At present it is hypothesized that NIHL is expressed with multiple effects on the inner ear. Besides the mechanical injury of the organ of Corti, due to the acoustical overstimulation, other subtle mechanisms involve the formation of reactive oxygen species -ROS- (Clerici et al, 1995; Jacono et al, 1998; Rao et al, 2001 ), the generation of nitric oxide and the co-involvement of glutamate receptors (Duan et al, 2000b) . Increased levels of ROS in the cochlea could cause cytotoxic effects through a variety of different biochemical mechanisms (Clerici et al, 1995; Ohinata et al, 2000a). The primary target of ROS is the mitochondria and the endoplasmatic reticulae. A number of in-vivo pilot studies has suggested that hair cell damage due to acoustic overstimulation can be effectively prevented by using drugs blocking the NMDA receptors , iron chelators and scavengers of reactive oxygen species (Agerman et al, 1999; Selvadurai et al, 2000; Soji et al; 2000a; 2000b; Shinohara et al, 2001; Suzuki et al, 2001). In vitro studies have also demonstrated that the administration of thiolic antioxidants increases the activity of respiratory mitochondrial enzymes, which in turn presumably attenuates the NIHL damage (Yamasoba et al, 1998).
       In this context, current research indicates that an increase of the cellular level of antioxidants facilitates and enhances the oto-protective mechanisms of the inner ear. The cellular level of antioxidants in the inner ear can be increased by a number of pathways : 1) by gene-therapy which might generate the production of antioxidants (van de Water et al, 1999; Duan et al, 2000); (2) by introducing of a non-hydrolyzable adenosine analogue (R-PIA) which has been found effective in upregulating the antioxidant enzyme activity levels (Hu et al, 1997) ; 3) by administering a cysteine pro-drug, which promotes rapid restoration of glutathione -GSH- (Yamasoba et al, 1998 ) ; and 4) by administering antioxidants, such as neurotrophins and glutamate antagonists, by a local or a systemic infusion (Henderson et al, 1999 ). The round window is probably the most important soft tissue interface between the middle ear and inner ear that can be used for pharmacological therapy of inner ear disorders.
       These otoprotection schemes target a high survival rate of outer hair cell (OHCs), inner hair cell(IHCs) and gaglion neurons. Testing the residual cochlear function (post-administration of the oto-protector) is commonly conducted with distortion product otoacoustic emissions spanning a wide range of frequencies i.e from 2.0 to 16.0 / 20.0 kHz (note: the reader should recall that the clinically employed TEOAEs, use click stimuli which in optimal conditions stimulate cochlear segments corresponding to 5-6 kHz). It is common to use Input-Output curves at a number of frequencies of interest (this depends on the animal species tested) and medium-intensity protocols ( i.e. 50-40 or 50-50 dB SPL) to evaluate the performance of the cochlear amplifier prior to saturation. The evaluation of the IHC and gaglion-neuron functional integrity is usually conducted with compound action potential (CAP) or ABR recordings. In theory functional alterations of the IHCs and the gaglion neurons are reflected by alterations to the efferent feedback effect on the OHCs, thus suppression studies might contribute information on the status of the auditory system "beyond" the OHCs.


Useful References

Agerman K, Canlon B, Duan M, Ernfors P. Neurotrophins, NMDA receptors, and nitric oxide in development and protection of the auditory system. Ann N Y Acad Sci 1999 Nov 28;884:131-42

Clerici WJ, DiMartino DL, Prasad MR . Direct effects of reactive oxygen species on cochlear outer hair cell shape in vitro. Hearing Res 1995;84, 30-40.

Campbell KC, Rybak LP, Meech RP, Hughes L. D-methionine provides excellent protection from cisplatin ototoxicity in the rat. Hear Res 1996;102:90-8

Duan ML, Ulfendahl M, Ahlberg A, Pyykko I, Borg E. Future cure of hearing disorders? Gene therapy and stem cell implantation are possible new therapeutic alternatives. Lakartidningen 2000a;97:1106-8, 1111-2.

Duan M, Agerman K, Ernfors P, Canlon B. Complementary roles of neurotrophin 3 and a N-methyl-D-aspartate antagonist in the protection of noise and aminoglycoside-induced ototoxicity.Proc Natl Acad Sci U S A. 2000b;97(13):7597-602.

Hamernik RP, Qiu W. Correlations among evoked potential thresholds, distortion product otoacoustic emissions and hair cell loss following various noise exposures in the chinchilla. Hear Res 2000;150:245-57.

Henderson D, McFadden SL, Liu CC, Hight N, and Zheng XY. The Role of Antioxidants in Protection from Impulse Noise. Ann NY Acad Sci 1999; 884: 368-380

Hu BH, Zheng XY, McFadden SL, Kopke RD, Henderson D . R-phenylisopyladenoside attenuates noise-induced hearing loss in chinchilla. Hearing Res; 113, 198-206, 1997.

Jacono AA, Hu BH, Kopke RD, Henderson D, Van De Water TR, Steinman HM. Changes in cochlear antioxidant enzyme activity after sound conditioning and noise exposure in the chinchilla. Hearing Res 117, 31-38, 1998.

Ohinata Y, Miller JM, Altschuler RA, Schacht J. Intense noise induces formation of vasoactive lipid peroxidation products in the cochlea. Brain Res. 2000a;878:163-73

Ohinata Y, Yamasoba T, Schacht J, Miller JM. Glutathione limits noise-induced hearing loss. Hear Res. 2000b ;146:28-34.

Rao DB, Moore DR, Reinke LA, Fechter LD. Free radical generation in the cochlea during combined exposure to noise and carbon monoxide: an electrophysiological and an EPR study. Hear Res 2001;161:113-22

Selvadurai DK, Etheridge S, Jones P, Mulheran M, Cook JA. Pharmacological protection of auditory function against noise and hypoxia with MK 801. Clin Otolaryngol. 2000;25(6):570-6.

Shoji F, Yamasoba T, Magal E, Dolan DF, Altschuler RA, Miller JM. Glial cell line-derived neurotrophic factor has a dose dependent influence on noise-induced hearing loss in the guinea pig cochlea. Hear Res. 2000a; 142:41-55.

Shoji F, Miller AL, Mitchell A, Yamasoba T, Altschuler RA, Miller JM. Differential protective effects of neurotrophins in the attenuation of noise-induced hair cell loss. Hear Res. 2000b;146:134-42.

Shinohara T, Bredberg G, Ulfendahl M, Pyykko I, Olivius NP, Kaksonen R, Lindstrom B, Altschuler R, Miller JM. Neurotrophic factor intervention restores auditory function in deafened animals. Proc Natl Acad Sci U S A. 2002 Feb 5;99:1657-60.

Van De Water TR, Staecker h, Halterman MW, and Federoff HJ. Gene Therapy in the Inner Ear: Mechanisms and Clinical Implications. Ann NY Acad Sci 1999 884: 345-360.

Yamasoba T, Nuttall AL, Harris C, Raphael Y, Miller JM. Role of glutathione in protection against noise-induced hearing loss. Brain Res 784, 82-90, 1998.