salicylates and Hearing-Loss

Salicylates and most NSAIDS in high doses cause mild to moderate temporary hearing loss, either flat or greater in the high frequencies. Hearing loss is accompanied by tinnitus and suprathreshold changes. Salicylates may or may not exacerbate hearing loss and cochlear damage induced by noise. The mechanism of salicylate ototoxicity seems to be multifactorial. Morphologic studies suggest that no permanent cochlear damage occurs with salicylate ototoxicity. Electrophysiologic, morphologic, and in vitro data conclusively demonstrate that salicylate affects outer hair cells. In addition, salicylates appear to decrease cochlear blood flow. Salicylates and NSAIDs inhibit PG-forming cyclooxygenase, and recent studies suggest that abnormal levels of arachidonic acid metabolites consisting of decreased PGs and increased LTs may mediate salicylate ototoxicity. As with salicylate, quinine ototoxicity appears to be multifactorial in origin. The mechanism includes vasoconstriction and decreases in cochlear blood flow, as measured by laser Doppler flowmetry, motion photographic studies, and histologic studies. Reversible alterations of outer hair cells also appear to play an important role, as demonstrated by histology, electron microscopy, isolated hair cell studies, and cochlear potential evaluations. Unlike with salicylate, however, the role of prostaglandins in quinine ototoxicity has not been clearly demonstrated. Also, one of quinine's principal actions, antagonism of calcium-dependent potassium channels, has yet to be investigated for its potential role in ototoxicity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cochlea; Hearing Loss; Humans; Quinine; Salicylates; Tinnitus

Aspirin, the prototype of the salicylates, is a ubiquitous agent. The availability of aspirin, other salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs) as prescription and over-the-counter medications means there is a wealth of clinical experience with these agents. Among the documented adverse effects of aspirin is the potential for ototoxicity. Tinnitus and hearing loss, usually reversible, are associated with acute intoxication and long term administration of salicylates. A range of measured serum concentrations are reported as correlating with documented ototoxicity (19.6 to > 67 mg/dl). Most case reports are based on total serum salicylate concentrations whereas unbound serum salicylate concentrations appear to reflect more closely the risk of ototoxicity. The pathophysiology of toxicity may be related to biochemical and subsequent electrophysiological changes in the inner ear and eighth cranial nerve impulse transmission. Localised drug accumulation and vasoconstriction in auditory microvasculature may be mediated by the antiprostaglandin activity of these agents. Ototoxicity, although not life-threatening, may add to the morbidity of patients taking salicylates or NSAIDs in therapeutic and toxic doses.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Hearing Loss; Humans; Salicylates; Tinnitus

Early-response auditory evoked potentials (AEPs) in humans are significantly altered in tinnitus. These changes are closely related to that seen in animals, leading to new approaches to study tinnitus based on objective parameters. The purpose of this study was to characterize the AEPs in animals with tinnitus, by assessing early to late latency responses. For behavioral evaluation, rats were trained using positive reinforcement to press a lever in the presence of an auditory stimulus and to not press during silence. The auditory brainstem response (ABR), middle latency response (MLR) and auditory late latency response (LLR) were correlated to the false-positive responses (pressing the lever during silence), after oral administrations of Sodium Salicylate (SS, 350 mg/kg). In the present study, SS significantly increased the hearing thresholds and reduced ABR peak I amplitudes across the frequency range (4-32 kHz). In contrast, increased amplitudes were observed for several peaks in ABR, MLR, and LLR. Moreover, reduced ABR latencies in response to 8, 16 and 24 kHz tone bursts were observed after SS administration. Similarly, the central evaluation also revealed significantly reduced latencies in MLR and LLR during SS administration. In contrast, increased latencies were observed for ABR latencies in response to 32 kHz tone bursts, and at the P1-N1 component of LLR. Correlational analysis revealed that latencies and amplitudes of peaks II and IV (8 and 16 kHz) of ABR, and N2 latency and P2-N2 amplitude of LLR were associated with behavioral tinnitus. We suggest that AEPs can be used in the rat to evaluate the reduced sensory input and the increased central gain in SS-induced tinnitus, as well as reduced latencies (8-16 kHz) to distinguish between hearing loss and tinnitus.

Topics: Acoustic Stimulation; Animals; Auditory Perception; Auditory Threshold; Brain Stem; Evoked Potentials, Auditory; Evoked Potentials, Auditory, Brain Stem; Female; Hearing; Hearing Loss; Noise; Rats; Rats, Sprague-Dawley; Reaction Time; Salicylates; Tinnitus

Increased prevalence of emotional distress is associated with tinnitus and hearing loss. The underlying mechanisms of the negative emotional response to tinnitus and hearing loss remain poorly understood, and it is challenging to disentangle the emotional consequences of hearing loss from those specific to tinnitus in listeners experiencing both. We addressed these questions in laboratory rats using three common rodent anxiety screening assays: elevated plus maze, open field test, and social interaction test. Open arm activity in the elevated plus maze decreased substantially after one trial in controls, indicating its limited utility for comparing pre- and post-treatment behavior. Open field exploration and social interaction behavior were consistent across multiple sessions in control animals. Individual sound-exposed and salicylate-treated rats showed a range of phenotypes in the open field, including reduced entries into the center in some subjects and reduced locomotion overall. In rats screened for tinnitus, less locomotion was associated with higher tinnitus scores. In salicylate-treated animals, locomotion was correlated with age. Sound-exposed and salicylate-treated rats also showed reduced social interaction. These results suggest that open field exploratory activity is a selective measure for identifying tinnitus distress in individual animals, whereas social interaction reflects the general effects of hearing loss. This animal model will facilitate future studies of the structural and functional changes in the brain pathways underlying emotional distress associated with hearing dysfunction, as well as development of novel interventions to ameliorate or prevent negative emotional responses.

Topics: Animals; Disease Models, Animal; Hearing Loss; Male; Maze Learning; Motor Activity; Rats; Rats, Sprague-Dawley; Salicylates; Social Behavior; Sound; Stress, Psychological; Tinnitus

Lesion-induced cochlear damage can result in synaptic outgrowth in the ventral cochlear nucleus (VCN). Tinnitus may be associated with the synaptic outgrowth and hyperactivity in the VCN. However, it remains unclear how hearing loss triggers structural synaptic modifications in the VCN of rats subjected to salicylate-induced tinnitus. To address this issue, we evaluated tinnitus-like behavior in rats after salicylate treatment and compared the amplitude of the distortion product evoked otoacoustic emission (DPOAE) and auditory brainstem response (ABR) between control and treated rats. Moreover, we observed the changes in the synaptic ultrastructure and in the expression levels of growth-associated protein (GAP-43), brain-derived neurotrophic factor (BDNF), the microglial marker Iba-1 and glial fibrillary acidic protein (GFAP) in the VCN. After salicylate treatment (300 mg/kg/day for 4 and 8 days), analysis of the gap prepulse inhibition of the acoustic startle showed that the rats were experiencing tinnitus. The changes in the DPOAE and ABR amplitude indicated an improvement in cochlear sensitivity and a reduction in auditory input following salicylate treatment. The treated rats displayed more synaptic vesicles and longer postsynaptic density in the VCN than the control rats. We observed that the GAP-43 expression, predominantly from medial olivocochlear (MOC) neurons, was significantly up-regulated, and that BDNF- and Iba-1-immunoreactive cells were persistently decreased after salicylate administration. Furthermore, GFAP-immunoreactive astrocytes, which is associated with synaptic regrowth, was significantly increased in the treated groups. Our study revealed that reduced auditory nerve activity triggers synaptic outgrowth and hyperactivity in the VCN via a MOC neural feedback circuit. Structural synaptic modifications may be a reflexive process that compensates for the reduced auditory input after salicylate administration. However, massive increases in excitatory synapses in the VCN may represent a detrimental process that causes central hyperactivity, leading to tinnitus.

Topics: Acoustic Stimulation; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cochlear Nucleus; Feedback, Physiological; Hearing Loss; Male; Nerve Net; Random Allocation; Rats; Rats, Wistar; Salicylates; Synapses

This study investigated the effect of systemic salicylate on central auditory and non-auditory structures in mice. Since cochlear hair cells are known to be one major target of salicylate, cochlear effects were reduced by using kanamycin to remove or impair hair cells. Neuronal brain activity was measured using the non-invasive manganese-enhanced magnetic resonance imaging technique. For all brain structures investigated, calcium-related neuronal activity was increased following systemic application of a sodium salicylate solution: probably due to neuronal hyperactivity. In addition, it was shown that the central effect of salicylate was not limited to the auditory system. A general alteration of calcium-related activity was indicated by an increase in manganese accumulation in the preoptic area of the anterior hypothalamus, as well as in the amygdala. The present data suggest that salicylate-induced activity changes in the auditory system differ from those shown in studies of noise trauma. Since salicylate action is reversible, central pharmacological effects of salicylate compared to those of (permanent) noise-induced hearing impairment and tinnitus might induce different pathophysiologies. These should therefore, be treated as different causes with the same symptoms.

Topics: Amygdala; Animals; Auditory Cortex; Auditory Threshold; Cochlea; Female; Hearing Loss; Hypothalamus; Kanamycin; Magnetic Resonance Imaging; Male; Manganese; Mice; Radiography; Salicylates

Salicylate's ototoxic properties have been well established, inducing tinnitus and a sensory hearing loss when administered in high doses. Peripherally, acute dosing of salicylate causes frequency dependent reductions in DPOAEs and CAP amplitudes in low (<10 kHz) and high (>20 kHz) frequencies more than mid frequencies (10-20 kHz), which interestingly corresponds to the pitch of behaviourally-matched salicylate-induced tinnitus. Chronic salicylate dosing affects the peripheral system by causing a compensatory temporary enhancement in DPOAE amplitudes and up-regulation of prestin mRNA and protein expression. Despite salicylate's antioxidant properties, cultured cochlea studies indicate it also impairs spiral ganglion neurons (SGNs) by paradoxically causing an upsurge of superoxide radicals leading to apoptosis. Centrally, salicylate alters γ-aminobutyric acid (GABA) and serotonin mediated neurotransmission in the central nervous system (CNS), which results in classical and non-classical auditory regions showing hyperactivity after salicylate administration. In the auditory cortex (AC) and lateral amygdala (LA), neuron characteristic frequencies (CF) shift upward and downward to mid frequencies (10-20 kHz) altering tonotopy following salicylate administration. Additionally, current source density (CSD) analysis showed enhanced current flow into the supergranular layer of the auditory cortex after a high systemic dose of salicylate. In humans, auditory perception changes following salicylate or aspirin, including decreased word discrimination and temporal integration ability. The results of previous studies have partially identified the mechanisms that are involved in salicylate-induced tinnitus and hearing loss, however to date some interactions remain convoluted. This review discusses current knowledge of salicylate ototoxicity and interactions.. Gli effetti ototossici del salicilato sono ben noti ed includono, ad alti dosaggi, acufene ed ipoacusia transitoria. In periferia, la somministrazione acuta di salicilato nell'animale induce una riduzione d'ampiezza dei prodotti di distorsione (DPOAE) e dei potenziali d'azione (CAP), prevalentemente per le basse (<10 kHz) e per le alte (>20 kHz) frequenze; è interessante come questa alterazione corrisponda alla tonalità dell'acufene indotto sperimentalmente. La somministrazione cronica causa invece un aumento transitorio dell'ampiezza dei DPOAEs ed una up-regulation dell'mRNA e dell'espressione proteica della prestina. In vitro la tossicità da salicilato si evidenzia prevalentemente a livello dei neuroni del ganglio spirale (SGNs) inducendo, a dispetto delle ben note proprietà antiossidanti, un rilascio paradosso di radicale superossido che avvia la catena apoptotica. Centralmente, il salicilato altera la trasmissione GABA e serotoninomediata inducendo una iperattività di specifiche popolazioni neuronali. A livello della corteccia uditiva (AC) e dell'amigdala laterale (LA) le frequenze caratteristiche neuronali (CF) variano alterando la tonotopia fisiologica, specialmente per le frequenze centrali (10-20 kHz). Inoltre, l'analisi della densità di corrente (CSD) ha dimostrato un maggior influsso negli strati supragranulari della corteccia uditiva in seguito alla somministrazione di dosi elevate di salicilato per via sistemica.Nell'uomo gli effetti ototossici del salicilato, oltre ad ipoacusia transitoria ed acufene, includono una diminuita discriminazione verbale e difficoltà nell'integrazione temporale. Sebbene diversi lavori in letteratura abbiano identificato i meccanismi fisiopatologici alla base delle alterazioni uditive indotte dal salicilato, ad oggi alcune interazioni rimangono poco chiare.

Topics: Hearing Loss; Humans; Neurotoxicity Syndromes; Salicylates; Tinnitus

Salicylate causes a moderate hearing loss and tinnitus in humans at high-dose levels. Salicylate-induced hearing loss has been attributed to impaired sound amplification by outer hair cells (OHCs) through its direct action on the OHC motility sensor and/or motor. However, there is a disparity of salicylate concentrations between the clinical and animal studies, i.e., extremely high extracellular concentrations of salicylate (from 1 to 10 mM) is required to produce a significant reduction of electromotility in animal studies. Such concentrations are above the clinical/physiological range for humans. Here, we showed that clinical/physiological concentration range of salicylate caused concentration-dependent and reversible reductions in I(K,n) (KCNQ4) and subsequent depolarization of OHCs. Salicylate reduced the maximal tail current of the activation curve of I(K,n) without altering the voltage-sensitivity (V(half)). The salicylate-induced reduction of I(K,n) was almost completely blocked by linopirdine (0.1 mM) and BaCl₂ (10 mM). Consistent with the finding in OHCs, salicylate significantly reduced KCNQ4-mediated current expressed in Chinese hamster ovarian (CHO) cells by comparable amplitude to OHCs without significantly shifting V(half). Nonstationary fluctuation analysis shows that salicylate significantly reduced the estimated single-channel current amplitude and numbers. Intracellular Ca²+ elevation resulting from cytoplasmic acidosis also contributes to the current reduction of I(K,n) (KCNQ4) of OHCs. These results indicate a different model for the salicylate-induced hearing loss through the reduction of KCNQ4 and subsequent depolarization of OHCs, which reduces the driving force for transduction current and electromotility. The major mechanism underlying the reduction of I(K,n) (KCNQ4) is the direct blocking action of salicylate on KCNQ4.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Electrophysiology; Female; Guinea Pigs; Hair Cells, Auditory, Outer; Hearing Loss; KCNQ Potassium Channels; Models, Animal; Patch-Clamp Techniques; Salicylates

Salicylate and quinine have been shown to reliably induce short-term tinnitus when administered at high doses. The present study compared salicylate and quinine-induced tinnitus in rats using the gap prepulse inhibition of acoustic startle (GPIAS).. Twenty-four rats were divided into 2 groups; the first group (n = 12) was injected with salicylate (300 mg kg d), whereas the second (n = 12) was treated with quinine orally at a dose of 200 mg kg d. Animals were treated daily for 4 consecutive days. All rats were tested for tinnitus and hearing loss before and 2, 24, 48, 72, and 96 hours after the first drug administration. Tinnitus was assessed using GPIAS; hearing function was measured with distortion product otoacoustic emissions (DPOAEs) and auditory brainstem response.. Salicylate treatment induced transient tinnitus with a pitch near 16 kHz starting 2 hours posttreatment, persisting over the 4-day treatment period and disappearing 24 hours later. Animals in the quinine group showed GPIAS changes at a higher pitch (20 kHz); however, changes were more variable among animals, and the mean data were not statistically significant. Hearing function varied across treatments. In the salicylate group, high-level DPOAEs were slightly affected; most changes occurred 2 hours posttreatment. Low-level DPOAEs were affected at all frequencies with a progressive dose-dependent effect. In the quinine group, only high-level DPOAEs were affected, mainly at 16 kHz.. The present study highlights the similarities and differences in the frequency and the time course of tinnitus and hypoacusis induced by salicylate and quinine. Transient tinnitus was reliably induced pharmacologically with salicylate, whereas hearing loss remained subclinical with only minor changes in DPOAEs.

Topics: Animals; Behavior, Animal; Evoked Potentials, Auditory, Brain Stem; Hearing Loss; Male; Noise; Otoacoustic Emissions, Spontaneous; Quinine; Rats; Rats, Sprague-Dawley; Reflex, Startle; Salicylates; Time Factors; Tinnitus

A sudden hearing loss in a woman on aspirin has uncovered a frequently neglected toxicological parameter.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Disease Progression; Female; Hearing Loss; Humans; Lupus Erythematosus, Systemic; Proteinuria; Salicylates; Tinnitus

Tinnitus is a phantom auditory perception, which can be induced via application of concentrated sodium salicylate, and is known to be associated with hearing loss and altered neuronal excitability in peripheral and central auditory neurons. The molecular features of this excitability, however, has been poorly characterized to date. Brain-derived neurotrophic factor (BDNF), the activity-dependent cytoskeletal protein (Arg3.1, also known as Arc), and c-Fos are known to be affected by changes in excitability and plasticity. Using reverse transcription-polymerase chain reaction, in situ hybridization, and immunohistochemistry, the expression of these genes was monitored in the rat auditory system after local (cochlear) and systemic application of salicylate. Induction of tinnitus and hearing loss was verified in a behavioral model. Regardless of the mode of salicylate application, a common pattern became evident: 1) BDNF mRNA expression was increased in the spiral ganglion neurons of the cochlea; and 2) Arg3.1 expression was significantly reduced in the auditory cortex. Local application of the GABA(A) receptor modulator midazolam resulted in the reversal not only of salicylate-induced changes in cochlear BDNF expression, but also in cortical Arg3.1 expression, indicating that the tinnitus-associated changes in cochlear BDNF expression trigger the decline of cortical Arg3.1 expression. Furthermore, local midazolam application reduced tinnitus perception in the animal model. These findings support Arg3.1 and BDNF as markers for activity changes in the auditory system and suggest a role of GABAergic inhibition of cochlear neurons in the modulation of Arg3.1 plasticity changes in the auditory cortex and tinnitus perception.

Topics: Animals; Auditory Cortex; Auditory Pathways; Auditory Perception; Behavior, Animal; Brain-Derived Neurotrophic Factor; Cochlea; Cytoskeletal Proteins; Female; Gene Expression Regulation; Hearing Loss; Midazolam; Models, Biological; Nerve Tissue Proteins; Neurons; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, GABA; RNA, Messenger; Salicylates; Tinnitus

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Antioxidants; Diuretics; Hearing Loss; History, 19th Century; History, 20th Century; History, Medieval; Humans; Otolaryngology; Quinine; Salicylates; Solvents

Acetylic acid, such as aspirin, is one of the most commonly used medication in Western societies. Aspirin overdosage causes ototoxic side effects in some patients, such as bilateral mild to moderate sensorineural hearing loss and tinnitus. Recent literature describes, that salicylates act as competitive inhibitors of Cl- anions at the anion-binding site of prestin, the motor protein of the outer hair cell. This molecular mechanism correlates well with the clinical audiological mainstays of aspirin-induced hearing loss, dose dependency, cochlear site of hearing loss and reversibility. We report about a young man with an acute moderate aspirin intoxication resulting in asymmetric hearing loss of 50 dB HL and tinnitus for five days. Otoacoustic emissions were absent on the first day of intoxication but could be measured again on the fifth day after the intoxication. As the ototoxic side effects resolve with in two or three days, no specific treatment is necessary for ototoxicity. Medical treatment of acute or chronic aspirin intoxications aims to decrease further drug absorption by gastrointestinal decontamination and to accelerate elimination by alkaline diuresis. Only in severe intoxications hemodialysis may be considered to treat neurologic, pulmonal, renal or cardial complications.

Topics: Adaptation, Physiological; Adult; Aspirin; Drug Overdose; Hearing Loss; Humans; Male; Otoacoustic Emissions, Spontaneous; Salicylates; Tinnitus

Recent advances in molecular pharmacology of the cochlea have lead to a much better understanding of the physiology, and especially the pathophysiology, of the sensorineural structures of the organ of Corti. Knowledge of the intimate molecular mechanisms of cellular dysfunction is of considerable use in the development of new therapeutic strategies. Herein, we summarize the mechanisms of sensory hair cell death after various injuries. Based on these molecular mechanisms, we propose novel therapeutic strategies to restore hearing. In addition to permanent hearing loss, exposure to noise or ototoxic drugs also induces tinnitus. We thus review recent findings obtained from a behavioral model of tinnitus in rats. In addition to providing evidence for the site and mechanism of generation of tinnitus induced by salicylate, these results support the idea that targeting cochlear N-methyl-D-aspartate receptors may represent a promising therapeutic strategy for treating tinnitus.

Topics: Animals; Apoptosis; Disease Models, Animal; Hair Cells, Auditory; Hearing Loss; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase Kinases; Neuroprotective Agents; Peptides; Riluzole; Salicylates; Signal Transduction; Tinnitus

Electrically evoked otoacoustic emissions (EEOAEs) are sounds emitted in the ear canal when an alternating current is delivered to the cochlea. Salicylate, which causes reversible hearing loss, decreases both the electromotility of the outer hair cells (OHCs) and the EEOAE output. The frequency response of EEOAEs is known to depend on the location of the stimulating electrode. Using electrodes placed in the first or third turn of the cochlea, we measured EEOAEs before and after salicylate administration in order to clarify the frequency range of EEOAEs from which exact information can be acquired.. A sinusoidal electrical signal (160 microA root-mean-square) at frequencies ranging from 500 Hz to 16 kHz was delivered to the first or third turn of the scala tympani of the guinea pig cochlea in order to determine EEOAEs. The EEOAE outputs were measured before and every 5 min after administration of salicylate (500 mg/kg) for 60 min. The threshold of the compound action potential (CAP) was measured before and 60 min after salicylate administration.. CAP thresholds were reduced at frequencies ranging from 2 to 12 kHz after salicylate administration. The maximum EEOAE output recorded with the first-turn electrode was obtained at 12 kHz with a gentle slope of low cutoff, whereas the frequency response of the EEOAE recorded with the third-turn electrode demonstrated a steep dip at 2 kHz.. EEOAE reduction after salicylate administration was restricted to frequencies close to that of the characteristic frequency (CF) of the electrode position. This was probably related to the fact that the EEOAE is the sum of waves from the CF of the electrode position and the stimulus frequency. In terms of studying the electromotility of OHCs, useful information obtained from EEOAEs is restricted to the narrow frequency band close to the CF of the electrode location.

Topics: Action Potentials; Animals; Cochlea; Cyclooxygenase Inhibitors; Electric Stimulation; Evoked Potentials, Auditory; Guinea Pigs; Hair Cells, Auditory, Outer; Hearing Loss; Otoacoustic Emissions, Spontaneous; Salicylates

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Child; Cochlear Nerve; Hearing Loss; Humans; Salicylates; Tinnitus

A pilot study evaluated once-daily treatment of rheumatoid arthritis with choline magnesium trisalicylate (CMT) in patients diagnosed as having classical or definite rheumatoid arthritis, with morning stiffness as a major complaint. Twenty patients were selected who, in an earlier phase of the study, had found twice-daily treatment with CMT effective and tolerable. Efficacy was evaluated in 15 of these patients and safety was evaluated in all 20. Comparisons were made with the twice-daily regimen and with previous nonsteroidal anti-inflammatory drug (NSAID) therapy. Changes in clinical indicators (numbers of painful and swollen joints and the duration of morning stiffness) showed that once-daily treatment with CMT was as effective as twice-daily treatment with CMT or as treatment with other prior NSAIDs in controlling signs and symptoms of rheumatoid arthritis. Side effects in both the twice-daily and the once-daily treatment regimens were similar in incidence and nature.

Topics: Adult; Aged; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Choline; Female; Hearing Loss; Humans; Male; Middle Aged; Pilot Projects; Salicylates; Tinnitus