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Life Extension Magazine May 2012


Different strategies in treating noiseinduced hearing loss with N-acetylcysteine.

BACKGROUND: The cellular mechanisms leading to noise-induced hearing loss (NIHL) involve the generation of reactive oxygen species (ROS). Recent studies on glutathione (GSH) and N-acetylcysteine (NAC) show that they can protect the cochlea from ROS-derived damage, increasing the levels of endogenous cellular defences. The purpose of this study was to verify NAC’s oto-protective efficacy and determine if drug administration timing influences the degree of oto-protection. MATERIAL/METHODS: Forty male Sprague Dawley albino rats were divided in four groups exposed to 8-kHz 105-dB SPL continuous noise. The groups were treated with diverse NAC administration modalities: group A received 4 injections during 48 hours (pre- and post-noise exposure), group B 1 injection prior to exposure, group C 1 injection 24 h after exposure, and group D served as untreated controls. The single injection dosage was 375 mg/kg; the controls received an equal volume of saline solution. Cochlear function was assessed by pre- and post-noise (after 168 hours) recordings of distortion product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABR). DPOAEs were obtained by three different asymmetric protocols (P1=60-50, P2=50-40, P3=40-30 dB SPL) for frequencies of 4-16 kHz. ABR responses were elicited by tone-bursts at 8 and 16 kHz. RESULTS: The most important outcome of the study was that the administration of NAC significantly reduced the threshold shifts in the treated animals. NAC provided different degrees of threshold reduction according to the timing of the drug injection. CONCLUSIONS: The role played by the timing of NAC injection was important for the OHC protection index. From a DPOAE perspective, the best protection scheme was observed in the group receiving NAC after noise exposure, but full recovery of cochlear function was not observed in any of the tested groups.

Med Sci Monit. 2008 Aug;14(8):BR159-64

Protective effects of N-acetylcysteine on noise-induced hearing loss in guinea pigs.

Increasing evidence suggests the involvement of oxidative stress in noise-induced hearing loss. The present study analysed, in an animal experimental model, the time course of the pathogenic mechanisms of noise-induced cochlear damage and the efficacy of the antioxidant drug N-acetylcysteine in reducing noise ototoxicity. Animals were divided into two groups, exposed to noise one treated with N-acetylcysteine for 3 days and one (the control group) with saline. Acoustic trauma was induced by a continuous pure tone of 6 kHz, at 120 dB SPL for 30 minutes. Electrocochleographic recordings were made from an implanted round window electrode and the compound action potentials were measured daily at 2-16 kHz for 7 days. Morphological changes were analysed by scanning electron microscopy. The acoustic threshold measured 1 hour after acoustic trauma was elevated in the control group to 70-90 dB in the higher frequencies of the compound action potential audiogram, with a maximum threshold elevation ranging between 12 and 16 kHz. During the first 24 h, following acoustic trauma, there was a partial recovery of compound action potential thresholds of about 20 dB to reach a final threshold elevation of about 50-70 dB; there was no further improvement over the remaining experimental week. Animals treated with N-acetylcysteine showed a similar temporary threshold shift but a clear improvement in the recovery of compound action potential thresholds, with significantly reduced permanent threshold shift and hair cell loss. These data suggest that N-acetylcysteine is able to attenuate the toxic effect of acoustic trauma and could represent an interesting molecule for preventing inner ear injuries.

Acta Otorhinolaryngol Ital. 2009 Apr;29(2):70-5

N-Acetyl-cysteine against noise-induced temporary threshold shift in male workers.

Previous animal studies showed protective effects of antioxidant medicines against noise-induced hearing loss (NIHL). It is unclear whether antioxidants would protect humans from NIHL. We conducted a study to determine whether N-Acetyl-cysteine (NAC) protected men against noise-induced temporary threshold shift (TTS), and whether subgroups with genetic polymorphisms of glutathione S-transferase (GST) T1 and M1 responded to NAC differently. In this prospective, double-blind, crossover study, 53 male workers were randomly assigned to receive either NAC (1200 mg/day, 14 days) during the first period and placebo during the second period, or placebo during the first period and NAC during the second period. Dosing periods were separated by a washout period of 2 weeks. The hearing threshold changes were determined before and after each dosing period. Pre-shift hearing threshold for high frequencies was 19.1 dB. Daily exposure to noise ranged from 88.4 to 89.4 dB. The noise levels of different frequencies ranged from 80.0 to 89.4 dB with a peak-value at 4 kHz. NAC significantly reduced TTS (p = 0.03). When the participants were grouped by GST M1/T1 genotypes, the NAC effect was only significant among workers with null genotypes in both GSTM1 and GSTT1 (p = 0.004). NAC may prevent noise-induced TTS among occupationally noise-exposed men. The protective effect of NAC was more prominent in subjects with both GSTM1-null and GSTT1-null genotypes. ( Identifier: NCT00552786).

Hear Res. 2010 Oct 1;269(1-2):42-7

The efficacy of N-acetylcysteine to protect the human cochlea from subclinical hearing loss caused by impulse noise: a controlled trial.

In military outdoor shooting training, with safety measures enforced, the risk of a permanent, noise-induced hearing loss is very small. But urban warfare training performed indoors, with reflections from walls, might increase the risk. A question is whether antioxidants can reduce the negative effects of noise on human hearing as it does on research animals. Hearing tests were performed on a control group of 23 military officers before and after a shooting session in a bunker-like room. The experiments were repeated on another group of 11 officers with peroral adminstration of N-acetyl-cysteine (NAC), directly after the shooting. The measurements performed were tone thresholds; transient-evoked otoacoustic emissions, with and without contralateral noise; and psycho-acoustical modulation transfer function (PMTF), thresholds for brief tones in modulated noise. Effects from shooting on hearing thresholds were small, but threshold behavior supports use of NAC treatment. On the PMTF, shooting without NAC gave strong effects. Those effects were like those from continuous noise, which means that strict safety measures should be enforced. The most striking finding was that the non-linearity of the cochlea, that was strongly reduced in the group without NAC, as manifested by the PMTF-results, was practically unchanged in the NAC-group throughout the study. NAC treatment directly after shooting in a bunkerlike room seems to give some protection of the cochlea.

Noise Health. 2011 Nov-Dec;13(55):392-401

Exploring the reasons why melatonin can improve tinnitus.

Melatonin has been proposed as a treatment for tinnitus, especially on the basis of its favourable effects on sleep and its vasoactive and antioxidant properties. However, to our knowledge no attempts of interpretation have been advanced through a detailed analysis of the various specific properties of melatonin possibly cooperating in a coincidental way to relieve tinnitus: among these, its modulatory effect on central nervous system resulting in a protective mechanism against an exaggerated sympathetic drive; its capacity to induce a more steady hemodynamic condition, through a multifactorial and multi-organ activity, resulting in a more regular labyrinthine perfusion; a possible action on the skeletal muscle tending to a reduction of the muscular tone, which could relieve tinnitus of muscular origin deriving from tensor tympani tonic contractions; its possible reported antidepressive effect, which could indirectly act on tinnitus; a direct regulation of inner ear immunity as proposed in literature when melatonin was reported to be present in the inner ear. All these observations seem to indicate melatonin as a tool deserving a greater attention than other antioxidants in the attempt of relieving tinnitus, justifying its application from a more precise rationale based on a series of physio-pathological aspects.

Med Hypotheses. 2010 Aug;75(2):190-1

Sulpiride and melatonin decrease tinnitus perception modulating the auditolimbic dopaminergic pathway.

OBJECTIVES: Sulpiride and melatonin decrease dopamine activity. Sulpiride, a D2 antagonist of dopamine receptors, and melatonin, a pineal substance with antidopaminergic action, are administered to tinnitus patients to decrease tinnitus perception. DESIGN: A prospective, randomized, double-blinded, placebo-controlled study was done. SETTING: General otorhinolaryngologic consultation for 2002-2004 in Seville, Spain. METHODS: One hundred twenty patients consulted for subjective tinnitus. They were included randomly in four groups of 30. One group took sulpiride (50 mg/8 h) alone, the second group took melatonin (3 mg/24 h), the third group took the same doses of sulpiride (50 mg/8 h) plus melatonin (3 mg/24 h), and the fourth group took placebo (lactose 50 mg/8 h), all for 1 month. Ninety-nine patients completed the study. MAIN OUTCOME MEASURES: Clinical history, tonal audiometry, tympanometry, and tinnitometry were done at the beginning and end of the study. Subjective grading of tinnitus perception and a visual analogue scale (0-10) were done for evaluation of results. RESULTS: Based on the subjective grading, tinnitus perception diminished by 56% in patients treated with sulpiride, by 40% in patients treated with melatonin, by 81% in patients treated with sulpiride plus melatonin, and by 22% in patients treated with placebo. Based on the visual analogue scale, tinnitus perception diminished from 7.7 to 6.3 in patients treated with sulpiride, to 6.5 in those treated with melatonin, to 4.8 in patients treated with sulpiride plus melatonin, and to 7.0 in those treated with placebo. CONCLUSIONS: Sulpiride and melatonin reduce tinnitus perception, decreasing dopamine activity. The tinnitus auditolimbic dopaminergic pathway has broad therapeutic implications.

J Otolaryngol. 2007 Aug;36(4):213-9

The role of free oxygen radicals in noise induced hearing loss: effects of melatonin and methylprednisolone.

The aim of this study was to investigate the role of cochlear damage caused by free oxygen radicals occurring as a result of exposure to noise and to determine the prophylactic effects of melatonin and methylprednisolone. Fifty male albino guinea pigs were randomly divided into five groups. All groups were exposed to 60 h of continuous wide band noise at 100+/-2 dB, except group I. Group I was not exposed to noise or treated with drugs. Group II was exposed to noise and not treated with drugs. Group III was exposed to noise and treated with melatonin. Group IV was exposed to noise and treated with methylprednisolone. Group V was exposed to noise and treated with melatonin and methylprednisolone. A high dose of 40 mg/kg methylprednisolone and/or 20 mg/kg melatonin were administered intramuscularly 24 h before exposure to noise, immediately before noise exposure and once a day until noise exposure was completed. Just after the noise ended, guinea pigs were decapitated. Venous blood was obtained into tubes with EDTA and it was used to measure activity levels of plasma malondialdehyde, erythrocyte glutathione peroxidase and the cochlear tissue malondialdehyde. After the noise ended, in comparison group II with I; it was found that the malondialdehyde activity of the plasma and tissue had increased, the erythrocyte glutathione peroxidase activity levels had decreased and consequently, hearing thresholds had increased (P<0.01). A significant difference was found in the malondialdehyde and erythrocyte glutathione peroxidase activity levels between groups II and III (P<0.01) and the hearing thresholds exhibited a parallel trend (P<0.05). The hearing threshold and malondialdehyde activity levels obtained from groups IV and V were found to be similar to those of group II (P>0.05). As a conclusion, we suggest that the use of methlyprednisolone in order to prevent the cochlear damage caused by noise does not provide sufficient prophylaxy, however the use of melatonin provides a more effective prophylaxy, thus being a promising alternative.

Auris Nasus Larynx. 2002 Apr;29(2):147-52

An experimental comparative study of dexamethasone, melatonin and tacrolimus in noise-induced hearing loss.

CONCLUSION: The calcineurin inhibitor tacrolimus (TCR) and the pineal gland hormone and antioxidant melatonin (MLT) have been shown to possess otoprotective properties against noise-induced hearing loss (NIHL). In contrast, dexamethasone (DXM) was not effective as an otoprotective agent against NIHL. Further studies are needed to understand the exact molecular mechanisms involved. OBJECTIVE: Exposure to noise pollution and use of audio devices for long periods of time at high volume is known to cause hearing loss or NIHL. Our goal was to evaluate the effectiveness of various known compounds such as the anti-inflammatory DXM, the antioxidant MLT and the immunosuppressant TCR against NIHL. MATERIALS AND METHODS: Thirty-two Wistar rats were randomly divided into groups that were then exposed to intense white noise at 120 dB SPL for 4 h. The day before and for a period of 14 days, test groups were administered one of the three compounds. The efficacy of the compounds against NIHL was determined after examining the shifts in the levels of distortion product otoacoustic emissions (DPOAEs) and changes in the threshold of auditory brainstem responses (ABRs). Cytocochleograms and determination of gene expression in whole rat cochlea were carried out at day 21. RESULTS: Treatment with DXM had no otoprotective effect, while animals treated with MLT experienced an improvement in their hearing functionality. This effect, which is probably linked to MLT’s ability to reduce c-fos and TNF-alpha gene expression thereby preventing outer hair cell (OHC) loss, was even more pronounced in week 3. For its part, TCR provided protection against injury to the cochlea from week 1, eventually leading to a full recovery in hearing. The compound reduced both c-fos and TNF-alpha expression, as well as OHC loss.

Acta Otolaryngol. 2009 Apr;129(4):385-9

Antioxidants in treatment of idiopathic sudden hearing loss.

OBJECTIVE: Assuming that superoxide anion radicals (O(2)-) may play a role in damage to the inner ear, the authors investigated the possible benefit of vitamin E as an antioxidant in the treatment of idiopathic sudden hearing loss. STUDY DESIGN: Prospective, double-blind study. SETTING: The Department of Otolaryngology of Rambam Medical Center serves as a tertiary referral center for a population of 1.2 million people. PATIENTS: A total of 66 patients, aged 15 to 70 years, with diagnoses of idiopathic sudden hearing loss of less than 7 days’ duration during 1998 to 2001, were included in the study. All were treated with bed rest, steroids, magnesium, and carbogen inhalation. The study group received vitamin E in addition. RESULTS: The recovery rate, calculated as hearing gain divided by the difference in hearing level between the affected and unaffected ear, was better than 75% in 41 of 66 (62.12%) patients. This rate was achieved in 26 (78.78%) patients in the study group treated with vitamin E, compared with 15 (45.45%) patients in the control group. CONCLUSIONS: Patients treated with the addition of vitamin E achieved better recovery than did the control patients. Further studies should be directed toward a better understanding of the role of antioxidants in idiopathic sudden hearing loss.

Otol Neurotol. 2003 Jul;24(4):572-5

Effects of alpha-tocopherol on noise-induced hearing loss in guinea pigs.

Preventing noise-induced hearing loss (NIHL) by antioxidants is based on the hypothesis that generation of reactive oxygen species is one of the causes of NIHL. alpha-Tocopherol is a naturally occurring antioxidant with no noticeable side effects. In this study, we attempted to protect guinea pigs from developing NIHL by administering alpha-tocopherol. Pigmented male guinea pigs were exposed to a noise (4 kHz octave band, 100 dB SPL), 8 h/day for 3 days consecutively. alpha-Tocopherol (10 mg/kg or 50 mg/kg daily) was given by intraperitoneal injection from 3 days before through 3 days after the noise exposure. Auditory evoked brainstem response (ABR) thresholds at 2, 4 and 8 kHz were recorded prior to the experiment, immediately post-noise, 2 and 8 days post-noise. On day 8 post-noise, after the ABR recording, guinea pigs were decapitated and the cochleae were removed for cochlear surface preparations and scanning electron microscope (SEM) study. ABR threshold shifts of groups receiving alpha-tocopherol were significantly smaller than those of groups not receiving alpha-tocopherol at all frequencies and all time points tested except that of group 3 at 8 kHz 8 days post-noise. No hair cell loss was seen on the surface preparations, but stereocilia loss was found by SEM study. The noise-induced stereocilia loss was significantly decreased by alpha-tocopherol. These results indicate that alpha-tocopherol can attenuate the noise-induced cochlear damage. Further investigations on the preventive effect of alpha-tocopherol on NIHL in noise-exposed workers are necessary.

Hear Res. 2003 May;179(1-2):1-8

Preventive effects of vitamin E on short-term noise-induced hearing loss in guinea pigs.

OBJECTIVE: To study the preventive effects of vitamin E on short-term noise-induced hearing loss (NIHL). METHODS: Forty-eight male pigmented guinea pigs were randomly divided into 6 groups, 8 animals in each group. The animals of group 1, 2, 3, 4 were exposed to the noise (4 kHz octave band noise, 100 dB SPL), 8 hours per day for 3 days consecutively and received normal saline, corn oil, 10 mg/kg vitamin E, 50 mg/kg vitamin E respectively daily by intraperitoneal injection from 3 days before the noise exposure, through the 3 noise exposure days to 3 days after the noise exposure. The animals of group 5 and group 6 days were not exposed to the noise but received normal saline and 50 mg/kg vitamin E injection respectively at the same time as that of group 1, 2, 3, 4. The preventive effects of vitamin E on NIHL were determined by comparing the threshold shifts of auditory brainstem responses (ABR) immediately, on the second day and on the 8th day after the exposure. RESULTS: The ABR threshold shifts immediately, on the second day and on the 8th day after the exposure for group 3 at 2, 4 and 8 kHz were (15.9 +/- 6.8), (39.4 +/- 4.8), (42.5 +/- 6.3), (0.3 +/- 2.5), (19.1 +/- 7.9), (21.9 +/- 6.4), (0.3 +/- 1.6), (10.9 +/- 8.6), (12.2 +/- 8.1) dB, respectively, which were significantly lower than those for group 1 [(30.9 +/- 11.3), (47.8 +/- 8.8), (49.7 +/- 6.9), (10.0 +/- 3.5), (29.1 +/- 6.5), (29.1 +/- 7.6), (4.7 +/- 3.6), (20.3 +/- 6.5), (17.5 +/- 9.0) dB, respectively] (P < 0.05). The ABR threshold shifts immediately, on the second day and on the 8th day after the exposure for group 4 at 2, 4 and 8 kHz were respectively (14.4 +/- 5.3), (36.6 +/- 4.4), (43.1 +/- 2.9), (0.3 +/- 2.5), (16.9 +/- 4.6), (19.4 +/- 3.2), (0.0 +/- 3.7), (7.5 +/- 4.2), (9.1 +/- 4.2) dB, which were significantly lower than those for group 1 (P < 0.05). CONCLUSION: Vitamin E has some preventive effects on the NIHL.

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2005 Dec;23(6):408-10