal, In were lack must sources. pigs and pigs, dietary guinea synthesis from guinea C it vitamin obtain as for enzyme such terminal including mammals, few ROS, a and other of Humans radicals. variety hydroxyl and a superoxide against effective idant bee (2-phenyl-1,2-benzisoselenazol-3(2H)- Ebselen nte eyitrsigsuyrpre that reported study interesting very Another antiox- water-soluble a is (ascorbate) C Vitamin 7.Oa oe ftecmon nte4 the in compound the of doses Oral 87). 92). 71 Downloaded By: [informa internal users] At: 08:00 11 May 2007 ail vra2mntm eid(0) Untreated (101). 40 a period shots experienced time rifle animals 2-min M-16 noise-exposed a simulated over of rapidly pairs 150 apoptosis to OHC were exposed Chinchilla of (107). noise onset state steady rapid to compared very cause consid- been to has important noise shown very impulse noise intense a example, of be For type eration. may The injury ear. the the causing damage may (106) noise noise- state steady (103). in chinchilla PTS exposed reducing was gavage in by effective NAC of also Delivery modiolar hair loss. reduced hearing Corti, and and cochlea, cell of the of organ wall lateral attenuated and the core, effectively in NAC noise peroxidation state that lipid steady found level in They high peroxidation (45). to lipid exposed and pigs loss guinea cell hair loss, of attenuation systemically hearing of other effectiveness to in agents NAC administered compared al. study, et subsequent a Ohinata In state (102). steady noise 6-h, band octave by kHz induced 4 loss OHC attenu- and PTS significantly ated reduced NAC- showed a diet combination noise administered salicylate protein state systemically steady low level Chinchilla a high (96). by on induced rats loss of hearing to administration of ester Systemic treatment GSH models. and rodent prevention in the AAT for loud studied from widely loss hearing reduce can (1,79,96,101). a noise GSH with an or of GSH the methionine ester NAC, of as of such replenishment prodrug injury glutathione and acoustic (100) enhances cochlea Induced deficiency (77,99). glu- exposure GSH are noise synthase, peroxidase, loud by glutathione cysteine modulated and glutamyl then reductase gamma enzymes, tathione and as GSH-related overexposure, increase (98). such initially acoustic decline levels to precipitously GSH response cochlear In demonstrated AAT- well cell’s been (96,97). against the has as injury system cochlear GSH defense induced of antioxidant role critical primary the a (GSH), The of glutathione in (95). depletion reduced occurs use rapid antioxidant, AAT key cells With cell’s GSH. that of adminis- pharmaceuticals synthesis by production of through GSH been tration of has models hearing enhancement rodent the in treating AAT to and due loss preventing toward homeostasis. approach GSH Enhancing three beginning exposure. given noise even were after PTS days compounds reduced the some demonstrate when to able were n 80 and eoeadatrteniewt intraperitoneally- with noise the after and before 72 mus 14,ipc 15,o ope kurtotic complex or (105), impact (104), Impulse been have GSH of precursors other and NAC ..Kopke R.D. 0%ls fOC hra nml treated animals whereas OHC, of loss 100% n eysuccessful very One 0BPTS 50dB entse nrdn oeso A.ALCAR AAT. of can and models production energy rodent mitochondrial has in improves that tested agent including one (1,110,113). been is disorders loss (ALCAR) associated loss hearing Acetyl-L-carnitine hearing been trauma-caused of has acoustic variety a mutations mito- with or DNA mitochondria can over- to chondrial acoustic Damage repair been with (112). associated exposure mitochondrial has damage It the inhibiting enhance mitochondria. or that of protect shown repair that the molecules enhance therapeutic to been administer has approach experimental effective Another repair and protection mitochondrial Enhancing (111). exposure noise state a steady during day five injection when daily pigs (1). by guinea systemically exposure in administered loss noise hearing partially permanent to 6-h shown prevent was a OTC, prodrug, after GSH Another and intraperito- before administered neally when hair chinchilla and in hearing loss permanent cell to reducing found in was effective D-methionine be AAT. in to GSH hearing secondary Other decrease effective to loss AAT. reported be prevent been also have to of might prodrugs trials basis NAC clinical the that human on data of number suggesting preclinical a in laboratories, and different The species, three different several (110). in for noise, tested exposure of was types noise NAC acute of effectiveness an decrease after to shortly shown given when been shifts threshold AAT-induced also noise permanent damaging has acute admi- NAC after when and exposures. loss before h hearing 48 and nistered cell significant produced hair doses in of reductions variety a at NAC tered in Three (103). reduction noted studied. significant was a was PTS exposure chinchilla noise after in weeks noise kurtotic induced intraperitone- shifts by threshold the of reduce for effectiveness to daily NAC The ally-injected twice (109). h and h 1 noise, 48 noise, after next to h prior intraperitoneal 1 days noise, two by before for administered daily mg/kg twice 100 was injection and NAC 50, with doses. noted also was significant However, attenuation effective. most was mg/kg dose impulse 325 a of of that indicated attenuation chinchilla the in PTS on noise-induced NAC the of study effect another In dosing PTS. of well reduction as of loss substantial OHC there as of injection paradigm attenuation complete treatment almost intraperitoneal was optimal the for para- Using used dosing NAC. in Different were noise (108). impulse digms of undertaken study was similar rats A 2). (Figure loss 40 a and PTS 30dB in reduction approximately an demonstrated NAC injected nsmay nrprtna n rlyadminis- orally and intraperitoneal summary, In 0 teuto fOHC of attenuation 50% Downloaded By: [informa internal users] At: 08:00 11 May 2007 ** isn arcl ecnaea ucino rqec n h hddaesrpeetteS ftema.C h enpretgsof percentages * B. mean panel The from C: derived mean. are the data The of kHz. SE 8 the to represent 2 areas from ranging shaded frequencies the to and corresponding frequency regions of cochlear in function missing a cells as hair percentage cell hair missing n he ek o otfeunistse.Teewr rgesv hehl hf erae ntetetdgop :Cmaio of Comparison B: group. treated after the h in 1 ( and decreases groups to one shift control prior at the threshold groups h and treated progressive 1 NAC-treated and and were the control h between There the 48 between counts tested. for found cell frequencies were (b.i.d.) hair differences day most outer Significant a cochlear days. for twice two weeks injection following the three intraperitoneal for by and b.i.d. given then (control) and carrier exposure or noise mg/kg) (325 NAC point. ersn h Eo h en.** means. the of SE the represent ree hrl fe os xoue(1)(iue3). (Figure (110) exposure noise after after and shortly impulse before even given and or loss to when (1) chinchilla state in hearing shown noise steady (101) acute permanent been by both the induced has reduce ALCAR dramatically of protect Systemic (115). administration and integrity membrane transport, mitochondrial metabolite restore the transcription, mitochondrial DNA enhance enzymes, mitochondrial respiratory can enhance mitochondrial tissues some are ALCAR of oxidatively-stressed activity that Furthermore, levels in (114). carnitine depleted and critically cardiolipin restore groups control the and NAC-treated the between shift threshold hair cochlear (ABR) and response loss hearing brainstem repetitions) 150 auditory for of SPL peak Comparisons ( (155dB noise-induced A: impulse on survival. (N-acetylcysteine) cell NAC of Effects 2. Figure cnrl ie yitaeioelijcintieady(... o 8had1hpirt n fe os xoueadte ...frthe for b.i.d. then and exposure noise after h 1 and to prior h 1 Otolaryngologica.). and Acta h of 48 courtesy for (b.i.d.) (Figure day days. a two twice following injection intraperitoneal by given (control) n p B / 2er o ohgop) ttretm-ons meitl fe mus os xoue(a ) ek n ek.Errbars Error weeks. 3 and week, 1 0), (day exposure noise impulse after immediately time-points: three at groups), both for ears 12 / .1frLDps o oprsn aebtencnrladNCtetdaiasa ahfeuny A 35m/g rcarrier or mg/kg) (325 NAC frequency. each at animals NAC-treated and control between made comparisons hoc post LSD for 0.01 p B / .1frLDps o oprsn aebtencnrladtetder tec rqec n time and frequency each at ears treated and control between made comparisons hoc post LSD for 0.01 ramn fccla nuyb hraooia methods pharmacological by injury cochlear of Treatment soitdwt A fe ed oporme cell stress programmed to oxidative leads the often AAT with that associated accumulating is Evidence inhibition death Cell neurologic improve (117). rats and in decay function neuro- age-related mitochondrial slow admin- to oxidative nal acid shown of Lipoic been has (116). evidence istration tissues reduce cochlear to in as stress well in PTS as noise-induced rodents attenuate to reported also acid, was lipoic alpha metabolite, mitochondrial Another n / 2er o ohgop) ie ersn h mean the represent Lines groups). both for ears 12 p B / 0.05, 73 Downloaded By: [informa internal users] At: 08:00 11 May 2007 ttretm ons meitl fe mus os xoue(a ) ek n ek.Errbr ersn h Eo h means. the of SE the represent bars Error weeks. 3 and week, 1 0), (day exposure noise impulse after immediately ** points: time three at en :Tema ecnae fhi el isn nccla ein orsodn ofeunisrnigfo o8kz h aaare data The the kHz. of 8 to SE 2 the from represent ranging areas frequencies shaded to the corresponding and * regions frequency cochlear B. of in panel function missing cells a from hair as derived of percentage percentages cell mean hair The missing C: mean mean. the represent Lines groups). both rqec.ACR(0 gk)o are cnrl ie yitaeioelijcintieady(... o 8had1hpirt n h 1 and to Otolaryngologica) prior Acta h of 1 courtesy and (Figure h days. 48 two for (b.i.d.) following day the a for twice b.i.d. injection then intraperitoneal and by given exposure (control) noise carrier after or mg/kg) (100 ALCAR frequency. arcl uvvl :Cmaioso B hehl hf ewe h LA-rae n h oto rus( groups cochlear control and the loss and hearing ALCAR-treated repetitions) the 150 between for shift SPL threshold peak ABR (155dB of noise-induced Comparisons impulse A: on survival. cell (acetyl-L-carnitine) hair ALCAR of Effects 3. Figure ntetetdgop :Cmaio fccla ue arcl onsbtenteACRtetdadtecnrlgop ( groups control the and ALCAR-treated the decreases between shift counts threshold progressive cell were hair There outer tested. cochlear frequencies of all Comparison for weeks B: three group. at treated groups the treated in and control the between found were lcsJKcl et aha ciainand activation pathway death cell CEP-1347 as an JNK from known blocks derived compound inhibitor kinase indolocarbazole molecule small of administration a systemic kinases the example, N-terminal For c-Jun (JNKs). the and (MAPKs) protein kinases mitogen-activated cell involving of pathways activation death the There AAT. implicating of evidence in- models growing death in is applied cell been have specific hibitors effects, death to cell antioxidant decrease may reported through GSH antioxidants of variety and Although a and deafness. membrane AAT-induced window to attenuate topically round or the systemically inhibitors administered death cell been of have variety a Accordingly, death. 74 p B / .1frLDps o oprsn aebtencnrladtetder tec rqec n iepit infiatdifferences Significant time-point. and frequency each at ears treated and control between made comparisons hoc post LSD for 0.01 ..Kopke R.D. p B / .5 ** 0.05, p B / .1frLDps o oprsn aebtencnrladACRtetdaiasa each at animals ALCAR-treated and control between made comparisons hoc post LSD for 0.01 aebe eotdi h ohe fe AAT after cochlea spectrum the broad caspases specific in of Theoretically, reported Activations (121,122). (120). been initiated have cell is programmed an death pathway, or receptor mitochondrial death intrinsic pro-caspase cell an inactive cysteine through injury-mediated either extrinsic an of activated are in caspases family When form. present a are Caspases, proteases, (119). rodents manner dose-dependent trauma-induced in a in acoustic loss hearing prevented permanent delivery Local D-JNKI-1 (119). the of D-JNK-1 of inhibitor membrane death window cell round topical the the in to been application has loss strategy Another hearing (118). rodents noise-induced attenuated partially n / 2er o ohgroups), both for ears 12 n / 2er for ears 12 Downloaded By: [informa internal users] At: 08:00 11 May 2007 teshsbe eotdi oetmdl 7 occurred. models rodent oxidative in has of reported burst been loss has delayed stress cell or of acute second hair number a an a Additionally, maximal take After noise before may (1). it be days acute exposure, apoptosis could noise an prevent tissues damaging after to cochlear treated injured window when therapeutic may exposure there a has that shift suggest be threshold Data a after (treatment). when anticipated shortly occurred exposure the given noise acute or after an (prevention) shortly exposure and noise during, given be before, could Medicines paradigms. different applied two be in could AAT for strategies Pharmacological rodent NT-3 this Treatment in injury. not was cochlear BDNF (125). model but AAT effective preventative a was against perfusion as NT-3 trauma to intracochlear strategy acoustic compared study, was if after BDNF another of loss shortly In hearing or (124). and during damage prevents cell present treatment after, h sensory GDNF 6 or cochlear topical 4 not before that but ear trauma, ear that indicating acoustic one in after h loss to 2 cell and hair GDNF and of hearing reduced application antioxidant neurons Local cochlear and intrinsic defenses. cells enhance also hair may may injured and factors of growth apoptosis These reduce neuro- (BDNF). include brain-derived factor and These trophic (NT-3), neuro- cochlea. factor-3 (GDNF), when trophic factor the PTS neurotrophic into noise-induced glial-derived for reduce locally tested to infused been ability have their factors neurotrophic Several factors Growth hearing permanent a provided of (123). and reduction loss degeneration dependent cell dose mini-pump osmotic hair when an via prevented death, cochlea the cell prevents into perfused necrosis-induced that and agent apoptosis- neuroprotective a zothiazole), were ben- drug Importantly, (2-amino-6-trifluoromethoxy the Riluzole of effective. noise. applications systemic impulse and to local both and exposure from continuous resulting hair loss both reduce hearing can and inhibition loss cell Src Their that cascade. revealed death cell studies of kinase inhibitor tyrosine an protein cells attenuation Src with reported injury sensory (107) cochlear AAT-induced al. in of et death Hu Finally, cell (120). noise-induced programmed prevent cochlear also might inhibitors caspase oesceshsbe eotdwe pharmacolo- when reported been has surprisingly, Not success (94). some exposure noise acute the after 0days 10 ramn fccla nuyb hraooia methods pharmacological by injury cochlear of Treatment aeafce h aa h upeetwswell was may supplement this The 25 and data. than baseline, the greater from However, affected threshold change have a group. a group than as placebo magnesium rather defined the was the in PTS to severe more compared more reported and significantly authors were fire frequent shifts The threshold rifle earplugs. hearing against that by eight protection afforded for the fashion noise augment double-blind placebo a to or received in weeks aspartate drink were liquid also magnesium a they of in and mg as 167 training either protection weapons hearing undergoing setting. prevent wore military (48) a to al. in Subjects magnesium PTS agent et supplemental noise-induced reducing Attias of an in efficacy (48,49). as the trials safe examined clinical and in effective NIHL be to dextran/pentoxifylline, (NAC). N-acetylcysteine diltiazem, and calcium blocker the These channel Several supplementation, trials. clinical magnesium circumstances. in tested include been some now have under a agents be might route application topical injury useful but in- the oral of be acoustic also post-treatment would With accidents, to are prolonged. due exposures juries or noise loud a when conjunction particularly protection situations in where hearing used certain with preferable is In be protection pharmacological might affordable. approach be prophylactic effec- be and be safe, injury, tive exceptionally acoustic be orally, of administered mechanisms specifically known would agent address pharmacological ideal The considerations Clinical (123). ther- perfusion less a but intracochlear trauma within than acoustic efficiently cochlea after h oral the 24 of an injec- window rescued apeutic than Intraperitoneal riluzole time. effective of round same more tion the be the at to given strategy to shown topical agent reasonable were a a agent it the with be if treatment might that injury membrane be a window acoustic may of It severe application (71). to exposure to moderate post up given h if even 21 loss reduced edaravone hearing rodents and of mentioned, damage cochlear perilymph continuously oxidative previously cochlear of into given As infused burst were (94). secondary noise stress drugs delayed the the the after through days PTS if five reduce exposure to administered reported when models of was even combination to salicylate rodent a and shown with Trolox Treatment in been 1). (Figure PTS have (110) noise-induced antioxidants combina- those attenuate and noise of PBN acute 4-OH- tions an ALCAR, after NAC, shortly injury. given is treatment gical ansu upeetto a enreported been has supplementation Magnesium 75 Downloaded By: [informa internal users] At: 08:00 11 May 2007 hehls rprycnetdsbet ( in subjects shifts consented and temporary was group, Properly only each thresholds. evaluated study for levels that exposure varia- measures preliminary subjects, noise of in number bility This small the by confounded attendees. que ta.(2)wsarnoie,dul-ln,pla- double-blind, noise- randomized, discothe voluntary a reducing involving design was cebo-controlled in (129) Kramer al. NAC by the study et first of at The changes. looking auditory efficacy induced initiated and or safety completed been either groups (128). treatment treatments when placebo to trauma compared loss were acoustic hearing relevant sudden particular acute clinically for this or no gains hearing fact, in in in concluded differences sudden were, there as was that well It study pla- as loss. AAT double-blind, hearing for randomized, study a cebo-controlled in studied were group, (127). therapy significant the statistically in not was results this better but for was tendency There otologic loss. a acoustic hearing during postoperative prevent groups much noise control showed nor to experimental drill the ability Neither otologic surgery. its from prospective, 100 assess trauma a involving to in study subjects tested double-blinded was randomized, (diltiazem) blocker (126). humans several in and NIHL measured levels of magnesium correla- parameters serum no between reported tion investigators Other tolerated. aeyadefcc nrdcn uioythreshold auditory reducing of in terms efficacy in and dou- study safety randomized, NAC prospective, placebo-controlled a oral ble-blinded, in evaluated placebo cochlear differ versus study the PTS Another and that TTS considerably. noise-induced hypothesis of the mechanisms are with completely data not consistent These was study (45,101,102,108,109). the threshold unexpected of tone outcome pure the temporary shifts, reducing effect in beneficial NAC large a of document reported not of do data majority animal the Because or delays measures. or tinnitus temporary shifts amplitude or DPOAE TTS in noise-induced differences no significant There no were ingestion. were NAC There the from ques- administered. side-effects reported tinnitus also were and sound-treated tionnaires questionnaires a discothe Side-effect in the performed van. again exiting were discothe Upon measures local a h. attending to NAC 2 effer- the prior to h (an odor 1 effervescent placebo and agent) taste an or identical of water) as tablet tap dose vescent in emissions single dissolved either mg tablet receive (900 otoacoustic to NAC randomized audiometry oral product were tone and pure (DPOAEs) distortion baseline and for assessed were 76 odt,svrlpeiiayciia rashave trials clinical preliminary several date, To pentoxifylline and/or dextran-40 study, another In channel calcium a of efficacy perioperative The ..Kopke R.D. qe audiometric `que, qefor `que n / 31) ` - r ut ifcl oprombtms eperformed be must but few perform studies to A These difficult safety. emerge. quite are to human begun have and studies further clinical animal need in in entities regarding side-effects chemical study effects few new with robust Other associated humans. shown are of and Some have rodents studies. compounds experimental in these loss loss cell hair hearing com- cochlear and Many reducing routes in of noise. variety effects a shown to by have cochlea due the to loss delivered pounds hearing cellular and cochlear many with injury uncovered associated has mechanisms effort molecular research decade and of past deal the great over A recovery the damage. the noise enhancing making or from, to, resistant toward more cochlea approaches potential exploring pharmacological are researchers inherent that have so empha- using limitations approaches in- increasingly these and Nevertheless, becoming programs sized. reduction are noise HPDs conservation dividual for pro- solutions worldwide important Hearing engineering an be blem. other to and continues recreation- AAT or ally occupationally to exposure noise due of types loss hearing Sensorineural Summary and difficult. consent quite informed be of can timely treatment identification by followed quick used, for subjects and injuries being for, acoustic controlled already accidental be is must among variables protection identified numerous be challenging hearing must are risk whom trauma at population acoustic a acute since such for Studies addi- these efficacy. in as and administration, pharmacokinetics of as to well timing tion as and safety, regarding route, learned dose, be initiated to yet being is Much is study preparation). ranging in be al., dose must et encoura- (Kopke a study are and this results ging of these rifle placebo preliminary, findings intense the considered to most the compared the While group to NAC group. shift exposed the threshold for ear noise tone a the be pure in to data addition, rates in of In reduction analysis placebo. initial significant the than in different appeared for there profile no pre- the side-effect but was the from analyzed, NAC that Data show being meal. results still each liminary are placebo with or study day NAC completed of a rando- mg times 900 were three either insert receive Subjects to in-the-ear devices. mized wore protection and required which issued hearing in of were rifles subjects weeks M-16 all with two training 566 weapons underwent routine in Subjects train- tinnitus weapons ing. and routine undergoing DPOAEs, subjects military in changes shifts, lnclsuiso diinlaet r expected. are agents additional of studies Clinical Downloaded By: [informa internal users] At: 08:00 11 May 2007 References programs. conservation the hearing in in adjunct that, place an a as possible have pharma- will very approaches this pharmacological is of future, It efficacy approach. and safety cological the establish to 5 aaeH aa ,Tkym ,KnsiK gciH, Iguchi K, Konishi M, Takayama Y, Nakai H, Yamane 15. 6 ok D le A edro ,Hfe ,FezD, Frenz M, Hoffer D, Henderson KA, Allen RD, Kopke 16. 4 i J unD.Aaoi orltso os induced noise of correlates Anatomic DE. Dunn DJ, Lim 14. 3 i J enc .Aosi aaeo h ohe.A cochlea. the of damage Acoustic W. Melnick DJ, Lim 13. 1 ete ,Sia .Teefcieeso ern protection hearing of effectiveness The N. Seixas R, Neitzel 11. 0 exsN,GlmnB hpadL ete ,Nro S, Norton R, Neitzel L, Sheppard B, Goldman NS, Seixas 10. 2 lpcyN vriwo ehncldmg oteinner the to damage mechanical of Overview N. Slepecky 12. .BcetW,CabranD ala ,MyJ wn SA, Hwang J, May E, Hallman D, Chamberlain WS, Beckett 8. .KpeR.Cmaighaigls ntemltr.Hearing military. the in loss hearing Combating RD. Kopke 4. practical loss-a hearing occupational Preventing NIOSH. 3. of organ the to damage mechanical Predicting GR. Price 2. .WleuhK,Ltrl E ah G akD.The DJ. Wark AG, Kamhi WE, Luttrell KS, Wolgemuth 5. .KpeR,ClmnJ,LuJ apelK,Riffenburgh KC, Campbell J, Liu JK, Coleman RD, Kopke 1. .BhkrB,Pg C oi ,BtsL,Mle G Sack JG, Muller LS, Betts G, Rovig JC, Page BK, Bohnker 6. .Lno ,BeseP hnY os xoue frail of exposures Noise Y. Chen P, Breysse P, Landon 9. Noise L. McWilliams M, Stephenson S, Wilkins D, Landen 7. otiuigt ern os cu nio e.2000; Med. Environ factors Occup J environmental source loss. hearing farmers: and to contributing for occupational conservation of Hearing apportionment al. et M, Gomez elhFl.2005;26 Fall. Health from: http://www.cdc.gov/niosh/95-106.html Oct:1-104:[Available 1996 NIOSH and [cited; 1995 guide. Loss Hearing 2005. of Canada; Ontario, Treatment Falls, and Niagra Tinnitus. Prevention Strate- for -Pharmacologic gies Symposium International In: Corti. fetvns fteNv’ ern osrainprogram. conservation 1995; hearing Med. Navy’s Mil the of effectiveness 806 132 eesst euenieidcdhaigls.Laryngo- loss. hearing noise-induced 2002; scope. reduce stress cochlear to intrinsic defenses enhancing thesis: Candidate’s RH. esne ygne n g rus i e.2002; Med. Mil groups. age and Conservation gender Hearing by personnel Corps Marine 1995 and Program, Navy US DM. okr taNrhAeia hmclfclt.A Ind J Am facility. chemical American 2005; North Med. a at workers J miners. gravel 2004; and Hyg. sand Environ among Occup loss hearing and exposure cutctam n tilbodflw caOtolaryngol Acta after flow. radicals blood free 1995; strial of (Stockh). Suppl emergence and The trauma al. acoustic et T, Nakagawa 513. omnptwy nhi eldah e ok n NY Ann York: New death. share 1999. cell trauma Sci; and Acad hair toxins in demise: pathways radical common A T. Water de van 227 ern os tlrno lnNrhA.1979; Am. North Clin Otolaryngol loss. hearing rhOoaygl 1971; Otolaryngol. Arch observation. microscopic electron transmission and scanning mn osrcinwres cu nio y.2005; Hyg. Environ Occup J workers. construction among mn osrcinidsr prnie.OcpEnviron Occup 2005; apprentices. hearing Med. to industry changes construction induced among noise Prospective SG. Kujawa a:niea olt rb oherfnto.Ha Res. Hear function. cochlear probe to tool a 1986; as noise ear: 13. 5. 38. /22: /307 /47: /62: /112: 21. /364 /309 /160: 99 enhaigtrsod o enlisted for thresholds hearing mean 1999: /1515 9. 17. /219 /519: 30. 32. /94: 22. /87 /1: /294 /532 92. 305. 41. /12: /493 /167: /42: /2: ramn fccla nuyb hraooia methods pharmacological by injury cochlear of Treatment / / / 6 uo ,Pe L evi ’li ,EblnM Pathophy- M. Eybalin C, d’Aldin Gervais JL, Puel R, Pujol 36. 5 av J aenkR,HnesnD uioynerve Auditory D. Henderson RP, Hamernik RJ, Salvi 25. 4 amK rodW ucsflteteto noise-induced of treatment Successful W. Arnold K, Lamm 34. 1 odi ,Kta J hvpj ,SimnM,Quirk MD, Seidman B, Shivapuja MJ, Kittan B, Goldwin 31. 7 ha ,BheB,HrigG.A nvv rcrstudy tracer vivo in An GW. Harding BA, Bohne M, Ahmad 27. Mechanically M. Roberto G, Turrentine RP, Hamernik 26. 2 ac ,Ta ,LRur J utl L ilrJM. Miller AL, Nuttall MJ, LaRouere M, Tsai M, Hatch 32. 3 ike O son P oi D unrblt ftip of Vulnerability SD. Comis MP, Osborne JO, Pickles 23. 2 iemnM.Crncutatutrlcagsi acoustic in changes ultrastructural Chronic MC. Liberman 22. 9 rshS,Srao A nii ehnss urOpin Curr mechanisms. Anoikis RA. Screaton SM, Frisch 29. 3 aoiJ hvpj ,SimnM,QikW.Pentoxifyl- WS. Quirk MD, Seidman B, Shivapuja J, Latoni 33. 4 spu ,ShcenP,Crol ,PprlaM. Paparella S, Cureoglu PA, Schachern V, Tsuprun 24. 0 auz .Nnlna set fotrhi eltransduction cell hair outer of aspects Non-linear R. Patuzzi 20. 8 aenkR,Tretn ,RbroM av ,Hender- R, Salvi M, Roberto G, Turrentine RP, Hamernik 18. 8 arsK,H ,Hnae ,HnesnD rvninof Prevention D. Henderson D, Hangauer B, Hu KC, Harris 28. 1 anesJ,FokA eoeyo hehl hf nhair-cell in shift threshold of Recovery A. Flock JC, Saunders 21. 0 hnt ,Mle M lshlrR,ShctJ Intense J. Schacht RA, Altschuler JM, Miller Y, Ohinata 30. 5 amK rodW h feto lo o promoting flow blood of effect The W. Arnold K, Lamm 35. 9 odanA,BheB,HrigG.Histopathological GW. Harding BA, Bohne AS, Nordmann 19. 7 yc D i .Cmonsfrtepeeto and prevention the for Compounds J. Kil ED, Lynch 17. ilg fteguaaegcsnpe nteccla Acta cochlea. the in synapses 1993; glutamatergic Otolaryngol. the of siology 219. ciiyadccla opooyatrnieexposure. noise after morphology 1979; Otorhinolaryngol. cochlear Arch and activity ohericei,hpxa n ern os n Acad Y N Ann 1999; loss. Sci. hearing and hypoxia, ischemia, cochlear eue eprr hehl hfsatrnie Otolaryn noise. and after 1998; microcirculation Surg. shifts Neck Head cochlear threshold temporary preserves reduces Sarthran WS. fnieidcddmg otertclrlmn.Ha Res. Hear lamina. reticular the 2003; to damage loss. noise-induced of hearing 1986. noise-induced Press; of Plenum York: editors. New aspects V, and London applied Colletti In: RP, and Corti. Hamernik of D, Asic organ Henderson the RJ, in Salvi changes morphological induced h fet fcroe,cro ixd,adoye on oxygen and 1991; dioxide, Res. Hear carbon loss. carbogen, hearing noise-induced of effects The ik ewe troii oaosi ruai h guinea the in trauma 1987; Res. acoustic Hear to pig. stereocilia between links 229 rua eilscinrcntuto fseeclaand stereocilia 1987; of Res. Hear plates. reconstruction cuticular serial-section trauma: elBo.2001; Biol. Cell eprr hehl hfsfloigaosi overstimula- 1996; attenuates acoustic Oto-Laryngologica. Acta and following tion. shifts microcirculation threshold cochlear temporary maintains line uioyhi udei eaint os xouei the in exposure noise of to morphology 2003; relation Neurocytol. and J in links chinchilla. bundle side hair stereocilia auditory the of Structure n h eprr hehl hfsatraosi trauma. acoustic after shifts 2002; Neurootol. threshold Audiol temporary the and ehncldmg nteccla erRs 1984; Res. Hear noise-induced cochlea. impulse the of in correlates damage Anatomical mechanical D. son os-nue ern oswt r-T niios Hear inhibitors. Src-PTK 2005; with Res. loss hearing noise-induced troii olwn xouet nes tmlto.Hear stimulation. intense 1986; to Res. exposure following stereocilia os nue omto fvsatv ii peroxidation 2000; lipid Res. Brain vasoactive cochlea. the of in products formation induces noise n shmcgie i ne a.Ha e.2000; and Res. Hear po(2) ear. inner hypoxic pig perilymphatic noise-damaged guinea ischemic and flow, and normal the blood in function cochlear auditory on drugs ifrne ewe eprr n emnn threshold permanent 2000; Res. and Hear shift. temporary between differences ramn fnieidcdhaigls.Du icToday. 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Rosenberg SA, Lipton 46. 0 uaiK aaeH aaaaM aaaaT Konishi T, Nakagawa M, Takayama H, Yamane K, Sunami 40. 8 uo ,RbladG ulJ,Lni ,EblnM, Eybalin M, Lenoir JL, Puel G, Rebillard R, Pujol 38. 2 unM gra ,EnosP alnB Complementary B. Canlon P, Ernfors K, Agerman M, Duan 42. 2 edwk ,RfnF rilnCo .Teaetcefficacy Therapeutic A. Braillon-Cros F, Raffin I, Sendowski 52. supplement magnesium Preventive F. Scheibe H, Haupt 51. 8 tisJ es ,AmgS hhrA inrM Joachims M, Wiener A, Shahar S, Almog G, Weisz J, Attias 48. 7 cto .Ecttr mn cdrcpo naoit:a antagonists: receptor acid amino Excitatory B. Scatton 47. 9 ocisZ ezrA sn ,Rbnic ,Ata ,Weisz J, Attias E, Rebentisch H, Ising A, Netzer Z, Joachims 49. noise- from Protection J. Schacht JM, Miller Y, Ohinata 45. NMDA LD. Fechter K, Reinhard J, Kong GD, Chen 41. oxidative and iNOS Up-regulated AL. Nuttall X, Shi 39. euto nnieidcdtmoaytrsodsitin Otolaryngol 2004; Clin shift Sci. intake. Allied threshold magnesium oral temporary following humans noise-induced in Reduction o rgidcdnuortcin Neuropharmacology. model neuroprotection? vivo 1992; in drug-induced pigs: guinea for in receptors glutamate cochlear 16. car- 2004; local Res. with Hear pigs. trauma guinea noise in administration against overine function auditory of 81. 26 131 671 32 ersiRs 2005; Res. Neurosci ototoxicity. J aminoglycoside-induced from cells hair cochlear unapg u rho trioaygl 2000; Otorhinolaryngol. the in of antagonist Arch receptor Eur glutamate pig. a guinea as acid kynurenic of n earo ohersnpe fe os-ruainduced 1998; noise-trauma Neuroreport. after loss. synapses hearing cochlear of repair and omnptwyfrnuooi iodr.NEg Med. J Engl N disorders. 1994; neurologic for pathway common ,Iuh .Csiepoet oherotrhi cells 1999; hair Otolaryngol. outer Acta cochlear toxicity. protects glutamate Cystine against H. Iguchi K, curn naen.At tlrno up.1990; Suppl. conditions Otolaryngol anoxic Acta a or ageing. cochlea: ischemic in the of occurring in consequence neurotoxicity possible Glutamate M. Recasens ttxct.Po a cdSiUA 2000; USA. aminoglycoside-induced Sci and Acad noise Nat of Proc ototoxicity. protection the antago- N-methyl-D-aspartate in a nist and 3 neurotrophin of roles ngie is caOoaygl 2006; Otolaryngol. Acta noise pigs. gunshot guinea by in caused trauma acoustic after magnesium of Res. Magnes pig. guinea the of in 2002; impairment oxygenation and noise-induced flow against blood ear inner the protects osidcdb os xoue mJOoaygl 1994; Otolaryngol. 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Za guinea the in loss hearing xprnli ycrilslae ice ipy Res Biophys Biochem and salvage. 1987; allopurinol radical Commun. myocardial of free action in as of inhibitor oxypurinol mechanism oxidase novel xanthine a of scavenger: Role PS. Rao ciaincnrbtst os-nue ern os J loss. hearing noise-induced 2004; Res. to Neurosci contributes activation 167: 832 aia rdcinb louio n atieoxidase. xanthine and 2006; allopurinol Pharmacol. Biochem by production radical ainswt ct ycrilifrto.Cr .2006; in J. edaravone Circ of infarction. efficacy myocardial Long-term acute al. with et patients Y, Nagayoshi J, atri io ri e.1999; Res. a Brain chelator, vivo. neurotrophic in iron line-derived factor cell an glial and by scavenger trauma radical free noise from damage cochlear nue oherdmg.OoayglHa ekSurg. Neck Head noise- on Otolaryngol 1993; dismutase damage. superoxide cochlear and induced allopurinol of effects ttxct fteio hltrdfrxmn.Ha Res. 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J Eur loss. 2005; hearing edaravone noise-induced of administration attenuates Post-exposure al. et K, Takeno eppi rtcssnoyhi el rmaosi trauma. acoustic from 1999; cells Neuroreport. hair sensory protects Leupeptin onnG a eWtrT.Mcaim fcl et in Audiol death 2002; strategies. cell otoprotective Neurootol. of system: Mechanisms auditory injured TR. Water the de van G, Moonen /125 7. /522: /112: /109: /4: /11 31. /116 /44 /1052 5. /34: 8. 21. /148: 6. /344 /7: /5: /165 /10: /78: /90 /314 6. /811 /383 70. /4: 8. /209: 9. /229 /83: /71: 6. 92. /86 /1564 /1747 /815: 36. 90. /42: /94: /317 72. 52. /227 /87 25. 93. 34. /70: / / Downloaded By: [informa internal users] At: 08:00 11 May 2007 5 orah ,Ymsb .Eslnatnae cochlear attenuates Ebselen T. Yamasoba A, Pourbakht 85. 6 cadnS,HnesnD hnY.Low-frequency YH. Shen D, Henderson SL, McFadden 76. 8 gw ,YsiooT iuh ,Sn ,SioI, Saito K, Sano H, Kikuchi T, Yoshimoto A, Ogawa 88. 1 urnP,Guhe R nuto fclua erssby necrosis cellular of Induction ER. 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Ong HM, Shen CF, Yang 90. 6 yc D uR ireC i .Ebselen-mediated J. Kil C, Pierce R, Gu ED, Lynch 86. Water de van D, Henderson RD, Kopke B, Hu AA, Jacono 77. aaecue yaosi rua erRs 2003; Res. Hear trauma. acoustic by caused damage nue hehl hfsi hnhla.Ha e.1997; Res. noise- Hear chinchillas. from in shifts protection threshold induced long-term provides ‘conditioning’ clso:Apaeocnrle,dul-ln lncltrial. 1999; Dis. clinical artery Cerebrovasc double-blind cerebral placebo-controlled, middle acute A in occlusion: Ebselen al. et T, Yamaguchi h lttin eoiaemmtcesln elBiochem. Cell J 2003; ebselen. mimetic peroxidase glutathione the 30. rae ihguahoemnehlse n -I.Hear R-PIA. and 2003; pre- monoethylester Res. chinchillas glutathione in with loss treated hearing Noise-induced T. Nicotera rsraino h ue arclsfo os ruaby trauma noise from 1995; cells Res. Hear hair conditioning. outer sound the of preservation ern osi h hnhla erRs 1997; Res. 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Hamernik TC, Morata D, Henderson 106. J, Liu JKM, Coleman RL, Jackson RD, Kopke EC, Bielefeld 103. 0.HnesnD aenkR.Iplenie rtclrve.J review. critical noise: Impulse RP. Hamernik D, Henderson 104. 0.H H edro ,Nctr M xrml rapid Extremely TM. Nicotera D, Henderson BH, Hu 107. 0.Da ,QuJ arl ,Ooso ,CutrS,Br E. Borg SA, Counter A, Olofsson G, Laurell J, Qiu M, Duan 108. 4 aaht ,JagH,L rl G cah ,Mle JM. Miller J, Schacht CG, Prell Le HY, Jiang D, Yamashita 94. 7 aaoaT arsC hj ,LeR,NtalA,Miller AL, Nuttall RJ, Lee F, Shoji C, Harris T, Yamasoba 97. Glutathione JM. Miller J, Schacht T, Yamasoba Y, Ohinata 96. 9 heilrK,MFde L igD,La M oYS. Ho PM, Lear DL, Ding SL, McFadden KK, Ohlemiller 99. 8 apelKM ec P ako L uhsL,Rybak LF, Hughes RL, Jackson RP, Meech KCM, Campbell 98. 5 vn ,HlielB rerdcl n ern.Cause, hearing. and radicals Free B. Halliwell P, Evans 95. 3 cadnS,WoJ,Mcaa ,Dn .Dietary D. Ding N, Michalak JM, Woo SL, McFadden 93. otepsr ramn teutsnieidcdhearing 2005; Neuroscience. noise-induced loss. attenuates treatment Post-exposure M nuneo nes on xoueo glutathione on 1998; Res. exposure Brain sound cochlea. the intense in synthesis of Influence JM. 2000; Res. Hear 34. loss. hearing noise-induced limits 40. agtdmtto ftegn o ellrglutathione 2000; cellular in Otolaryngol. Res loss for Assoc hearing J gene noise-induced mice. increases the (Gpx1) peroxidase of mutation Targeted xdzdadrdcdguahoelvl safnto of Otolaryngol function Res a Assoc 2003; chinchilla. as cochlear Abs. the alters levels in exposure duration glutathione exposure Noise reduced al. and et oxidized JKM, Coleman LP, osqec,adciei.AnNYAa c.1999; Sci. Acad Y N Ann criteria. and consequence, osi unapg.Ha e.2005; Res. Hear pigs. hearing guinea noise-induced in reduces loss supplementation C vitamin ntmclefcso matnie erRs 1994; Res. 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Res. doi: Hear hearing 2006, acetyl-l-carnitine. induced and noise N-acetylcysteine of using rescue loss Pharmacological al. et GE, 231. 101 138 nassigters fwr-eae ern os Noise loss. hearing work-related of 2001; risk Health. the assessing on 1986; Am. Soc Acoust (in 2006 (Stockh) and Otolaryn. doses, press). Acta NAC exposures, administration. N-acetyl-l-cysteine noise of of routes with variety a protection using (NAC) Noise D. Henderson ohe olwn xouet mus os.Ha Res. chinchilla Hear the noise. in impulse apoptosis to cell 2006; exposure hair following outer cochlea of induction ctlytieaantiplenietam.Ha Res. 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