Wayne S. Quirk

The protective effects of allopurinol and superoxide dismutase on noise-induced cochlear damage.

Several studies have demonstrated that noise exposure may result in local vasoconstriction of cochlear vessels. The subsequent decrease in cochlear blood flow may lead to hypoxia and predispose to the formation of free oxygen radicals (FORs). If hypoxia occurs in response to noise exposure, then drugs that scavenge or block the formation of FORs should protect the cochlea from damage resulting from hypoxic or ischemic events as well as noise trauma. Rats were exposed to 60 hours of continuous broad-band noise (90 dB SPL) and treated with superoxide dismutase — Polyethylene glycol (SOD-PEG), allopurinol, or a control vehicle. Exposure to noise resulted in significant threshold shifts at each frequency tested (3, 8, 12, and 18 kHz) as measured by tone burst-evoked compound action potentials and cochlear microphonics recorded from the round window. Both of these thresholds In drug-treated animals were attenuated compared with animals exposed to noise alone. These findings show that SOD-PEG and allopurinol may preserve cochlear sensitivity associated with noise exposure. This suggests that noise-induced damage to the cochlea may be related to the activity of FORs.

Biologic activity of mitochondrial metabolites on aging and age-related hearing loss.

HYPOTHESIS Compounds that upregulate mitochondrial function in an aging model will improve hearing and reduce some of the effects of aging. BACKGROUND Reactive oxygen metabolites (ROM) are known products of oxidative metabolism and are continuously generated in vivo. More than 100 human clinical conditions have been associated with ROM, including atherosclerosis, arthritis, autoimmune diseases, cancers, heart disease, cerebrovascular accidents, and aging. The ROM are extremely reactive and cause extensive DNA, cellular, and tissue damage. Specific deletions within the mitochondrial DNA (mtDNA) occur with increasing frequency in age and presbyacusis. These deletions are the result of chronic exposure to ROM. When enough mtDNA damage accrues, the cell becomes bioenergetically deficient. This mechanism is the basis of the mitochondrial clock theory of aging, also known as the membrane hypothesis of aging. Nutritional compounds have been identified that enhance mitochondrial function and reverse several age-related processes. It is the purpose of this article to describe the effects of two mitochondrial metabolites, alpha-lipoic acid and acetyl L-carnitine, on the preservation of age-related hearing loss. METHODS Twenty-one Fischer rats, aged 24 months, were divided into three groups: acetyl-l-carnitine, alpha-lipoic acid, and control. The subjects were orally supplemented with either a placebo or one of the two nutritional compounds for 6 weeks. Auditory brainstem response testing was used to obtain baseline and posttreatment hearing thresholds. Cochlear, brain, and skeletal muscle tissues were obtained to assess for mtDNA mutations. RESULTS The control group demonstrated an expected age-associated threshold deterioration of 3 to 7 dB in the 6-week study. The treated subjects experienced a delay in progression of hearing loss. Acetyl-l-carnitine improved auditory thresholds during the same time period (p<0.05). The mtDNA deletions associated with aging and presbyacusis were reduced in the treated groups in comparison with controls. CONCLUSIONS These results indicate that in the proposed decline in mitochondrial function with age, senescence may be delayed by treatment with mitochondrial metabolites. Acetyl-l-carnitine and alpha-lipoic acid reduce age-associated deterioration in auditory sensitivity and improve cochlear function. This effect appears to be related to the mitochondrial metabolite ability to protect and repair age-induced cochlear mtDNA damage, thereby upregulating mitochondrial function and improving energy-producing capabilities.

Mechanisms of Alterations in the Microcirculation of the Cochlea

ABSTRACT: Labyrinthine function is tightly coupled to proper homeostasis. This includes appropriate blood flow that is under strict autoregulatory control. Perturbations in labyrinthine microcirculation can lead to significant cochlear and vestibular dysfunction. The etiology of many otologic disorders, including sudden sensorineural hearing loss, presbyacusis, noise‐induced hearing loss, and certain vestibulopathies, are suspected of being related to alterations in blood flow. Some of the mechanisms responsible for hypoperfusion and possibly ischemia, within the cochlea, are addressed, with emphasis on the possibility that both noise and age contribute to localized low blood‐flow states and stasis. This reduction in blood supply to the cochlea is likely, in part, responsible for reduced auditory sensitivity associated with chronic noise exposure and aging.

Lipid peroxidation inhibitor attenuates noise-induced temporary threshold shifts

The purpose of this study was to investigate the protective effects of U74389F (Upjohn Co. Kalamazoo, MI), a 21-aminosteroid/lipid peroxidation inhibitor, and a member of the lazaroid drug class, on temporary threshold shifts in animals exposed to prolonged noise stimulation. Animals treated with U74389F and exposed to noise showed attenuated cochlear action potential threshold (CAP) shifts and cochlear microphonic (CM) when compared to non-drug treated noise-exposed subjects. These data suggest that inhibition of FOR induced lipid peroxidation is an important mechanism in noise-induced asymptotic temporary threshold shifts.

Influence of lecithin on mitochondrial DNA and age-related hearing loss.

;OBJECTIVES: Lecithin is a polyunsaturated phosphatidylcholine (PPC), which are high energy functional and structural elements of all biologic membranes. PPC play a rate-limiting role in the activation of numerous membrane-located enzymes, including superoxide dismutase and glutathione, which are important antioxidants protecting cell membranes from damage by reactive oxygen species (ROS). ROS-induced damage to mitochondrial DNA may lead to reduced mitochondrial function in the cochlea and resultant hearing loss. STUDY DESIGN AND SETTING: The effects of lecithin on aging and age-associated hearing loss were studied in rats by measuring hearing sensitivities using auditory brainstem responses (ABR). In addition, mitochondrial function as a measure of aging was assessed by determining mitochondrial membrane potentials using flow cytometry and by amplifying mitochondrial DNA deletions associated with aging. Harlan-Fischer rats aged 18 to 20 months (n = 14) were divided into 2 groups. The experimental group was supplemented orally for 6 months with lecithin, a purified extract of soybean phospholipid (Nutritional Therapeutics, Allendale, NJ). RESULTS: The data obtained were compared with the control group. ABRs were recorded at 2-month intervals and showed significant preservation of hearing sensitivities in the treated subjects. Flow cytometry revealed significantly higher mitochondrial membrane potentials in the treated subjects, suggesting preserved mitochondrial function. Finally, the common aging mitochondrial DNA deletion (mtDNA4834) were amplified from brain and cochlear tissue including stria vascularis and auditory nerve. This specific deletion was found significantly less frequent in all tissues in the treated group compared with the controls. CONCLUSION: These experiments support our hypothesis and provide evidence that lecithin may preserve cochlear mitochondrial function and protect hearing loss associated with aging.

The protective effects of allopurinol and superoxide dismutase-polyethylene glycol on ischemic and reperfusion-induced cochlear damage

The purpose of this study was to assess the protective effects of allopurinol, a blocker of free oxygen radical (FOR) formation, and superoxide dismutase-polyethylene glycol (SOD-PEG), a scavenger of FORs, on Ischemic and reperfusion-induced cochlear damage. Fifteen Wistar Kyoto rats (WKY) were randomly assigned to three groups: (1) a control group (5 animals) that was exposed to 15 minutes of cochlear ischemia by clamping the anterior inferior cerebellar artery (AICA), followed by 15 minutes of reperfusion as documented by laser Doppler flowmetry; (2) a drug-treated group (5 animals) that received allopurinol before ischemia/reperfusion; and (3) a drug-treated group (5 animals) that received SOD-PEG before ischemia/reperfusion. In the control group, the tone burst-evoked compound action potential (CAP) recorded from the round window (RW) of the cochlea was abolished, and the cochlear microphonic (CM) was reduced after ischemia. In contrast, both allopurinol and SOD-PEG–treated animals showed post-reperfusion sensitivity in CAP and CM measures. We interpret these results to indicate that damage to the cochlea from ischemia and subsequent reperfusion can be attenuated by pretreatment with allopurinol or SOD-PEG. This provides indirect evidence that FORs may be partially responsible for cochlear damage resulting from ischemic conditions.

Age-related hearing loss and its association with reactive oxygen species and mitochondrial DNA damage

Age-related hearing loss, known as presbyacusis, is characterized by the progressive deterioration of auditory sensitivity associated with the aging process and is the leading cause of adult auditory deficiency in the USA. Presbyacusis is described as a progressive, bilateral, high-frequency hearing loss that is manifested on audiometric assessment by a moderately sloping pure tone audiogram. Approximately 23% of the population between 65 and 75 years of age, and 40% of the population older than 75 years of age are affected by this condition. It was estimated in 1980 that 11% of the population was 76 years or older and this number is expected to almost double by the year 2030. When one considers that the population over 65 years of age is experiencing the most accelerated development of hearing loss, the potential socioeconomic ramifications are staggering. Curiously, the frequency of presbyacusis varies across different societies. This discrepancy has been attributed to many factors including genetics, diet, socioeconomic factors, and environmental variables. The purpose of this article is to review the various molecular mechanisms underlying presbyacusis and to offer insights into potential methods of mitigating the effects of aging on hearing impairment.

Association of Mitochondrial DNA Deletions and Cochlear Pathology: A Molecular Biologic Tool†‡

The purpose of these experiments was to develop a method of isolation, amplification, and identification of cochlear mitochondrial DNA (mtDNA) from minute quantities of tissue. Additionally, studies were designed to detect mtDNA deletions (mtDNA del) from the cochlea that previously have been amplified from other organ systems and tissues. MtDNA del have been associated with many pathologies, including neurological disorders, sensorineural hearing loss, ischemia, cardiomyopathies, and aging.

Betahistine increases vestibular blood flow

Betahistine is used for treatment of several vestibular disorders. Despite the accepted use of this histamine-like substance, its mechanism of action is not well understood. The purpose of this study was to assess the possibility that one of the activities of betahistine is increasing blood flow in the peripheral vestibular end organs. Using a novel surgical approach, we identified the posterior semicircular canal ampulla of guinea pigs and placed a laser Doppler probe in position to obtain blood flow measurements from the posterior semicircular canal ampulla. Blood pressure, heart rate, and vestibular blood flow were continuously recorded. Concentration-response curves were obtained for betahistine (2.5, 5, 7.5, and 10 mg/kg) and control-vehicle (0.15 mol/L NaCl) infusions. A separate group of subjects was pretreated with the competitive selective H3 agonist, thioperimide maleate, before betahistine treatment. Increases in vestibular blood flow and decreases in blood pressure were observed in response to betahistine infusions. Pretreatment with thioperamide maleate abolished these changes at low doses of betahistine and attenuated the responses at higher doses of betahistine. These results show that betahistine administration induces increases in vestibular blood flow. These findings support the potential use of betahistine for treatment of vestibular disorders, which may be caused by compromised circulation.

The protective effects of tirilated mesylate (U74006F) on ischemic and reperfusion-induced cochlear damage.

We have recently demonstrated that allopurinol, a blocker of free oxygen radical (FOR) production, and superoxide dismutase (SOD), a scavenger of FOR, protect the cochlea from damage associated with ischemia/reperfusion. The purpose of this present study was to determine if tirilated mesylate (U74006F), a potent inhibitor of lipid peroxidation, can also protect the cochlea from ischemia/reperfusion. Eleven Wistar-Kyoto rats were randomly assigned to two groups: (1) a control group (6 animals) that was exposed to 15 minutes of cochlear ischemia by clamping the anterior-inferior cerebellar artery (AICA), followed by 15 minutes of reperfusion, and (2) a drug-treated group (5 animals) that received U74006F before ischemia/reperfusion. In the control group, the tone burstevoked compound action potential (CAP) recorded from the round window (RW) was abolished and cochlear microphonic (CM) was reduced. In contrast, the U74006F-treated animals showed post-reperfusion sensitivity in CAP, and less of a CM threshold shift. We interpret these results to indicate that U74006F lessens cochlear damage occurring as a result of ischemia/reperfusion and supports the hypothesis that FOR-induced lipid peroxidation may be partly responsible for the cochlear damage that occurs from ischemia.