Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly population. SAMP8 mouse model presents accelerated senescence and has been identified as a model of gerontological research. SAMP8 displays a progressive age-related decline in brain function associated with a progressive hearing loss mimicking human aging memory deficits and ARHL. The molecular mechanisms associated with SAMP8 senescence process involve oxidative stress leading to chronic inflammation and apoptosis. Here, we studied the effect of N-acetylcysteine (NAC), an antioxidant, on SAMP8 hearing loss and memory to determine the potential interest of this model in the study of new antioxidant therapies. We observed a strong decrease of auditory brainstem response thresholds from 45 to 75 days of age and an increase of distortion product amplitudes from 60 to 75 days in NAC treated group compared to vehicle. Moreover, NAC treated group presented also an increase of memory performance at 60 and 105 days of age. These results confirm that NAC delays the senescence process by slowing the age-related hearing loss, protecting the cochlear hair cells and improving memory, suggesting that antioxidants could be a pharmacological target for age-related hearing and memory loss.
Marie Aurore,Meunier Johann,Brun Emilie, et al. N-acetylcysteine Treatment Reduces Age-related Hearing Loss and Memory Impairment in the Senescence-Accelerated Prone 8 (SAMP8) Mouse Model[J]. Aging and disease,
2018, 9(4): 664-673.
Figure 1. Experimental procedure and animal weight
A) Schema of the experimental study. B) Mouse body weight evolution of NAC or vehicle treated group during the study. Data are shown as mean ± SEM. Significance was set at **p < 0.01. n = 6 mice by group.
Figure 2. ABR thresholds representation
Auditory Brain Response thresholds of NAC (red line) and vehicle (black) treated mice at 8, 16, 20, 24 and 32KHz at the indicated age (A-F). The age of mice is indicated on each the graph (days old). ABR thresholds of NAC (red line) and vehicle (black) treated mice at 16 kHz (G) and 24 KHz (H) during the time experiment. Data are shown as median ± MAD. Significance was set at *p < 0.05 and ** p < 0.01. n = 6 mice by group.
DPOAE amplitude level of NAC (red line) and vehicle (black line) at 1, 4, 6, 8, 10, 12, 16, 20, 25 and 32 kHz and an intensity of 63 dB SPL. The age of mice is indicated on each the graph (days old). Data are shown as mean ± SEM. Significance was set at *p < 0.05. n = 6 mice by group.
Figure 4. Scanning electron microscopy cochleae representative images of mice treated with NAC (right panels) and vehicle (left panels)
A) Global view of middle part of cochlea showing the presence of IHC and OHC of treated mice. Arrows and asterisks mark the loss of OHC and IHC respectively. Scale bar = 15 µm. B) Magnification of OHC stereocilia of NAC and vehicle treated mice. Scale bar = 3 µm. C) Magnification of IHC stereocilia of NAC and vehicle treated mice. Scale bar = 5 µm. n = 3 mice by group. These images are representative images of 3 independent animals.
Figure 5. Object recognition test representation
Working memory test of NAC and vehicle treated mice at 60 and 105 days old represented as % of frequency of interactions with the new object (A) and % of time spent with the new object (B) respectively. Data are shown as mean ± SEM. Significance was set at **p < 0.01 and ***p < 0.001. n = 6 mice by group.
Thompson DC, McPhillips H, Davis RL, Lieu TL, Homer CJ, Helfand M (2001). Universal newborn hearing screening: summary of evidence. JAMA, 286, 2000-2010.
Someya S, Prolla TA (2010). Mitochondrial oxidative damage and apoptosis in age-related hearing loss. Mech Ageing Dev, 131:480-486.
Yamasoba T, Lin FR, Someya S, Kashio A, Sakamoto T, Kondo K (2013). Current concepts in age-related hearing loss: epidemiology and mechanistic pathways. Hear Res, 303, 30-38.
Unal M, Tamer L (2005). N-acetyltransferase 2 gene polymorphism and presbycusis. Laryngoscope, 115:2238-41
Bared A, Ouyang X, Angeli S, Du LL, Hoang K, Yan D, Liu XZ (2010). Antioxidant enzymes, presbycusis, and ethnic variability. Otolaryngol. Head Neck Surg, 143, 263-268.
Takeda T, Matsushita T, Kurozumi M, Takemura K, Higuchi K, Hosokawa M (1997). Pathobiology of the Senescence-accelerated Mouse (SAM). Experimental Gerontology, 32:117-127.
Tomobe K, Nomura Y (2009). Neurochemistry, neuropathology, and heredity in SAMP8: a mouse model of senescence. Neurochem Res, 34(4):660-9.
Hosokawa M, Ueno M (1999). Aging of blood-brain barrier and neuronal cells of eye and ear in SAMP mice. Neurobiol Aging, 20(2):117-23.
Menardo J, Tang Y, Ladrech S, Lenoir M, Casas F et al. (2012). Oxidative stress, inflammation, and autophagic stress as the key mechanisms of premature age-related hearing loss in SAMP8 mouse Cochlea. Antioxid Redox Signal, 16(3):263-74.
Sen CK (2001). Antioxidant and redox regulation of cellular signaling: introduction. Med Sci Sports Exerc, 33:368-370
Maurice T, Roman FJ, Su TP, Privat A (1996). Beneficial effects of sigma agonists on the age-related learning impairment in the senescence-accelerated mouse (SAM). Brain Res, 733(2):219-30.
Meunier J, Villard V, Givalois L, Maurice T (2013). The γ-secretase inhibitor 2-[(1R)-1-[(4-chlorophenyl) sulfonyl](2,5-difluorophenyl) amino] ethyl-5-fluorobenzenebutanoic acid (BMS-299897) alleviates Aβ1-42 seeding and short-term memorydeficits in the Aβ25-35 mouse model of Alzheimer’s disease. Eur J Pharmacol, 698(1-3):193-9.
Ladrech S, Wang J, Simonneau L, Puel JL, Lenoir M (2007). Macrophage Contribution to the Response of the Rat Organ of Corti to Amikacin. J Neuros Res, 85:1970-1979
Hurley MM, Resch JM, Maunze B, et al. (2016). N-acetylcysteine (NAC) decreases binge eating in a rodent model. Int J Obes (Lond), 40(7): 1183-1186
McClure EA, Gipson CD, Malcolm RJ, Kalivas PW, Gray KM (2014). Potential Role of N-Acetylcysteine in the Management of Substance Use Disorders. CNS drugs, 28(2):95-106.
Marie A, Larroze-Chicot P, Cosnier-Pucheu S, Gonzalez-Gonzalez S (2017). Senescence-accelerated mouse prone 8 (SAMP8) as a model of age-related hearing loss. Neurosciences Letters, 656:138-143.
Kemp DT (2002). Otoacoustic emissions, their origin in cochlear function, and use. Br Med Bull, 63223-241.
Lonsbury-Martin BL, Martin GK (1990). The clinical utility of distortion-product otoacoustic emissions. Ear Hear, 11144-154.
Uchida Y, Ando F, Shimokata H, Sugiura S, Ueda H, Nakashima T (2008). The effects of aging on distortion-product otoacoustic emissions in adults with normal hearing. Ear Hear, 29(2):176-84.
Akiguchi I, Pallàs M, Budka H, Akiyama H, Ueno M, et al. (2017). SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda’s legacy and future directions. Neuropathology, doi: 10.1111/neup.12373.
Wang J, Cheng X, Zeng J et al. (2017). LW-AFC Effects on N-glycan Profile in Senescence-Accelerated Mouse Prone 8 Strain, a Mouse Model of Alzheimer’s Disease. Aging Dis, 1; 8(1):101-114.
Fujimoto C, Yamasoba T (2014). Oxidative Stresses and mitochondrial dysfunction in age-related hearing loss. Oxid Med Cell Longev, 582-849.
Shi X, Nuttall AL (2003). Upregulated iNOS and oxidative damage to the cochlear stria vascularis due to noise stress Brain Res, 967(1-2):1-10.
Tavanai E, Mohammadkhani G (2017). Role of antioxidants in prevention of age-related hearing loss: a review of literature. Eur Arch Otorhinolaryngol, 274(4):1821-1834
Johnson KR, Yu H et al. (2010). Separate and combined effects of Sod1 and Cdh23 mutations on age-related hearing loss and cochlear pathology in C57BL/6J mice. Hear Res, 268(1-2):85-92.
Attias J, Bresloff I, Haupt H, Scheibe F, Ising H (2003). Preventing noise induced otoacoustic emission loss by increasing magnesium (Mg2+) intake in guinea-pigs. J Basic Clin Physiol Pharmacol, 14(2):119-36.
Quaranta A, Scaringi A, Bartoli R, Margarito MA, Quaranta N (2004). The effects of ’supra-physiological’ vitamin B12 administration on temporary threshold shift. Int J Audiol, 43(3):162-5.
Kramer S, Dreisbach L, Lockwood J, Baldwin K, Kopke R, Scranton S, O’Leary M (2006). Efficacy of the antioxidant Nacetylcysteine (NAC) in protecting ears exposed to loud music. J Am Acad Audiol, 17(4), 265-278.
Kopke R, Slade MD, Jackson R, Hammill T, Fausti S (2015). Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss: a randomized clinical trial. Hear Res, 323:40-50.