Otolaryngology–
Head and Neck Surgery
ORIGINAL ARTICLES
Effects of resveratrol on acoustic trauma
MICHAEL SEIDMAN, MD, SEILESH BABU, MD, WENXUE TANG,
Michigan, and Ellensburg, Washington
OBJECTIVE: The purpose of the study is to test the
ability of resveratrol to protect the auditory system
from reactive oxygen species (ROS)-mediated
noise damage. Oxidative stress is mediated by
ROS, which are known to cause cellular and mo-
lecular damage. Interfering with this process, using
ROS inhibitors/scavengers such as antioxidants has
shown promise in protecting specific systems from
oxidative damage. Among the antioxidants receiv-
ing recent attention is resveratrol, an active com-
ponent in red wine.
STUDY DESIGN AND SETTING: Ten Fischer rats were
used for this study. The experimental group (n ⴝ 5)
received 7 weeks of resveratrol treatment (430/␮g/
kg/day), by gavage, and the control group (n ⴝ 5)
received normal saline solution by gavage. Base-
line auditory brainstem responses (3, 6, 9, 12 and 18
kHz) were determined for both groups. After 21
days, animals were exposed to noise (105 dB, 4500
to 9000 Hz for 24 hours). Postnoise auditory brain-
stem responses were assessed at 4 recovery time
From the Department of Otolaryngology (Drs Seidman,
Babu, Tang, and Naem), Henry Ford Health System, De-
troit, Michigan, and Central Washington University (Dr
Quirk), Ellensburg, Washington.
Presented at American Academy of Otolaryngology Head and
Neck Surgery Meeting in Denver, Colorado, September
2001.
Reprint requests: Michael Seidman, MD, Department of Oto-
laryngology, Henry Ford Health System, One Ford Place,
Detroit, MI 48202; e-mail, mseidma1@hfhs.com.
Copyright © 2003 by the American Academy of Otolaryn-
gology–Head and Neck Surgery Foundation, Inc.
0194-5998/2003/$30.00 ⫹ 0
doi:10.1016/S0194-5998(03)01586-9
NOVEMBER 2003 VOLUME 129 NUMBER 5
MD, EMAD NAEM, MD, and WAYNE S. QUIRK, PHD, Detroit,
points: immediate, at 3 days, 7 days, and 4 weeks
after noise exposure.
RESULTS: Results demonstrate that the resveratrol
group showed reduced threshold shifts compared
with the control group after noise exposure. These
shifts were significantly different between groups at
6 and 9 kHz (P < 0.05), corresponding to the region
most represented by the frequency of the traumatic
noise.
CONCLUSION/SIGNIFICANCE: Initial studies in our
laboratory as well as other investigators have
shown the importance of specific antioxidant ther-
apy in the prevention of ischemic, noise, and age
related hearing loss. The current study demon-
strates a protective effect of resveratrol on noise-
induced hearing loss. (Otolaryngol Head Neck
Surg 2003;129:463-70.)
N oise-induced hearing loss (NIHL) is a problem
of epidemic proportions. The National Institute of
Deafness and Other Communication Disorders re-
cently estimated that 10 million Americans have
irreversible acoustic damage and more than 30
million people are exposed to dangerous levels of
noise on a daily basis. Additionally, NIHL is a
leading work-related disease and injury. Accord-
ing to the World Health Organization, it is esti-
mated that the cost of NIHL in developed coun-
tries ranges from 0.2% to 2% of the gross national
product.1
There are many unresolved issues concerning
NIHL. For instance, uncertainties exist over sus-
ceptibility, prevention, and treatment of NIHL. A
variety of experimental strategies have been used
463

464 SEIDMAN et al
to affect acoustic damage. Some interventions that
reduce acoustic damage include lowering the body
temperature, stimulating the efferent olivocochlear
bundle, treating with various pharmacological
compounds or endogenous factors, and increasing
oxygenation with carbogen or oxygen.2,3 Studies
from our laboratory and others have achieved sim-
ilar partial protection from noise damage by inter-
fering with the activity of reactive oxygen species.
Resveratrol, found mainly in the skin of grapes, is
noted for its antioxidant and anti-inflammatory
properties, as well as its potential to prevent can-
cer and heart disease. Epidemiological evidence
has shown that moderate consumption of red wine
is inversely correlated with the incidence of de-
mentia and ischemic heart disease.4 Direct neuro-
protective effects of resveratrol against oxidative
stress have been demonstrated in PC12 cells.5
Resveratrol stimulates a key enzyme in the brain
known as Map-kinase, which is involved in nerve
regeneration and neural protection from the dam-
age caused by systemic injection of the excito-
toxin kainic acid.6 Our study will assess the pos-
sible protective effects of resveratrol on noise
damage by evaluating noise-induced temporary
threshold shifts (TTS), permanent threshold shifts
(PTS), and inner ear histologic changes.
MATERIAL AND METHODS
Subjects
Ten healthy male Fischer rats (130 to 175 gm)
were used to study noise-induced TTS and PTS as
determined by auditory brainstem response (ABR)
measurements. These animals were randomly as-
signed to either the resveratrol treatment group (n
⫽ 5) or the control group (n ⫽ 5). The use of
experimental animals for this study was approved
by the Care for Experimental Animals Committee
at Henry Ford Health System. Additionally, all
procedures were conducted in strict compliance
with the National Institutes of Health guidelines
for experimental animal subjects.
Auditory Brainstem Response (ABR)
Baseline ABR measurements were obtained
from these 10 healthy male Fischer rats at initial
entry into the study. Animals were anesthetized
with a mixture of ketamine and xylazine (100
Otolaryngology–
Head and Neck Surgery
November 2003
mg/kg and 15 mg/kg, respectively) given subcu-
taneously.
Auditory stimuli were generated using a D/A
converter (Model DA3-2; Tucker-Davis Technol-
ogies (TDT), Gainesville, FL, USA) with a sam-
pling frequency of 100 kHz. The output of the D/A
converter was connected to a programmable at-
tenuator (Model PA4; TDT), a weighted summer
(Model SM3; TDT), a headphone buffer (Model
HB6; TDT), and an earphone (Model DT-48;
Beyer Dynamic, Heilbronn, Germany), which was
placed within 1 to 2 mm from the tympanic mem-
brane of the animal. The stimuli consisted of tone
bursts with a rise/fall time of 1 ms, a duration of
15 ms, and a period of 100 ms. A series of stimuli
were produced at 3, 6, 9, 12 and 18 kHz test
frequencies with intensities ranging from 5 to 100
dB SPL in 5 dB increments. The system was
calibrated at the tympanic membrane using a
probe microphone (Model ER-7C; Etymotic Re-
search, Elk Grove Village, IL), which was con-
nected to an A/D converter (Model AD2, TDT)
and a computer. Automated calibrating routines
were used for online calibration.
Auditory brainstem responses were collected
using subcutaneous electrodes (Model E2; Grass
Instruments, Quincy, MA, USA) placed at the
vertex and under both pinnae of each animal. This
output was channeled into a biologic amplifier
(Model P5 Series; Grass Instruments) with a gain
of 100,000X. The response was filtered between
0.3 and 3.0 kHz, and then the output was sent to an
A/D converter (Model AD2; TDT). Custom-de-
signed software allowed these responses to be
displayed with a sampling rate of 50 kHz in real
time on a computer monitor. For each recording, a
20-ms neural response was averaged 1,024 times.
For each of the 5 test frequencies, auditory thresh-
olds were determined by identifying the smallest
intensity (in dB SPL) at which ABR waveforms
became consistently evident at 1 mV responses.
This was determined objectively by the computer
and confirmed by direct observation of the wave-
form.
After baseline ABR testing, treatment group
animals (n ⫽ 5) received 3 weeks of trans-resvera-
trol (430/ug/kg/day) treatment by gavage feeding.
Trans-resveratrol was purchased from Sigma (St
Louis, MO) and was dissolved in 100% ethanol
Otolaryngology–
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Volume 129 Number 5
Fig 1. Baseline auditory brainstem response thresholds. Mean auditory threshold levels of treatment group (dark line) and
control group (light line) at 5 test frequencies. Measurements were obtained before treatment with resveratrol. (Bars
represent Standard Error of the mean.)
(10 mg/ml), stocked at ⫺–20°C, and diluted with
0.9% NaCl to final ethanol concentration of 2.5%
vol/vol as necessary. The control group (n ⫽ 5)
was gavaged with an equivalent volume of 0.9%
NaCl. The animals were then placed in an acous-
tically insulated noise booth (Industrial Acoustics,
New York, NY) and exposed to 105 dB SPL at
4500 to 9000 Hz narrow band noise for 24 con-
tinuous hours. After the completion of the noise
exposure, experimental group animals received
another 4 weeks of resveratrol (430/ug/kg/day) by
gavage, and the control group was gavaged with
an equivalent volume of 0.9% NaCl. Although
caging was designed to be acoustically transpar-
ent, calibration measurements throughout the cage
revealed a variance of 2 to 3 dB from the front of
the cage to the back. To determine temporary
threshold shifts (TTS) and permanent threshold
shifts (PTS), ABR measurements were recorded at
various times: immediately, 3 days, 7 days, and 4
weeks after the completion of the noise exposure.
Cochlear Histology
At the end of the 7-week study period, 8 of the
animals involved in the auditory sensitivity studies
were sacrificed; 4 from the resveratrol treatment
group and 4 from the control group. One animal in
each group had expired before the cochleae was
able to be harvested. The cochleae were perfused
in vivo with a 2.5% glutaraldehyde solution in
veronal acetate buffer (pH ⫽ 7.4) via transcardiac
SEIDMAN et al 465
aortic perfusion. The bullae were rapidly removed
and the cochleae were perfused in vitro with a
2.5% glutaraldehyde solution in veronal acetate
buffer (pH ⫽ 7.4) through the oval and round
windows. The tissues were fixed in the same so-
lution at 4°oC for 48 hours. The cochleae were
perfused with 1% osmium tetroxide in veronal
acetate buffer (pH ⫽ 7.4) through the oval and
round windows for 30 minutes. The cochleae were
dehydrated using ethanol of ascending strength
from 30% through 50% to 70% and decalcified
overnight in 0.35 M ethylenediaminetetracetic
acid (EDTA) in veronal acetate buffer (pH 7.4).
The organ of Corti was then dissected in 70%
ethanol. Each cochlear turn was mounted with
99% glycerol and examined under an optical mi-
croscope. The hair cells were counted at ⫻400
using a differential interference contrast micro-
scope (Carl Zeiss GFL, Goettingen, Germany).
These data were then used to generate a cytoco-
chleogram as a frequency-position map based on
the following mathematical derivation: f (kHz) ⫽
3.109 * (10 (100-d)*0.0142) - 0.7719), where d is the
percent distance from the cochlear base.7
Outer and inner hair cell loss was evaluated
for each animal as a percent hair cell loss and
plotted against basilar membrane distance (cal-
culated from the cochlear apex). The basilar
membrane length was also matched for frequen-
cy-position. The pattern of hair cell loss was
 Otolaryngology–
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466 SEIDMAN et al November 2003

Fig 2. Auditory treshold shifts. Mean auditory shifts measured immediately (A), 3 days (B), 7 days (D), and 4 weeks (D) after
high-level noise exposure. Dark lines represent resveratrol treatment group and light lines represent control group at 5 test
frequencies (3, 6, 9, 12, and 18 kHz). (Standard Error bars are plotted for each condition.)

compared between the treatment and control
groups.
RESULTS
Auditory Brainstem Response (ABR)
ABR thresholds were recorded at 5 test frequen-
cies (3, 6, 9, 12, and 18 kHz) and 5 time points
(baseline, 0, 3, 7 days, and 4 weeks after noise
exposure) as described previously. ABR measure-
ments obtained before resveratrol treatment indi-
cated that there were no significant differences in
mean auditory thresholds between the treatment
and control groups at baseline (Fig 1). Subsequent
mean auditory threshold shifts from baseline were
also graphed (Fig 2). Statistically significant re-
ductions in auditory threshold shifts were noted
when comparing the resveratrol treatment group to
the control group at 2 test frequencies (6 kHz and
9 kHz) at all 4 times: immediately, 3 days, 7 days,
and 4 weeks after noise exposure (SigmaStat Soft-
ware). Significant differences in audiologic data
between the 2 groups were assessed using Stu-
dent’s t test.
Also reductions were noted in threshold shifts at
12 kHz in the immediate and 7 day time points.
Cochlear Histology
Figure 3 displays surface preparations of the
organ of Corti from a control ear and a resveratrol
treated ear from representative animals. All of the
selected animals showed outer hair cell loss, but
the loss was significantly less in the resveratrol
treated group. Figure 4 depicts a mean cytoco-
chleogram for both the control and resveratrol
treatment groups. Outer hair cell (OHC) loss was
determined over 0.24 mm intervals along the co-
chlea from apex to base. The mean basilar mem-
brane length in the control group was 8.9 mm. The
Otolaryngology–
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Volume 129 Number 5 SEIDMAN et al 467

Fig 3. Cochlear histology. Photomicrographs (⫻40) of surface mount preparation of the organ of Corti from a control ear
(A) and resveratrol-treated ear (B). (Three outer hair cell rows are labeled 1, 2, and 3; I, single hair cell row; arrowhead
points to outer hair cells loss.)

mean basilar membrane length in the resveratrol
treatment group was 8.97 mm. The mean OHC
loss was 1.3% in the control group. OHC loss in
the resveratrol treatment group was 0.48%. In the
control group, peak outer hair cell loss was 5.2%,
corresponding to 7 to 9 kHz. In the resveratrol
group, peak outer hair cell loss was 2.7%, corre-
sponding to 7 to 8 kHz. A significant change of the
inner hair cells was not detected in either group of
animals.
DISCUSSION
The current study shows that treatment with
resveratrol prevents significant noise-induced
hearing loss based on auditory brainstem response
testing and histologic examination. Statistically

468 SEIDMAN et al
Fig 4. Cochlear histology. Mean cytocochleograms of control (dark line) and rseveratrol-treated group (light line) show
percentage of hair cell loss as a function of frequency position on basilar lamina.
significant reductions in auditory threshold shifts
were noted when comparing the resveratrol treat-
ment group to the control group at 2 test frequen-
cies (6 and 9 kHz) at all 4 time points: immedi-
ately, 3 days, 7 days, and 4 weeks after noise
exposure. The traumatic noise exposure consisted
of frequencies between 4500 and 9000 Hz, thus
accounting for the threshold shift at 6 and 9 KHz
and the protective effects of resveratrol at these
frequencies as well. Additionally, a greater loss of
hair cells was found in the control group compared
with the resveratrol treated group. This demon-
strates a protective effect of resveratrol on the
cochlea. Although unlikely this effect may have
been influenced by the use of ethanol as the dis-
solving agent for resveratrol. Ongoing studies are
investigating the role of ethanol causing a protec-
tive role.
Otolaryngology–
Head and Neck Surgery
November 2003
Hypoperfusion and ischemia to the cochlea is a
possible mechanism of damage associated with
noise-induced hearing loss. Ischemia, which is
known to cause injury to the cochlea, results in
oxidative stress that stimulates the generation and
release of reactive oxygen species (ROS).8 These
ROS affect energy production and ultimately re-
duce outer hair cell function. This damage is evi-
dent in the auditory system in the form of thresh-
old shifts. Many studies have shown signs of
vascular insufficiency following noise expo-
sure.9-11 Our in vivo studies have shown hypoper-
fusion and ischemia in the cochlear microcircula-
tion during noise exposure.12 Reductions in
cochlear blood flow, such as occurs with noise
exposure, have long been known to decrease au-
ditory sensitivity.13 Indeed, recent evidence sug-
gests an increase in ROS following noise expo-
Otolaryngology–
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sure.14 Several studies from our laboratories have
shown ROS scavenger treatment in the auditory
system reduces these threshold shifts following
experimentally induced cochlear ischemia.15,16
ROS are also implicated in other ototoxic insults
such as cisplatin, trimethyltin, and aminoglyco-
sides.5,9,17,18 Studies have also demonstrated that
a reduction of ROS attenuates noise-induced hear-
ing loss.19,20 In summary, noise results in isch-
emia, a condition known to affect auditory thresh-
olds. This ischemia results in the generation of
ROS and the damaging effects of these radicals
can be attenuated with scavengers and inhibitors
in the auditory system.
Resveratrol is found in over 70 fruits and plants,
many of which are edible, such as mulberries,
peanuts, and grapes. It is thought that this chem-
ical is produced in response to environmental
stress or attack by pathogens including mold.
Grapes contain particularly high concentrations of
resveratrol in the skin. Trans-resveratrol was first
detected in grapevines in 1976 by Langcake and
Pryce,21 who found that the compound was syn-
thesized by leaf tissues in response to fungal in-
fection or exposure to ultraviolet light.5 Resvera-
trol was brought to the public attention when its
presence in wine was reported in 1992 by Siemann
and Creasy.22 The authors suggested that this
compound might be the biologically active ingre-
dient of red wine.23 The consumption of red wine
is becoming increasingly popular due to the in-
trigue created by the French Paradox. Despite the
high fat diet and smoking tendencies of the pop-
ulation in Southern France, there is an astonishing
42% lower incidence of heart disease than that
found in Americans.4 The effect known as the
French Paradox has been attributed to the con-
sumption of red wine. World Health Organization
data indicate that resveratrol may be one of the
active ingredients in the wine that reduces the risk
of coronary heart disease by up to 40% in red wine
drinkers.1
Resveratrol has many important biologic activ-
ities including: inhibition of lipid peroxidation;
chelation of copper; free-radical scavenging; alter-
ation of eicosanoid synthesis; inhibition of platelet
aggregation; anti-inflammatory activity; vasore-
laxing activity; modulation of lipid metabolism;
anticancer activity; estrogenic activity; cardiopro-
SEIDMAN et al 469
tection; and neuroprotection.24-28 Bertelli et al29
investigated the absorption, the concentration in
different organs, and the excretion of natural trans-
and cis-Resveratrol after red wine oral administra-
tion to rats. Their results show that prolonged
administration of red wine in the diet could lead to
an increased resveratrol concentration in different
tissues even though the amount of resveratrol in
these different tissues was lower than that required
for pharmacological activity. This may explain its
beneficial role against coronary heart disease.
Oxidative stress in the central nervous system
may cause oxidation of lipoprotein particles. The
oxidized lipoproteins may damage cellular and
subcellular membranes, leading to tissue injury
and cell death. Draczynska-Lusiak et al30 have
shown that antioxidants, such as vitamins E or C,
or resveratrol, protect neuronal cell damage from
oxidative stress in vitro. Results indicated that
oxidized lipoproteins may serve as an oxidative
stressor, which may initiate the neuronal cell death
leading to the manifestation of Alzheimer disease.
Zini et al31 studied the possible effects of resvera-
trol on the mitochondrial respiratory chain in rat
brains. Resveratrol was found to decrease complex
III activity in rat brain by competition with coen-
zyme Q. This property is especially interesting as
this complex is the site where reactive oxygen
substances (ROS) are generated. By decreasing
the activity of complex III, resveratrol not only
opposes the production of ROS but also scavenges
them.31 Virgili and Contestabile14 report that
chronic administration of resveratrol to young
adult rats, significantly protects from the damage
caused by systemic injection of the excitotoxin
kainic acid in the olfactory cortex and the hip-
pocampus.
Several studies have demonstrated that antioxi-
dants can attenuate hearing loss in various condi-
tions, such as noise-induced hearing loss, ototox-
icity, ischemia, and presbycusis.2,16,32-33
CONCLUSION
Considering the importance of the biological
activities of resveratrol, along with previous stud-
ies from our laboratory showing the protective
effects of antioxidants and dietary restriction on
noise-induced and age-induced hearing loss, the
current study demonstrates similar effects with

470 SEIDMAN et al
resveratrol. Thus, resveratrol appears to protect
the cochlea from acoustic trauma and ongoing
studies are being done to evaluate the efficacy of
resveratrol on age-related hearing loss.
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