Abstract
High-intensity sound or blast-induced hearing impairment is a common injury for Service members. Epidemiology studies revealed that the blast-induced hearing loss is associated with the traumatic brain injury (TBI), but the mechanisms of the formation and prevention of auditory injuries require further investigation. Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been reported as a potential treatment strategy for TBI-caused memory deficits; however, there is no study on therapeutics of GLP-1R for blast-induced hearing damage. This paper reports our current study on progressive hearing damage after repeated exposures to low-level blasts in the animal model of chinchilla and the mitigation of hearing damage using liraglutide. Chinchillas were divided into three groups (N = 7 each): blast control, pre-blast treatment, and post-blast treatment. All animals were exposed to six consecutive blasts at the level of 3–5 psi (21–35 kPa) on Day 1. The auditory brainstem response (ABR) was measured on Day 1 (pre- and post-blast) and Days 4, 7, and 14 after blast exposure. Upon the completion of the experiment on Day 14, the brain tissues of animals were harvested for immunofluorescence studies. Significant damage was revealed in blast-exposed chinchillas by increased ABR thresholds, decreased ABR wave I amplitudes, and cell apoptosis in the inferior colliculus in the blast control chinchillas. Treatment with liraglutide appeared to reduce the severity of blast-induced hearing injuries as observed from the drug-treated chinchillas comparing to the blast controls. This study bridges the gap between TBI and hearing impairment and suggests a possible intervention for blast-induced hearing loss for Service members.
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References
Athauda D, Foltynie T (2016) The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson’s disease: mechanisms of action. Drug Discov Today 21:802–818. https://doi.org/10.1016/j.drudis.2016.01.013
Bielefeld EC (2014) Influence of dose and duration of isoflurane anesthesia on the auditory brainstem response in the rat. Int J Aud 53:250–258. https://doi.org/10.3109/14992027.2013.858280
Blatchley BJ, Cooper WA, Coleman JR (1987) Development of auditory brainstem response to tone pip stimuli in the rat. Dev Brain Res 32(1):75–84. https://doi.org/10.1016/0165-3806(87)90140-4
Briyal S, Shah S, Gulati A (2014) Neuroprotective and anti-apoptotic effects of liraglutide in the rat brain following focal cerebral ischemia. Neurosci 281:269–281. https://doi.org/10.1016/j.neuroscience.2014.09.064
Carr W, Stone JR, Walilko T, Young LA, Snook TL, Paggi ME, Tsao JW, Jankosky CJ, Parish RV, Ahlers ST (2016) Repeated low-level blast exposure: a descriptive human subjects study. Mil Med 181:28–39. https://doi.org/10.7205/MILMED-D-15-00137
Cederholm JME, Froud KE, Wong ACY, Ko M, Ryan AF, Housley GD (2012) Differential actions of isoflurane and ketamine-based anaesthetics on cochlear function in the mouse. Hear Res 292:71–79. https://doi.org/10.1016/j.heares.2012.08.010
Chen T, Smith K, Jiang S, Zhang T, Gan RZ (2019) Progressive hearing damage after exposure to repeated low-intensity blasts in chinchillas. Hear Res 378:33–42. https://doi.org/10.1016/j.heares.2019.01.010
Chen T-J, Chen S.-S, (1991) Generator study of brainstem auditory evoked potentials by a radiofrequency lesion method in rats. Exp Brain Res 85. https://doi.org/10.1007/BF00231737
Cho SI, Gao SS, Xia A, Wang R, Salles FT, Raphael PD, Abaya H, Wachtel J, Baek J, Jacobs D, Rasband MN, Oghalai JS (2013) Mechanisms of hearing loss after blast injury to the ear. PLoS ONE 8:e67618. https://doi.org/10.1371/journal.pone.0067618
Clark RSB, Kochanek PM, Watkins SC, Chen M, Dixon CE, Seidberg NA, Melick J, Loeffert JE, Nathaniel PD, Jin KL, Graham SH (2000) Caspase-3 mediated neuronal death after traumatic brain injury in rats. J Neurochem 74:740–753. https://doi.org/10.1046/j.1471-4159.2000.740740.x
Dougherty AL, MacGregor AJ, Han PP, Viirre E, Heltemes KJ, Galarneau MR (2013) Blast-related ear injuries among U.S. military personnel. J Rehabil Res Dev 50:893–904. https://doi.org/10.1682/JRRD.2012.02.0024
Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. The Lancet 368:1696–1705. https://doi.org/10.1016/S0140-6736(06)69705-5
Elmore S (2007) Apoptosis: A Review of Programmed Cell Death. Toxicol Pathol 35(4):495–516. https://doi.org/10.1080/01926230701320337
Fausti SA, Wilmington DJ, Gallun FJ, Myers PJ, Henry JA (2009) Auditory and vestibular dysfunction associated with blast-related traumatic brain injury. J Rehabil Res Dev 46:797–810. https://doi.org/10.1682/JRRD.2008.09.0118
Gallun FJ (2017) Auditory processing after traumatic brain injury. Perspect ASHA Special Interest Groups 2:147–151. https://doi.org/10.1044/persp2.SIG2.147
Gallun FJ, Lewis MS, Folmer RL, Diedesch AC, Kubli LR, McDermott DJ, Walden TC, Fausti SA, Lew HL, Leek MR (2012) Implications of blast exposure for central auditory function: A review. Bull Prosthet Res 49:1059–1074. https://doi.org/10.1682/JRRD.2010.09.0166
Gan RZ, Nakmali D, Ji XD, Leckness K, Yokell Z (2016) Mechanical damage of tympanic membrane in relation to impulse pressure waveform — a study in chinchillas. Hear Res 340:25–34. https://doi.org/10.1016/j.heares.2016.01.004
Gan RZ, Smith K, Chen T, Jiang S (2019) Mitigation of auditory damage after blast exposure with Glucagon-like Peptide-1 (GLP-1) – a study in Chinchilla. Association for Research in Otolaryngology (ARO) - Midwinter Meeting, Baltimore, MD
Gu G, Roland B, Tomaselli K, Dolman CS, Lowe C, Heilig JS (2013) Glucagon-like peptide-1 in the rat brain: distribution of expression and functional implication. J Comp Neurol 521:2235–2261. https://doi.org/10.1002/cne.23282
Guan X, Jiang S, Seale TW, Hitt BM, Gan RZ (2015) Morphological changes in the tympanic membrane associated with Haemophilus influenzae-induced acute otitis media in the chinchilla. Int J Pediatr Otorhinolaryngol 79:1462–1471. https://doi.org/10.1016/j.ijporl.2015.06.030
Hakon J, Ruscher K, Romner B, Tomasevic G (2015) Preservation of the blood brain barrier and cortical neuronal tissue by liraglutide, a long acting glucagon-like-1 analogue, after experimental traumatic brain injury. PLoS ONE 10:e0120074. https://doi.org/10.1371/journal.pone.0120074
Han EX, Fernandez JM, Swanberg C, Shi R, Bartlett EL (2020) Longitudinal auditory pathophysiology following mild blast induced trauma. bioRxiv. https://doi.org/10.1101/2020.11.06.371591
Henry KS, Kale S, Scheidt RE, Heinz MG (2011) Auditory brainstem responses predict auditory nerve fiber thresholds and frequency selectivity in hearing impaired chinchillas. Hear Res 280:236–244. https://doi.org/10.1016/j.heares.2011.06.002
Hickman TT, Smalt C, Bobrow J, Quatieri T, Liberman MC (2018) Blast-induced cochlear synaptopathy in chinchillas. Sci Rep 8:1–12. https://doi.org/10.1038/s41598-018-28924-7
Irimescu I, Chende A, Ghiurco F, Damian A (2014) Anatomical study of the cerebral hemispheres in the chinchilla (chinchilla lanigera). Bulletin UASVM Vet Med 71:130–136
Jiang S, Seale TW, Gan RZ (2016) Morphological changes in the round window membrane associated with Haemophilus influenzae-induced acute otitis media in the chinchilla. Int J Pediatr Otorhinolaryngol 88:74–81. https://doi.org/10.1016/j.ijporl.2016.06.049
Kelley PE, Frisina RD, Zettel ML, Walton JP (1992) Differential calbindin-like immunoreactivity in the brain stem auditory system of the chinchilla. J Comp Neurol 320:196–212. https://doi.org/10.1002/cne.903200205
Kozin ED, Black NL, Cheng JT, Cotler MJ, McKenna MJ, Lee DJ, Lewis JA, Rosowski JJ, Remenschneider AK (2016) Design, fabrication, and in vitro testing of novel three-dimensionally printed tympanic membrane grafts. Hear Res 340:191–203. https://doi.org/10.1016/j.heares.2016.03.005
Land R, Burghard A, Kral A (2016) The contribution of inferior colliculus activity to the auditory brainstem response (ABR) in mice. Hear Res 341:109–118. https://doi.org/10.1016/j.heares.2016.08.008
Laumen G, Ferber AT, Klump GM, Tollin DJ (2016) The physiological basis and clinical use of the binaural interaction component of the auditory brainstem response. Ear Hear 37:e276–e290. https://doi.org/10.1097/AUD.0000000000000301
Lew HL, Jerger JF, Guillory SB, Henry JA (2007) Auditory dysfunction in traumatic brain injury. J Rehabil Res Dev 44:921–928
Li Y, Bader M, Tamargo I, Rubovitch V, Tweedie D, Pick CG, Greig NH (2015) Liraglutide is neurotrophic and neuroprotective in neuronal cultures and mitigates mild traumatic brain injury in mice. J Neurochem 135:1203–1217. https://doi.org/10.1111/jnc.13169
Liberman MC, Kujawa SG (2017) Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms. Hear Res 349:138–147. https://doi.org/10.1016/j.heares.2017.01.003
Mao JC, Pace E, Pierozynski P, Kou Z, Shen Y, VandeVord P, Haacke EM, Zhang X, Zhang J (2011) Blast-induced tinnitus and hearing loss in rats: behavioral and imaging assays. J Neurotrauma 29:430–444. https://doi.org/10.1089/neu.2011.1934
Mayorga MA (1997) The pathology of primary blast overpressure injury. Toxicol 121:17–28
Niwa K, Mizutari K, Matsui T, Kurioka T, Matsunobu T, Kawauchi S, Satoh Y, Sato S, Shiotani A, Kobayashi Y (2016) Pathophysiology of the inner ear after blast injury caused by laser-induced shock wave. Sci Rep 6:1–10. https://doi.org/10.1038/srep31754
Oleksiak M, Smith BM, St Andre JR, Caughlan CM, Steiner M (2012) Audiological issues and hearing loss among Veterans with mild traumatic brain injury. J Rehabil Res Dev 49:995–1004
Patterson JH, Hamernik RP (1997) Blast overpressure induced structural and functional changes in the auditory system. Toxicol 121:29–40. https://doi.org/10.1016/S0300-483X(97)03653-6
Race N, Lai J, Shi R, Bartlett EL (2017) Differences in postinjury auditory system pathophysiology after mild blast and nonblast acute acoustic trauma. J Neurophysiol 118:782–799. https://doi.org/10.1152/jn.00710.2016
Rachmany L, Tweedie D, Li Y, Rubovitch V, Holloway HW, Miller J, Hoffer BJ, Greig NH, Pick CG (2013) Exendin-4 induced glucagon-like peptide-1 receptor activation reverses behavioral impairments of mild traumatic brain injury in mice. Age 35:1621–1636. https://doi.org/10.1007/s11357-012-9464-0
Ruebhausen MR, Brozoski TJ, Bauer CA (2012) A comparison of the effects of isoflurane and ketamine anesthesia on auditory brainstem response (ABR) thresholds in rats. Hear Res 287:25–29. https://doi.org/10.1016/j.heares.2012.04.005
Sajja VSSS, LaValle C, Salib JE, Misistia AC, Ghebremedhin MY, Ramos AN, Egnoto MJ, Long JB, Kamimori GH (2019) The role of very low level blast overpressure in symptomatology. Front Neurol 10:891. https://doi.org/10.3389/fneur.2019.00891
Salcedo I, Tweedie D, Li Y, Greig NH (2012) Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders. Br J Pharmacol 166:1586–1599. https://doi.org/10.1111/j.1476-5381.2012.01971.x
Smith KD, Chen T, Gan RZ (2020) Hearing damage induced by blast overpressure at mild TBI level in a chinchilla model. Mil Med 185:248–255. https://doi.org/10.1093/milmed/usz309
Song H, Konan LM, Cui J, Johnson CE, Langenderfer M, Grant DA, Ndam T, Simonyi A, White T, Demirci U, Mott DR, Schwer D, Hubler GK, Cernak I, DePalma RG, Gu Z (2018) Ultrastructural brain abnormalities and associated behavioral changes in mice after low-intensity blast exposure. Behav Brain Res 347:148–157. https://doi.org/10.1016/j.bbr.2018.03.007
Theodoroff SM, Lewis MS, Folmer RL, Henry JA, Carlson KF (2015) Hearing impairment and tinnitus: prevalence, risk factors, and outcomes in us service members and veterans deployed to the iraq and afghanistan wars. Epidemiol Rev 37:71–85. https://doi.org/10.1093/epirev/mxu005
Thiele N, Köppl C (2018) Gas anesthesia impairs peripheral auditory sensitivity in barn owls (Tyto alba). eNeuro 5. https://doi.org/10.1523/ENEURO.0140-18.2018
Tweedie D, Rachmany L, Rubovitch V, Lehrmann E, Zhang Y, Becker KG, Perez E, Miller J, Hoffer BJ, Greig, Nigel H, Pick CG (2013) Exendin-4, a glucagon-like peptide-1 receptor agonist prevents mTBI-induced changes in hippocampus gene expression and memory deficits in mice. Exp Neurol 239:170–182. https://doi.org/10.1016/j.expneurol.2012.10.001
Tweedie D, Rachmany L, Rubovitch V, Li Y, Holloway HW, Lehrmann E, Zhang Y, Becker KG, Perez E, Hoffer BJ, Pick CG, Greig NH (2016) Blast traumatic brain injury–induced cognitive deficits are attenuated by preinjury or postinjury treatment with the glucagon-like peptide-1 receptor agonist, exendin-4. Alzheimer’s & Dementia 12:34–48. https://doi.org/10.1016/j.jalz.2015.07.489
University of Wisconsin, Michigan State Comparative Mammalian Brain Collections, National Museum of Health and Medicine, National Science Foundation, National Institutes of Health (n.d.) Cell Stain Brain Atlas of Long-tailed Chinchilla (Chincilla lanigera) #65-103. Comparative Mammalian Brain Collections. http://www.brainmuseum.org/Specimens/rodentia/chinchilla/sections/cellthumbnail.html. Accessed 10 May 2022
Veterans Benefits Administration (2019) Annual benefit report fiscal year 2018. https://www.benefits.va.gov/REPORTS/abr/docs/2019-compensation.pdf. Accessed 23 Apr 2021
Wada S-I, Starr A (1983) Generation of auditory brain stem responses (ABRs). III. Effects of lesions of the superior olive, lateral lemniscus and inferior colliculus on the ABR in guinea pig. Electroencephalogr Clin Neurophysiol 56:352–366. https://doi.org/10.1016/0013-4694(83)90261-4
Wan G, Corfas G (2017) Transient auditory nerve demyelination as a new mechanism for hidden hearing loss. Nat Commun 8:14487. https://doi.org/10.1038/ncomms14487
Zheng F, Zuo J (2017) Cochlear hair cell regeneration after noise-induced hearing loss: Does regeneration follow development? Hear Res 349:182–196. https://doi.org/10.1016/j.heares.2016.12.011
Zhong Z, Henry KS, Heinz MG, Heinz MG (2014) Sensorineural hearing loss amplifies neural coding of envelope information in the central auditory system of chinchillas. Hear Res 309:55–62. https://doi.org/10.1016/j.heares.2013.11.006
Acknowledgements
We gratefully acknowledge Dr. Emi Kiyotake, Dr. John Clegg, and Dr. Michael Detamore from Stephenson School of Biomedical Engineering at the University of Oklahoma for sharing their equipment, environment, and technology for the IF study presented in this paper.
Funding
This study was supported by the Department of Defense (DOD) grant W81XWH-19–1-0469.
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Appendix
Appendix
Figure 10 presents the screenshots of the ABR waveforms measured at different epoch numbers ranging from 16 to 908. The waveforms were recorded at 8 kHz, 95 dB. As can be seen from the figure, some random fluctuations were observed at 16, but it was hard to observe changes with the epoch number changing from 142 to 908. Therefore, 150 was an adequate number of sweeps to produce replicable ABR waveforms and allowed for threshold and peak picking analysis in our experimental paradigm.
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Jiang, S., Welch, P., Sanders, S. et al. Mitigation of Hearing Damage After Repeated Blast Exposures in Animal Model of Chinchilla. JARO 23, 603–616 (2022). https://doi.org/10.1007/s10162-022-00862-2
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DOI: https://doi.org/10.1007/s10162-022-00862-2