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Sulpiride and Melatonin Decrease Tinnitus Perception Modulating the Auditolimbic Dopaminergic Pathway
Abstract
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.
A prospective, randomized, double-blinded, placebo-controlled study was done.
General otorhinolaryngologic consultation for 2002-2004 in Seville, Spain.
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.
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.
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.
Sulpiride and melatonin reduce tinnitus perception, decreasing dopamine activity. The tinnitus auditolimbic dopaminergic pathway has broad therapeutic implications.
... No sufficient evidence of an effect on tinnitus could be produced for a wide variety of other drugs, including antidepressants [21], melatonin [85], pramipexole [188], alprazolam [86], sulpiride and melatonin [114], sertraline [212], botox A [184], and nortriptyline [186]. Though positive results were sometimes shown in the RCT, methodological analysis revealed low methodological quality and insufficient effect size. ...
... Furthermore, a wide range of studies do not provide appropriate information due to insufficient methodological quality: sulpiride and melatonin due to non-double-blind, inadequate study design [113,114], misoprostol due to inadequate statistics [3,203] and inadequate study design [30], EGb 761 due to inadequate methodology and high drop-out rate [123], amitriptyline due to inadequate study design [22], alprazolam due to inadequate study design [91], carbamazepine due to inadequate report quality and too little information on study design [83], melatonin due to inadequate report quality with no information on drop-outs, means without unity, and no details regarding study design [126,127] and inadequate methodology and statistics [165], sulpiride and melatonin due to inadequate methodology and statistics [114], zinc due to inadequate methodology and statistics [9] and inadequate statistics [9], Paaske et al. [142], inadequate methodology and statistics, Yetiser et al. [202], inadequate statistics, non-controlled, non-randomised, no effects, Ochi et al. [131], inadequate statistics, cross-sectional comparison with healthy individuals, not randomised, Paaske et al. [141], inadequate study design, no distress/ annoyance endpoint, no effect, pramipexole, and D2/D3 dopamine due to inadequate study design, inadequate statistics, and follow-up of only 4 weeks [188]. ...
... Furthermore, a wide range of studies do not provide appropriate information due to insufficient methodological quality: sulpiride and melatonin due to non-double-blind, inadequate study design [113,114], misoprostol due to inadequate statistics [3,203] and inadequate study design [30], EGb 761 due to inadequate methodology and high drop-out rate [123], amitriptyline due to inadequate study design [22], alprazolam due to inadequate study design [91], carbamazepine due to inadequate report quality and too little information on study design [83], melatonin due to inadequate report quality with no information on drop-outs, means without unity, and no details regarding study design [126,127] and inadequate methodology and statistics [165], sulpiride and melatonin due to inadequate methodology and statistics [114], zinc due to inadequate methodology and statistics [9] and inadequate statistics [9], Paaske et al. [142], inadequate methodology and statistics, Yetiser et al. [202], inadequate statistics, non-controlled, non-randomised, no effects, Ochi et al. [131], inadequate statistics, cross-sectional comparison with healthy individuals, not randomised, Paaske et al. [141], inadequate study design, no distress/ annoyance endpoint, no effect, pramipexole, and D2/D3 dopamine due to inadequate study design, inadequate statistics, and follow-up of only 4 weeks [188]. ...
The majority of tinnitus patients are affected by chronic idiopathic tinnitus, and almost 60 different treatment modalities have been reported. The present study is a multidisciplinary systematic analysis of the evidence for the different forms of treatment for chronic tinnitus. The results are used to form the basis of an S3 guideline. A systematic search was carried out in PubMed and the Cochrane Library. The basis for presenting the level of evidence was the evidence classification of the Oxford Centre of Evidence-based Medicine. Whenever available, randomised controlled trials were given preference for discussing therapeutic issues. All systematic reviews and meta-analyses were assessed for their methodological quality, and effect size was taken into account. As the need for patient counselling is self-evident, specific tinnitus counselling should be performed. Due to the high level of evidence, validated tinnitus-specific, cognitive behavioural therapy is strongly recommended. In addition, auditory therapeutic measures can be recommended for the treatment of concomitant hearing loss and comorbidities; those should also be treated with drugs whenever appropriate. In particular, depression should be treated, with pharmacological support if necessary. If needed, psychiatric treatment should also be given on a case-by-case basis. With simultaneous deafness or hearing loss bordering on deafness, a CI can also be indicated. For auditory therapeutic measures, transcranial magnetic or direct current stimulation and specific forms of acoustic stimulation (noiser/masker, retraining therapy, music, and coordinated reset) for the treatment of chronic tinnitus the currently available evidence is not yet sufficient for supporting their recommendation.
... A prospective, randomized, double-blind, placebo controlled study was reported by Lopez-Gonzalez et al. [34]. They showed the alleviation of subjective tinnitus by using melatonin. ...
... In this report, melatonin (3 mg, daily) was compared with sulpiride-D 2 dopamine receptor antagonist (50 mg, daily) or combination of both for perception of tinnitus. The duration of treatment was 30 days and at the end of the treatment, it was found that melatonin reduced tinnitus by 40%, sulpiride lowered it by 56% and combination caused an 81% drop in subjective tinnitus [34]. ...
... In several studies mentioned above, short-term melatonin usage up to 3 months looked like safe for the majority of adults (1,2,4,(33)(34)(35)(36)(37)(38)(39)(40). But, it may cause nausea, headache, daytime sleepiness, short term feelings of depression, stomach cramps, dizziness, irritability and low body temperature [38]. ...
Oxidative stress and reactive oxygen species (ROS) have been working in the pathophysiology of various chronic diseases. Under normal circumstances, the human cochlea has some antioxidant molecules which can scavenge the oxidant substances and ROS to avoid the possible damage into the inner ear. In tinnitus therapy, several forms of complementary and alternative medicine (CAM) are increasingly popular but they are generally selected with or without professional guidance. Although several antioxidant agents like vitamin A, C, E and glutathione can be used in the treatment of tinnitus as CAM, melatonin, N-acetyl cysteine (NAC) and coenzyme Q10 (CoQ10) were especially used as alternative for classic antioxidants. According to the literature, it seems antioxidant therapy in patients with idiopathic tinnitus may reduce oxidative stress and damage to the inner ear. And also it can reduce the intensity and discomfort of tinnitus. Further clinical studies are necessary to determine antioxidants' protective role and to choose the appropriate therapeutic protocol.
... No improvement was noted in the control group. The authors concluded that melatonin in combination with sulodexide can be considered an effective treatment option for central or sensorineural tinnitus [20]. ...
... Hurtuk et al. [12] achieved randomization with a computergenerated list. In the articles of Rosenberg et al., Neri et al. and Lopez-Gonzalez et al., it is not clearly reported what randomization procedure was adopted by investigators [18,20,21]. It has been proven that the lack of details on randomization represents a common source of selection bias [22,23]. ...
... The authors indicated the reason of the dropouts, but they did not perform an ITT analysis [21]. No dropouts were reported in the article of Neri et al. [20]. ...
We performed a review with the purpose to summarise, analyse and discuss the evidence provided by clinical studies evaluating effectiveness of melatonin in the cure of tinnitus. Due to the fact that there is no satisfactory treatment for tinnitus, clinical research has explored new therapeutic approaches.
A search of Pubmed, Medline, Embase, Central and Google Scholar was conducted to find trials published prior March 2014 on melatonin in the treatment of tinnitus. Design of the studies, randomization, allocation concealment procedures and diagnostic instruments (scales for tinnitus evaluation) were critical evaluated.
Five clinical studies have been included. Three of them tested effectiveness of melatonin alone, the remaining two along with sulpiride and sulodexide respectively. Considered clinical trials adopted various experimental designs: single arm, randomised placebo-controlled and randomised placebo-controlled followed by crossover. These studies were characterised by several methodological weaknesses.
Confirmation of melatonin clinical effectiveness in the treatment of tinnitus cannot be given in the light of the biases observed in the considered evidence. Melatonin seems to improve sleep disturbance linked to tinnitus.
... 17,18 Tinnitus is often comorbid with anxiety, depression, and sleep disturbances. 19 The mechanism underlying tinnitus is suggested to involve oxidative stress damage and/or neuroinflammation, 20,21 dysfunction of NMDA receptors, 22 GABA receptors, 23 dopamine receptors, 24,25 and ion channels/cotransporters. 24 Studies of the relationship between parasomnias and tinnitus are rare, even these two diseases might share a similar etiology and/or pathophysiology. This study aims to investigate the relationship between parasomnias and chronic tinnitus in patients according to age. ...
... 17,18 Tinnitus is often comorbid with anxiety, depression, and sleep disturbances. 19 The mechanism underlying tinnitus is suggested to involve oxidative stress damage and/or neuroinflammation, 20,21 dysfunction of NMDA receptors, 22 GABA receptors, 23 dopamine receptors, 24,25 and ion channels/cotransporters. 24 Studies of the relationship between parasomnias and tinnitus are rare, even these two diseases might share a similar etiology and/or pathophysiology. This study aims to investigate the relationship between parasomnias and chronic tinnitus in patients according to age. ...
Background/purpose
Sleep disturbances are associated with chronic tinnitus in humans. However, whether parasomnias are associated with chronic tinnitus is unclear. This study aims to investigate this issue.
Methods
Clinical data for 2907 subjects who had visited the Sleep Center of a community hospital in Taiwan during November 2011 to June 2017 were collected retrospectively. The association of chronic tinnitus with sleep terror, sleep walking, and sleep talking was analyzed using Pearson's Chi-Square test and multivariate logistic regression.
Results
The cohort age ranged from 7 to 91 years old, with a mean age of 49.8 years (standard deviation, 14.3 years). The cohort included 1937 patients without and 970 patients with chronic tinnitus. The percentage of patients who experienced sleep terror was significantly higher among those with tinnitus than those without (p < 0.001). The percentage of patients reporting sleep walking was slightly higher in subjects with tinnitus than in those without, with borderline significance (p = 0.063). The percentage of patients experiencing sleep talking did not differ significantly between the groups. Multivariate logistic regression also showed that sleep terror but not sleep walking was significantly associated with tinnitus after adjusting for age, sex, hearing loss, and insomnia. After adjusting for other factors, subgroup analysis by age showed that sleep terror was significantly positively associated with chronic tinnitus in patients aged 20–44 years but not in those aged 7–19 or >45 years.
Conclusion
Sleep terror is positively associated with chronic tinnitus, especially in young adults.
... This retrospective study based on clinical and PSG data showed that PLMS, one kind of sleep disturbances, was not significantly associated with chronic tinnitus before and after adjusting other variables. This clinical finding did not support the expectation based on the dopaminergic system dysfunction for both of PLMS and chronic tinnitus 15,18,19 . Also, although PLMS-related complications and/or sequelae might contribute to tinnitus 2,3,5-7 , current results did not show positive correlation between PLMS and chronic tinnitus in humans at all. ...
... On the other hand, the results about tinnitus-related dopaminergic pathway dysfunction varied. For example, sulpiride, an agonists and antagonists of dopamine receptors (DRs) can reduce tinnitus 18 . Pramipexole, an agonist of DR2/3, could reduce tinnitus associated with presbycusis 24 . ...
Both of periodic limb movements during sleep (PLMS) and tinnitus were related with dopaminergic system dysfunction. However, it was still unclear whether PLMS, one kind of sleep disturbances, was associated with chronic tinnitus or not. Thus, we aimed to investigate this issue in humans. Clinical and overnight polysomnographic data of 2849 adults from a community hospital during Nov. 2011 to Jun 2017 in Taiwan was collected retrospectively. The association of PLMS and chronic tinnitus was analyzed by Student’s t-test, Pearson’s Chi-Square test, and multivariate logistic regression. The results showed that the mean age was 50.6 years old (standard deviation, SD = 13.3, range = 18~91) for all subjects. There were 1886 subjects without tinnitus and 963 subjects with tinnitus in this study. The PLMS was not significantly different between subjects without tinnitus (mean = 1.0/h, SD = 3.5/h) and subjects with tinnitus mean = 1.1/h, SD = 3.4/h) by Student’s t-test. The severity of PLMS was not significantly between non-tinnitus and tinnitus subjects by Pearson’s Chi-Square test. Multivariate logistic regression also showed that PLMS was not significantly associated with tinnitus after adjusting age, sex, subjective hearing loss, Parkinson’s disease, and insomnia. In conclusion, PLMS was not associated with chronic tinnitus in humans.
... Los neurolépticos o antipsicóticos llamados tranquilizantes mayores, actúan bloqueando los receptores específicos de la Dopamina D2 en el sistema límbico y cortical (vías mesolímbicas y mesocortical) (23,28). Usados en trastornos psicosomáticos, bipolares, alucinaciones y esquizofrenia. ...
... Usados en trastornos psicosomáticos, bipolares, alucinaciones y esquizofrenia. Dentro de este grupo se encuentra la sulpirida que junto los pacientes la intensidad de los acúfenos (28). La melatonina también tiene actividad antidopaminérgica, lo que podría guardar relación con sus efectos beneficiosos sobre los acúfenos (28). ...
Hacemos una puesta al día práctica y completa, basada en la concepción moderna del tinnitus. Abarcando aspectos de epidemiología y las teorías y mecanismos fisiopatológicos más aceptados.
Por otra parte, describimos una guía práctica sobre su evaluación, con las pruebas fundamentales para su diagnóstico y el manejo terapéutico actual. En especial mencionando los tratamientos sonoros de habituación y los fármacos disponibles.
... Increased activity in the hypothesized auditolimbic dopaminergic pathway is potentially involved in emotional aspects of tinnitus and may produce the distress in tinnitus sufferers. This theory provides a means to modulate the dopamine actions using dopaminergic agonistic and antagonistic drugs [42]. Sulpiride, a dopamine D2 antagonist and atypical antipsychotic drug, significantly reduced [42]. ...
... This theory provides a means to modulate the dopamine actions using dopaminergic agonistic and antagonistic drugs [42]. Sulpiride, a dopamine D2 antagonist and atypical antipsychotic drug, significantly reduced [42]. Piribedil, a dopamine D2/D3 agonist approved for Parkinsonism, was not superior to placebo. ...
Pharmacotherapy has been constantly chosen by the clinician among the available treatment options for tinnitus. Medications that have been prescribed off-label to treat tinnitus can be grouped into several categories: benzodiazepines, antidepressants, anticonvulsants, N-methyl-D-aspartate (NMDA) receptor antagonists, dopamine receptor modulators, muscle relaxants, and others. In this article, a wide variety of compounds once used in the treatment of tinnitus and evidenced by clinical trials are reviewed with respect to the mechanisms of action and the drug efficacy. Only a few of the various pharmacological interventions investigated have some beneficial effects against tinnitus: clonazepam, acamprosate, neramexan, and sulpiride. Sertraline and pramipexole were effective in subgroups of patients with psychiatric symptoms or presbycusis. However, no agents have been identified to provide a reproducible long-term reduction of tinnitus in excess of placebo effects. In rodent tinnitus models, L-baclofen, memantine, and KCNQ2/3 channel activators have been demonstrated to reduce tinnitus development. Limitation of the use of an effective high dosage during a longer treatment duration due to dose-dependent side effects of the centrally acting drugs may influence the results in clinical studies. More effective and safer innovative agents should be developed based on the further understanding of tinnitus neural mechanisms and valid animal models, and should be supported by improved clinical trial methodology. The management of tinnitus patients through a tailored treatment approach depending on the detailed classification of tinnitus subtypes will also lead to better treatment outcomes.
... Dopaminergic pathways have been linked with tinnitus and its management, as it is proposed to support the functional neuroanatomy of tinnitus perception. For example, in a human trial involving 120 patients, sulpiride (a selective antagonist of dopamine D 2 , D 3 and serotonin 1A receptors) decreased tinnitus perception by 56%, melatonin (a free radical scavenger) administration decreased it by 40%, and sulpiride along with melatonin decreased it by 81% [213]. One reason behind the low success rate of clinical trials relating to tinnitus could be due to the lack of identifying the primary target and its manipulation through different drug dosages. ...
Tinnitus is originally derived from the Latin verb tinnire, which means “to ring”. Tinnitus, a complex disorder, is a result of sentient cognizance of a sound in the absence of an external auditory stimulus. It is reported in children, adults, and older populations. Patients suffering from tinnitus often present with hearing loss, anxiety, depression, and sleep disruption in addition to a hissing and ringing in the ear. Surgical interventions and many other forms of treatment have been only partially effective due to heterogeneity in tinnitus patients and a lack of understanding of the mechanisms of tinnitus. Although researchers across the globe have made significant progress in understanding the underlying mechanisms of tinnitus over the past few decades, tinnitus is still deemed to be a scientific enigma. This review summarises the role of the limbic system in tinnitus development and provides insight into the development of potential target-specific tinnitus therapies.
... A recent study showed that melatonin reduced the subjective ratings of tinnitus and tinnitus loudness more than placebo; these improvements were larger if melatonin was combined with the antipsychotic sulpiride, a selective dopamine D2 antagonist. [33] Memantine Memantine is presently used for the treatment of Alzheimer's disease and has shown positive effects in managing depression. [34] It also acts as a voltage-dependent antagonist of NMDA receptors and decreases excitotoxicity by preventing the prolonged influx of calcium. ...
... In addition to the effectiveness of melatonin in reducing symptoms, they concluded that this drug would be much more effective when combined with sulpiride. 10 In all the mentioned studies, melatonin has most often been used in a dose of 3 mg/d orally. ...
Background: Tinnitus is described as the perception of sounds occurring in one or both ears or inside the human head without external auditory stimuli. Objectives: This study aimed to compare the efficacy of amitriptyline and melatonin in the treatment of tinnitus. Methods: This study was a randomized double-blind clinical trial of 60 patients referred to the neurology clinics of Kashani and Al-Zahra hospitals in Isfahan, Iran in 2020. Each patient was randomly assigned 1 code. Patients first filled in the tinnitus handicap inventory (THI) and visual analogue scales (VAS) questionnaires and were given either one of the two drugs (melatonin and amitriptyline) for 6 weeks. After collecting the desired information using an independent t test and paired t test in SPSS 26 software and error level of 0.05 the results were analyzed. Results: Thirty patients were in the amitriptyline group and 30 patients were in the melatonin group, of which 25 were men (41.7%) and 35 were women (58.3%) with a minimum age of 18 years and a maximum of 65 years. There was no significant difference between the reduction of tinnitus before and after taking the drugs based on VAS scale in amitriptyline and melatonin groups (P=0.234), however there was a significant difference between the effect of two amitriptyline and melatonin drugs on the reduction of tinnitus based on the THI questionnaire (P=0.018). Conclusion: The rate of tinnitus in patients decreased for 6 weeks with the use of amitriptyline and melatonin, but amitriptyline had a better effect on reducing the complications and pain of tinnitus.
... The overt oxidative stress [5] and imbalance antioxidant enzyme [7] is considered one possible etiology of tinnitus. The supplementation of antioxidants such as melatonin has been shown to be effective in tinnitus management [53]. Although the findings of potential benefits of melatonin in tinnitus management could support the hypothesis of a tinnitus auditolimbic dopaminergic pathway and overt-oxidative stress in tinnitus, future clinical trials should focus on the etiology of tinnitus. ...
Background
Although tinnitus has a prevalence between 20 and 42.8%, the currently recommended management for tinnitus, such as tinnitus support and psychologic therapies, are relatively time-consuming and expensive. Several new pharmacologic treatments designed for tinnitus patients without specific origin had been developed but their efficacy remains unclear.
Methods
The current Network Meta-Analysis (NMA) of randomised controlled trials (RCTs) was conducted to evaluate the efficacy of different pharmacologic treatments for tinnitus management in tinnitus patients without specific or treatable origin (i.e. primary tinnitus). Databases were searched from inception to April 5th, 2021. All network meta-analytic procedures were conducted under the frequentist model. We calculated the effect size of outcomes with different rating scales with standardized mean difference. PROSPERO registration: CRD42020177742.
Findings
Overall, 36 RCTs were included with 2,761 participants. The main results revealed that pharmacologic interventions with brain-acting effect (for example, amitriptyline, acamprosate, and gabapentin) and those with anti-inflammation/anti-oxidant effect (for example, intra-tympanic dexamethasone injection plus oral melatonin) were associated with superior improvement in tinnitus severity and response rate compared to placebo/control. Oral amitriptyline were associated with the highest improvement in tinnitus severity and the fourth highest response rate. None of the investigated interventions was associated with different changes in quality of life compared to placebo/control. All the investigated treatments were associated with similar drop-out rate to placebo/control.
Interpretation
The current NMA suggests a potential role for treatments with brain-acting effect (for example, amitriptyline, acamprosate, and gabapentin) or anti-inflammation/anti-oxidant effect (for example, intra-tympanic dexamethasone injection plus oral melatonin) as the preferable effective treatments for tinnitus without specific or treatable origin.
Funding
none.
... The sample size (61 patients) is in the range of that observed in previous studies on tinnitus (Morgenstern and Biermann 2002;Lopez-Gonzalez et al. 2007;Tziridis et al. 2014;Abtahi et al. 2017) and higher than in several of them (Rosenberg et al. 1998;Arda et al. 2003;Cevette et al. 2010;Radunz et al. 2019). The high dropout rate (52.5%) noted in our study is worth mentioning, resulting in only 29 patients with complete data at the end of follow-up. ...
To assess the effectiveness of a food supplement (Tinnitan Duo®) containing 5-hydroxytryptophan, Ginkgo biloba, magnesium, melatonin, vitamin B5 and B6, and zinc at improving tinnitus response and intensity. Prospective, single-center interventional study including patients with subjective tinnitus and emotional affectation. The primary endpoint was the change in the Tinnitus Handicap Inventory (THI) total score and the emotional subscale after 3 months of treatment. Secondary endpoints were the change from baseline to month 3 in (1) the Tinnitus Distress Rating (TDR) scale, and (2) in hearing status, and the safety profile of patients throughout the study. Sixty-one patients were included, and 29 completed the study. The THI total score was significantly reduced after 3 months of treatment in the per-protocol (PP, all the patients with no major protocol deviations) and intention-to-treat (ITT) populations (−15.7 and −7.5, respectively; p = 0.001). The emotional subscale score significantly decreased after 3 months of treatment by −5.6 in the PP (p = 0.001) and by −2.6 in the ITT populations (p = 0.001). Perceived tinnitus loudness significantly decreased after 3 months of treatment (p = 0.001). The audiogram showed no significant changes in hearing status after 3 months of treatment. Of the five adverse events (AEs) reported, all were mild or moderate, and three were related to the study treatment (two headaches and one dizziness). This new food supplement was associated with an improved tinnitus-related emotional affectation and with a good safety profile.
... Simultaneous treatment with sulpiride plus melatonin or hydroxyzine, however, resulted in significantly greater reductions in both the tinnitus and tinnitus perception VAS scores than administration of placebo. In contrast, piribedil, a D2/D3 agent currently used to treat patients with Parkinson's disease, had no effect on tinnitus [81]. ...
Various medications are currently used in the treatment of tinnitus, including anesthetics, antiarrhythmics, anticonvulsants, antidepressants, antihistamines, antipsychotics, anxiolytics, calcium channel blockers, cholinergic antagonists, NMDA antagonists, muscle relaxants, vasodilators, and vitamins. To date, however, no medications have been specifically approved to treat tinnitus by the US Food and Drug Administration (FDA). In addition, medicines used to treat other diseases, as well as foods and other ingested materials, can result in unwanted tinnitus. These include alcohol, antineoplastic chemotherapeutic agents and heavy metals, antimetabolites, antitumor agents, antibiotics, caffeine, cocaine, marijuana, nonnarcotic analgesics and antipyretics, ototoxic antibiotics and diuretics, oral contraceptives, quinine and chloroquine, and salicylates. This review, therefore, describes the medications currently used to treat tinnitus, including their mechanisms of action, therapeutic effects, dosages, and side-effects. In addition, this review describes the medications, foods, and other ingested agents that can induce unwanted tinnitus, as well as their mechanisms of action.
... 26 Moreover, there is evidence that lowfrequency rTMS affects GABAergic neurotransmission not only in the stimulated brain region but also in various regions widely spread over the cortex. 27 Given the association of tinnitus with a reduced GABA concentration in the auditory cortex and changes in tinnitus perception by pharmacologically modulating the auditolimbic dopaminergic pathway, 28,29 corresponding rTMS protocols as implemented in our study might reduce tinnitus by manipulating neurochemistry in candidate regions. It seems thus plausible that the baseline configuration of the respective regions determines the(ir) responsivity to rTMS. ...
Noninvasive brain stimulation can reduce severity of tinnitus phantom sounds beyond time of stimulation by inducing regional neuroplastic changes. However, there are no good clinical predictors for treatment outcome. We used machine learning to investigate whether brain anatomy can predict therapeutic outcome. Sixty-one chronic tinnitus patients received repetitive transcranial magnetic stimulation of left dorsolateral prefrontal and temporal cortex. Before repetitive transcranial magnetic stimulation, a structural magnetic resonance image was obtained from all patients. To predict individual treatment response in new subjects, we employed a support-vector machine ensemble for individual out-of-sample prediction. In the cross-validation, the support-vector machine ensemble based on stratified subsampling and feature selection yielded an area under the curve of 0.87 for prediction of therapy success in new, previously unseen subjects. This corresponded to a balanced accuracy of 83.5%, sensitivity of 77.2%, and specificity of 87.2%. Investigating the most selected features showed the involvement of auditory cortex but also revealed a network of nonauditory brain areas. These findings suggest that idiosyncratic brain patterns accurately predict individual responses to repetitive transcranial magnetic stimulation treatment for tinnitus. Our findings may hence pave the way for future investigations into precision treatment of tinnitus, involving automatic identification of the appropriate treatment method for the individual patient.
... A study of the dopamine agonist pramipexole showed alleviation of presbycusis-related tinnitus [80]. the dopamine antagonist sulpiride was also found to be effective in reducing tinnitus perception both alone and in combination with either melatonin or hydroxyzine [81,82]. Nevertheless, negative results for the dopamine agonist piribedil were also reported, and 19 out of 75 participants quit the study owing to side effects such as nausea and dizziness [83]. ...
Tinnitus, which is the perception of sound in the absence of a corresponding external acoustic stimulus, including change of hearing and neural plasticity, has become an increasingly important ailment affecting the daily life of a considerable proportion of the population and causing significant burdens for both the affected individuals and society as a whole. Here, we briefly review the epidemiology and classification of tinnitus, and the currently available treatments are discussed in terms of the available evidence for their mechanisms and efficacy. The conclusion drawn from the available evidence is that there is no specific medication for tinnitus treatment at present, and tinnitus management might provide better solutions. Therapeutic interventions for tinnitus should be based on a comprehensive understanding of the etiology and features of individual cases of tinnitus, and more high quality and large-scale research studies are urgently needed to develop more efficacious medications.
... 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, concluding that Sulpiride and melatonin reduce tinnitus perception, decreasing dopamine activity. The tinnitus auditor-limbic dopaminergic pathway has broad therapeutic implications [43]. ...
Tinnitus is common and can severely affect life quality in many. There are no FDA approved drugs for tinnitus treatment and no
surgery for sensorineural tinnitus. Up till now, there are no medications or supplements approved for tinnitus; our impression is
that they are widely used. Therefore, we believe it is helpful to review the literature and provide some suggestions for clinicians and
sufferers. We review studies which describe current and emerging pharmacotherapies. In addition, we describe recent advances in
the tinnitus field which may help overcome obstacles faced in the pharmacological treatment of tinnitus.
... In addition, combination with some drugs appears to exert a synergistic effect. In a study conducted in patients divided into 4 treatment groups including placebo, tinnitus perception decreased by up to 81% in patients treated with sulpiride plus MT [41]. It also appears that the combination of MT and sulodexide, a highly purified mixture of glycosaminoglycans composed of low molecular weight heparin (80%) and dermatan sulphate (20%), has better results in central and peripheral tinnitus, according to the results on THI test and acufenometry thresholds [42]). ...
The purpose of this review is to summarize the advances and discoveries in the potential treatment with hormone analogs and some challenges still pending, beyond the classic treatment with corticosteroids. We conduct a review of the functions of hormones on hearing, in human and animal models, the presence of their most relevant receptors, and the desirable and undesirable effects for their therapeutic uses. Different hormones play a regulatory role in the development and maintenance of hearing. Hormone receptors in the ear have been identified over the years, which can be a support to use them as new therapeutic targets Moreover, their mediators, that include cells, neurotrophic factors, or other hormones, could be also useful for treating various hearing impairments The use of synthetic analogs could exert a therapeutic effect on hearing. Hormone therapy, in fact, can contribute positively to the treatment and prevention of various auditory pathologies, through the regeneration or protection. Considering that an optimal result has to be a garantee, it is a must to know their unwanted effects and contraindications. The use of hormones may protect, regenerate, and modulate multiple pathological conditions of the ear, but it would be necessary to standardize drug dosages, find alternative routes, and conduct prospective studies in humans.
... Greater benefits were observed with patients with sleep disorders. Other studies have revealed similar results [76][77][78][79]. ...
ulation. Any pathology of auditory pathways or any system of the human body may result with tinnitus. The pathophysiology of tinnitus accompanying the disorders of auditory system is not fully understood. In researches, a lot of therapy modalities have been used many years but there is no definitive treatments for tinnitus. Pharmacological treatments of various pharmacological interven-tions have been investigated for the treatment of tinnitus. However, no drug has been approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for the treatment of tinnitus. The use of complementary and alternative medicine (CAM) is very popular in most countries, and several CAM products are often used by individuals with tinnitus with or without medical guidance. Nonconventional approaches for tinnitus have increased in prevalence and acceptance among both patients and practitioners. Many of these approaches have been shown to benefit some tinnitus sufferers. Complementary treatments may be particularly well suited for treating the dysfunction associated with tin-nitus, as they specifically target aspects of tinnitus that are often overlooked in con-ventional medicine. CAM has frequently been used to treat tinnitus. The objective of this review was to assess complementary therapies as a treatment for the tinnitus.Keywords: tinnitus, treatment, complementary, alternative, therapy
(13) (PDF) Complementary and Alternative Treatments for Tinnitus. Available from: https://www.researchgate.net/publication/332335102_Complementary_and_Alternative_Treatments_for_Tinnitus [accessed Aug 01 2019].
... Los resultados muestran que la percepción de acúfeno mejoró en el 81% de los pacientes con sulpirida e hidroxicina, y un 56% en el grupo con sulpirida y placebo, frente al 21% con placebo solo, diferencias que son estadísticamente significativas. El mismo grupo, en otro ensayo clínico, ha evaluado el tratamiento combinando sulpirida y melatonina y ha encontrado una reducción del acúfeno en el 40% de los sujetos del grupo de melatonina solo y un 81% en el de sulpirida más melatonina [52]. ...
... Melatonin induced hypothermia in rats is significantly reduced by treatment with either a 5-HT 2A receptor agonist or 5-HT 1A receptor antagonist (Lin and Chuang 2002). In patients, sulpiride and melatonin decrease tinnitus perception by decreasing dopamine activity (Lopez-Gonzalez et al. 2007). Clinical and experimental studies demonstrate that melatonin interacts with the α 2 -agonist clonidine. ...
Objectives:
Melatonin initiates physiologic and therapeutic responses in various tissues through binding to poorly defined MT receptors regulated by G-proteins and purine nucleotides. Melatonin's interaction with other G-protein regulated receptors, including those of serotonin, is unclear. This study explores the potential for the interaction of melatonin with nucleotide and receptor ligand structures.
Methods:
The study uses a computational program to investigate relative molecular similarity by the comparative superimposition and quantitative fitting of molecular structures to adenine and guanine nucleotide templates.
Results:
A minimum energy melatonin conformer replicates the nucleotide fits of ligand structures that regulate Gαi and Gαq proteins via serotonin, dopamine, opioid, α-adrenoceptor, and muscarinic receptor classes. The same conformer also replicates the nucleotide fits of ligand structures regulating K+ and Ca2+ ion channels. The acyl-methoxy distance within the melatonin conformer matches a carbonyl-hydroxyl distance in guanine nucleotide.
Conclusion:
Molecular similarity within the melatonin and ligand structures relates to the established effects of melatonin on cell receptors regulated by purine nucleotides in cell signal transduction processes. Pharmacologic receptor promiscuity may contribute to the widespread effects of melatonin.
... In one double-blind, placebo-controlled study, the dopamine antagonist sulpiride significantly reduced subjective ratings of tinnitus. Effects were more pronounced when sulpiride was combined with either hydroxyzine (an antihistamine and anxiolytic) or melatonin (112,113). The dopamine agonist piribedil was investigated in a doubleblind, placebo-controlled crossover study and was not superior to placebo (114). ...
Tinnitus is a highly prevalent condition that is associated with hearing loss in most cases. In the absence of external stimuli, phantom perceptions of sounds emerge from alterations in neuronal activity within central auditory and nonauditory structures. Pioneering studies using lidocaine revealed that tinnitus is susceptible to pharmacological interventions. However, lidocaine is not effective in all patients, and no other drug has been identified with clear efficacy for the long-term treatment of tinnitus. In this review, we present recent advances in tinnitus research, including more detailed knowledge of its pathophysiology and involved neurotransmitter systems. Moreover, we summarize results from animal and clinical treatment studies as well as from studies that identified tinnitus as a side effect of pharmacological treatments. Finally, we focus on challenges in the development of pharmacological compounds for the treatment of tinnitus, namely the limitations of available animal models and of standardized clinical research methodologies. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... Chlorpromazine, a dopamine antagonist antipsychotic drug, induced tinnitus in pediatric patients without prominent hearing loss (Levy and Swanson 2001). Sulpiride, a D2 antagonist, blocked dopaminergic activity and has been shown to alleviate tinnitus (Lopez-Gonzalez et al. 2007). Some agents with dopaminergic activity such as nortriptyline and venlafaxine can mitigate tinnitus (Sullivan et al. 1989;Robinson et al. 2007). ...
Quinine is an antimalarial drug that is toxic to the auditory system by commonly inducing hearing loss and tinnitus, presumably due to its ototoxic effects on disruption of cochlear hair cells and blockade of ion channels of neurons in the auditory system. To a lesser extent, quinine also causes ataxia, tremor, and dystonic reactions. As dopaminergic neurons are implicated to play a role in all of these diseases, we tested the toxicity of quinine on induced dopaminergic (iDA) neurons derived from human pluripotent stem cells (iPSCs) and primary dopaminergic (DA) neurons of substantia nigra from mice brain slices. Patch clamp recordings and combined drug treatments were performed to examine key physiological properties of the DA neurons. We found that quinine (12.5–200 μM) depolarized the resting membrane potential and attenuated the amplitudes of rebound spikes induced by hyperpolarization. Action potentials were also broadened in spontaneously spiking neurons. In addition to quinine attenuating hyperpolarization-dependent conductance, the tail currents following withdrawal of hyperpolarizing currents were also attenuated. Taken together, we found that iPSC-derived DA neurons recapitulated all the tested physiological properties of human DA neurons, and quinine had distinct effects on the physiology of both iDA and primary DA neurons. This toxicity of quinine may be the underlying mechanism for the movement disorders of cinchonism or quinism and may play a role in tinnitus modulation.
... [12] The protection effects of melatonin against tinnitus have been evaluated in different studies. [7,13] As Reiter et al. have concluded, [14] melatonin is a safe and cost-effective drug which is effective to decrease drug-mediated ototoxicity by aminoglycosides and cancer chemotherapeutic agents. Along with these findings, it is been also reported that melatonin limits subjective tinnitus in patients by dosage of 3 mg daily. ...
Background
Tinnitus is the perception of noise or ringing without external acoustic stimulants which affects almost 10% of general population. Many therapies have been recommended including diet modifications, herbal remedies, and chemical drugs. Most common utilized drugs for tinnitus are melatonin and antidepressants such as sertraline which have been proven in different studies. In this study, we aimed to compare the efficacy of melatonin and sertraline in treating tinnitus for the first time.
Methods
In this clinical trial, 70 patients with tinnitus according to inclusion and exclusion criteria were included and randomly divided into two groups: melatonin group, taking melatonin 3 mg once daily and sertraline group taking sertraline 50 mg once daily, all treating for 3 months. Before and after treatments, every patient received Tinnitus Handicap Inventory (THI) questionnaire and severity of tinnitus was assessed, and data analysis was performed.
Results
Before treatments, the mean of THI score for melatonin and sertraline groups were 45.02 ± 17.67 and 44.85 ± 20.57, respectively. There was no significant difference between both groups THI score (P = 0.23). After 3 months, the mean of THI scores for melatonin and sertraline groups were 30.29 ± 19.62 and 36.96 ± 25.03, respectively which the mean of THI scores in two groups was decreased significantly (P < 0.01, for-both). In addition, indicated the significant decline in THI score of melatonin group who were under treatments with melatonin 3 mg once daily (P = 0.02).
Conclusions
Here in this clinical trial, we demonstrated that both melatonin and sertraline are efficient in treating tinnitus, but the usage of melatonin 3 mg once daily is more effective.
... Subjective tinnitus is most commonly believed to originate from the cochlear and/or central nervous system dysfunction at the levels of the brainstem, subcortical and cortical level, as well as the limbic system [1,2]. The functions of certain neurotransmitter receptors, ion channels and/or co-transporters have been proposed to be associated with tinnitus, for example, activation of vanilloid receptors in the inner ear [3], N-methyl D-aspartate receptor (NMDA receptor, NR) in the inner ear [4], acetylcholine receptors in the auditory cortex [5], and dopamine receptors in the auditolimbic dopaminergic pathway exhibited excitatory effects on tinnitus [6]. On the contrary, activation of cannabinoid receptors in the ventral cochlear nucleus [7] and γ-amino butyric acid receptors (GABA receptor, GR) in the inferior colliculus (IC) [8] or auditory cortex [9] exhibited inhibitory effects on tinnitus. ...
Background:
Although the activity of tinnitus-related ion co-transporter are known, their mRNA expressions has seldom been reported. We aimed to investigate the mRNA expressions of tinnitus-related ion co-transporter genes, and treatment effects of Spirulina.
Methods:
The mRNA expressions of K(+)-Cl(-) co-transporter (KCC2) and Na-K-2Cl co-transporter 1 (NKCC1) genes in the cochlea and brain of mice were evaluated after tinnitus was induced by intraperitoneal injection of salicylate. The effects of spirulina water extract on these gene expressions were investigated.
Results:
Compared to the control group, the tinnitus scores increased significantly, however, the salicylate-induced tinnitus could be reduced significantly by spirulina water extract. The tinnitus group had higher of borderline significance mRNA expression of KCC2 gene in the cochlear, significantly higher in the temporal lobes and in the frontal lobes. Meanwhile, compared to the tinnitus group, the spirulina group had significantly lower mRNA expression of KCC2 gene in the cochlear, temporal lobes, frontal lobes and parahippocampus/hippocampus. However, the NKCC1 mRNA expression was not significantly different between three groups in the cochlea and these brain areas.
Conclusion:
Salicylate-induced tinnitus might be associated with increased mRNA expression of KCC2 gene, but not with mRNA expressions of NKCC1 gene in the cochlear and some tinnitus-related brain areas. Spirulina reduced the expression of KCC2 genes in salicylate-induced tinnitus.
... They reported that the combination was better than melatonin alone in decreasing handicap level. Gonzalez-Lopes et al. reported melatonin combined with sulpiride which is an antidopmaninergic agent to be more effective than melatonin alone [24] . ...
Objective: In this study we aimed to investigate the psychological status of tinnitus patients as well as the sleep quality and their relation to handicap caused by tinnitus using various scales. Additionally, serum melatonin levels and the effectiveness of melatonin treatment were studied. Study Design: Prospective, double blind, randomized controlled trial Materials and Methods: Patients were divided randomly into two groups as study (melatonin, n=13) and placebo (control, n=11) groups. Tinnitus Handicap Inventory (THI), Symptom Check List (SCL), Hospital Anxiety and Depression Scale (HAD), Beck Depression Inventory (BDI), Pittsburg Sleep Quality Index (PSQI) were applied. After filling the scales and giving the venous blood sample for melatonin measurements the patients were instructed to take one tablet (placebo or 3 mg melatonin) before sleep every night. After 8 weeks, second order scales were filled and melatonin measurements were repeated. Results: Serum melatonin levels were between 1-260 pg/ml; the mean was 38,7 pg/ml. The correlation of melatonin levels with THI and tinnitus duration was not significant. THI was found to correlate with different measures of the PSQI, HAD, and BDI in both groups. Statistical analysis failed to show any significant difference within and between groups in respect of anxiety, depressive symptoms and sleep as well as melatonin and handicap levels. When the groups were assessed according to the THI severity (mild/moderate to severe;THI 2); in the control group there was significant differences in PSQI 1 and PSQI 1 (p=0.0008, p=0.18), HAD 1, HAD 2 (0.002, 0.03), HAD Depression 1-2 (0.0, 0.006) BDI (p=0.007) PSQI 2 sleep disturbance (p=0.018) parameters. However, in the melatonin group it was found that there were significant differences in SCL 2 sleep latency, PSQI 2 sleep duration and total PSQI 2 parameters. (p=0.022, 0.027, 0.006 respectively)Conclusion: Patients with higher handicap may benefit melatonin in respect of sleep latency and duration as well as sleep quality comparing with the patients taking placebo. Moreover, melatonin efficiency may be related to its antidepressive effect.
... Decreasing dopamine activity seems to reduce tinnitus perception [111]. Furthermore, serotonin has long been hypothesized to play a role in tinnitus and its comorbidity with depression and insomnia [112,113]. ...
Tinnitus and chronic pain are sensory–perceptual disorders associated with negative affect and high impact on well-being and behavior. It is now becoming increasingly clear that higher cognitive and affective brain systems are centrally involved in the pathology of both disorders. We propose that the ventromedial prefrontal cortex and the nucleus accumbens are part of a central ‘gatekeeping’ system in both sensory modalities, a system which evaluates the relevance and affective value of sensory stimuli and controls information flow via descending pathways. If this frontostriatal system is compromised, long-lasting disturbances are the result. Parallels in both systems are striking and mutually informative, and progress in understanding central gating mechanisms might provide a new impetus to the therapy of tinnitus and chronic pain.
... Los resultados muestran que la percepción de acúfeno mejoró en el 81% de los pacientes con sulpirida e hidroxicina, y un 56% en el grupo con sulpirida y placebo, frente al 21% con placebo solo, diferencias que son estadísticamente significativas. El mismo grupo, en otro ensayo clínico, ha evaluado el tratamiento combinando sulpirida y melatonina y ha encontrado una reducción del acúfeno en el 40% de los sujetos del grupo de melatonina solo y un 81% en el de sulpirida más melatonina [52]. ...
Introduction:
Chronic tinnitus affects 5-15% of the general population; in 1% of individuals with tinnitus this condition severely affects their quality of life. Pharmacological treatment is one of the options for the management of tinnitus patients, but their efficacy remains controversial. AIM. To evaluate the level of evidence to support the use of different drugs in reducing the severity of tinnitus.
Development:
The pharmacological groups that have been investigated for the treatment of tinnitus include anesthetics, anticonvulsants, antidepressants, antihistamines, benzodiazepines, diuretics, corticosteroids, and of other substances. Intravenous lidocaine seems to be effective, but the short duration of the effect and the adverse reactions prevent its use. Compared with placebo, carbamazepine and gabapentine have not demonstrated effectiveness although they may be effective in some patients with auditory nerve vascular compression or myoclonus. Tricyclic antidepressants are no more effective than placebo at reducing tinnitus severity although they may improve comorbid depression. There is insufficient evidence to evaluate the effectiveness of selective serotonin reuptake inhibitors and benzodiazepines. Acamprosate may decrease the severity of tinnitus, but the level of evidence is low. There are no consistent results in the studies with intratympanic gentamicin or steroids in tinnitus associated with Meniere's disease.
Conclusions:
The use of pharmacotherapy in reducing the severity of tinnitus is not well supported by prospective, randomized, placebo-controlled clinical trials. Various drugs have been shown to be effective in some studies, but the clinical evidence is limited. Large randomized clinical trials are needed.
... Melatonin possibly has an antidepressant effect, it improves sleep, and it is thought to be protective against exaggerated sympathetic drive. 70 Not surprisingly, all melatonin studies report improvement in sleep quality 66,68,69 which by itself is known to reduce tinnitus-related distress. 2 Currently auditory stimulation therapies that aim at reducing tinnitus loudness and behavioural therapies that aim at reducing tinnitus-related distress are the therapies that appear to specifically address the tinnitus perception or the related distress with notable success, and they are low in potential complications. ...
Tinnitus is an auditory sensation that is generated by aberrant activation within the auditory system. Sleep disturbances are a frequent problem in the tinnitus population. They are known to worsen the distress caused by the tinnitus which in turn worsens sleep quality. Beyond that, disturbed sleep is a risk factor for mental health problems and distressing tinnitus is often associated with enhanced depressivity, anxiety, and somatic symptom severity. Moreover there is evidence that therapies which alleviate tinnitus-related distress have a positive influence on sleep quality and help interrupt this vicious cycle. This suggests that distressing tinnitus and insomnia may both be promoted by similar physiological mechanisms. One candidate mechanism is hyperarousal caused by enhanced activation of the sympathetic nervous system. There is increasing evidence for hyperarousal in insomnia patients, and animal models of tinnitus and insomnia show conspicuous similarities in the activation pattern of limbic and autonomous brain regions. In this article we review the evidence for this hypothesis which may have implications for therapeutic intervention in tinnitus patients with comorbid insomnia.
Tinnitus, the phantom perception of sound in the absence of a corresponding external source, is highly prevalent. In many cases, the tinnitus percept is associated with autonomic arousal or emotional or cognitive dysfunction, and may lead to behavioral changes and functional disability. Tinnitus results from alterations of neuronal activity in central auditory and non-auditory structures and to alterations of various neurotransmitter systems. Lidocaine can transiently suppress tinnitus, indicating that tinnitus is susceptible to pharmacological interventions. However, up to know there exists no pharmacological compound that has demonstrated clear efficacy for the long-term treatment of tinnitus.
In this chapter, I will summarize recent advances in tinnitus research and provide an overview about its pathophysiology and involved transmitter systems. I will give an overview over available animal and clinical treatment studies and about studies that identified tinnitus as a side effect of pharmacological treatment. Finally, I will discuss the challenges in the development of pharmacological compounds for the treatment of tinnitus, namely the limitations of available animal models and of clinical research methodology.
Despite the pressing need for effective drug treatments for tinnitus, currently, there is no single drug that is approved by the FDA for this purpose. Instead, a wide range of unproven over-the-counter tinnitus remedies are available on the market with little or no benefit for tinnitus but with potential harm and adverse effects. Animal models of tinnitus have played a critical role in exploring the pathophysiology of tinnitus, identifying therapeutic targets and evaluating novel and existing drugs for tinnitus treatment. This review summarises and compares the studies on pharmacological evaluation of tinnitus treatment in different animal models based on the pharmacological properties of the drug and provides insights into future directions for tinnitus drug discovery.
It has been increasingly recognized that tinnitus is likely to be generated by complex network changes. Acoustic trauma that causes tinnitus induces significant changes in multiple metabolic pathways in the brain. However, it is not clear whether those metabolic changes in the brain could also be reflected in blood samples and whether metabolic changes could discriminate acoustic trauma, hyperacusis and tinnitus. We analyzed brain and serum metabolic changes in rats following acoustic trauma or a sham procedure using metabolomics. Hearing levels were recorded before and after acoustic trauma and behavioral measures to quantify tinnitus and hyperacusis were conducted at 4 weeks following acoustic trauma. Tissues from 11 different brain regions and serum samples were collected at about 3 months following acoustic trauma. Among the acoustic trauma animals, eight exhibited hyperacusis-like behavior and three exhibited tinnitus-like behavior. Using Gas chromatography–mass spectrometry and multivariate statistical analysis, significant metabolic changes were found in acoustic trauma animals in both the brain and serum samples with a number of metabolic pathways significantly perturbated. Furthermore, metabolic changes in the serum were able to differentiate sham from acoustic trauma animals, as well as sham from hyperacusis animals, with high accuracy. Our results suggest that serum metabolic profiling in combination with machine learning analysis may be a promising approach for identifying biomarkers for acoustic trauma, hyperacusis and potentially, tinnitus.
Tinnitus is a common symptom for which there is in most cases no causal therapy. The search for an improvement of tinnitus through pharmacological interventions has a long tradition. The observation that tinnitus can be transiently suppressed by the use of lidocaine has shown that the symptom is susceptible to pharmacotherapy. So far, however, no medication has been found for either acute or chronic subjective tinnitus that reliably leads to a long-term reduction or even complete disappearance of the symptom for the majority of tinnitus sufferers. Nevertheless, in everyday clinical life, drugs are frequently used, usually off-label, to relieve tinnitus or tinnitus-associated symptoms (e.g. sleep disturbance, depression, anxiety disorder or hearing loss). This chapter shows the different approaches to acute and chronic subjective tinnitus by means of pharmacotherapeutic interventions. Furthermore, this review reports on the scientific studies carried out in this area in recent years and explains the difficulties in finding a suitable medication for most forms of tinnitus. In addition, it reports on the pharmacotherapeutic options for objective tinnitus and describes the development of tinnitus as a side effect of certain drugs. Finally, possible target structures are mentioned, which should possibly be addressed in pharmacological studies in the near future.
Tinnitus is a hearing disorder characterized by the perception of sound without external acoustic stimuli, which is caused by damage to the auditory system in response to excessive levels of noise, ototoxic agents and aging. Neural plasticity, oxidative/nitrosative stress and apoptosis play important roles in the pathogenesis of tinnitus. The expression of neural plasticity related to excessive glutamatergic neurotransmission leads to generation of abnormal sound in one's ears or head. Furthermore, hyperactivation and over-expression of NMDA receptors in response to excessive release of glutamate contribute to the calcium overload in the primary auditory neurons and subsequent cytotoxicity. Reactive oxygen/nitrogen species are endogenously produced by different type of cochlear cells under pathological conditions, which cause direct damage to the intracellular components and apoptotic cell death. Cochlear hair-cell death contributes to the progressive deafferentation of auditory neurons, which consequently leads to the aberrant activity in several parts of the auditory pathway. Therefore, targeting neural plasticity, oxidative/nitrosative stress, apoptosis and autophagy may ameliorate tinnitus. Melatonin is an endogenously produced indoleamine synchronizing circadian and circannual rhythms. Based on laboratory studies indicating the protective effect of melatonin against cochlear damage induced by acoustic trauma and ototoxic agents, and also clinical studies reporting the ability of melatonin to minimize the severity of tinnitus, melatonin is suggested to be a treatment option for the patient with tinnitus. Herein, we describe the ameliorative effect of melatonin on tinnitus, focusing on neural plasticity, oxidative/nitrosative stress, apoptotsis and autophagy.
This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effectiveness of melatonin for the treatment of subjective idiopathic tinnitus.
The purpose of this study was to investigate the mRNA expression of the dopamine receptor 1A (DR1A) and cannabinoid receptor 1 (CR1) genes in mice with tinnitus. Sixteen 3-month-old male SAMP8 mice were randomly and equally divided into two groups (8 mice in each group): a control (saline-treated) group and a tinnitus (salicylate-treated) group. The mRNA expression of the DR1A and CR1 genes in the cochleae and brains of the mice was evaluated after tinnitus had been induced by intraperitoneal injection of sodium salicylate (300 mg/kg body weight). The results showed that 4-day salicylate treatment (unlike 4-day saline treatment) caused a significant increase in the tinnitus score and in mRNA expression of the DR1A gene in the cochlea, the brainstem and inferior colliculus, the hippocampus and parahippocampus, and the temporal lobe, but not the frontal lobe. Conversely, 4-day salicylate treatment caused significantly lower mRNA expression of the CR1 gene in the cochlea and all the brain areas tested. In summary, salicylate-induced tinnitus may be associated with increased mRNA expression of the DR1A gene - but with decreased mRNA expression of the CR1 gene - in the cochlea and in many tinnitus-related brain areas.
Available treatments for the management of tinnitus are diverse. These include counseling and cognitive–behavioral therapies; different forms of sound therapies; methods that attempt to increase input to the auditory system, such as hearing aids and cochlear implants (for use in patients whose tinnitus is caused by deprivation of signals to the auditory nervous system); pharmacological treatment; neurobiofeedback; and various forms of electrical stimulation of brain structures, either through implanted electrodes or by inducing electrical current in the brain with transcranial magnetic stimulation. The existence of many different treatment approaches derives from the fact that there exist different subgroups of tinnitus that differ in their pathophysiology and their response to treatment. In clinical practice it is frequently difficult to choose the optimal treatment approach for an individual patient. The treatment approaches presented in this chapter (pharmacological, magnetic, or electrical brain stimulation) are all at early stages of development. The further development of these new treatment options will depend on the extent to which we understand the pathophysiology of the different forms of tinnitus.
Tinnitus is the perception of sound that does not have an external correlate. It is a symptom that has been experienced by humans for millennia and is not limited by social, cultural or economic variables. Chronic tinnitus is a complex phenomenon that has challenged clinicians who treat tinnitus patients and scientists exploring the mechanisms that result in a phantom perception. In the vast majority of people with tinnitus the perception is not intrusive, disruptive or bothersome. For some, the experience of a continuous sound from which there is no escape or relief is debilitating. In some cases tinnitus is a symptom of an otologic disorder that requires, and can benefit from, surgical intervention. In other cases tinnitus is a secondary symptom of a non-otologic disorder that improves or resolves with medical intervention for the primary problem, such as environemtal allergies, migraine headaches or hypertension. Most cases of chronic bothersome tinnitus result from sensorineural hearing loss. This association has significant implications for the current views on mechanisms of tinnitus pathology and appropriate treatments, which will be discussed. Treatments aimed at elimination of tinnitus have been available for centuries. Most early tinnitus treatments were based on empiricism and anecdotal evidence. Advances in neuroscience, availability of tools assessing neural correlates of tinnitus and the development of models for testing tinnitus theories have led to theory-driven clinical studies. An overview of the theoretical basis of current tinnitus treatments will be presented and promising areas for translating basic science to clinical treatments will be suggested. Advances in tinnitus treatments, and the rationale basis for these treatments will be reviewed.
Objective:
To analyze existing tinnitus treatment trials with regard to eligibility criteria, outcome measures, study quality, and external validity and to recognize the effect of patient demographics, symptom duration, severity, and otologic comorbidity on research findings to help practitioners apply them to patient encounters.
Data sources:
Systematic literature search conducted by an information specialist for development of the American Academy of Otolaryngology-Head and Neck Surgery Foundation's tinnitus clinical practice guideline.
Review methods:
Articles were assessed for eligibility with the PRISMA protocol (Preferred Reporting Items for Systematic Reviews and Meta-analyses) and data extracted by 2 independent investigators. Studies were assessed for methodological quality, inclusion and exclusion criteria, patient demographics, and outcome measures.
Results:
A total of 147 randomized trials met inclusion criteria. Nearly all studies took place in a specialist setting. More than 50% did not explicitly define tinnitus, and 44% used a subjective severity threshold, such as "severely disturbing." Fifty-four percent required symptom duration of at least 6 months for study eligibility, and up to 33% excluded patients with "organic" hearing loss or otologic conditions. Mean age was 52.2 years, and median follow-up was 3 months. Only 20% had a low risk of bias.
Conclusion:
Randomized trials of tinnitus interventions are most applicable to older adults with tinnitus lasting ≥6 months who are evaluated in specialty settings. High risk of bias, short follow-up, and outcome reporting raise concerns about the validity of findings and may influence how clinicians apply trial results to individual patients and establish treatment expectations, thus demonstrating the need for further quality research in this field.
Tinnitus is a subjective perception of phantom sound that currently cannot be objectively measured. However, there is growing evidence suggesting that the biological source of tinnitus may exist in one or more than one place in the auditory pathway. Recent studies have found that neurotransmitters or modulators, such as glutamate, γ-aminobutyric acid(GABA), serotonin, dynorphin, dopamine, neurosteroid, acetylcholine(ACh) and substance P, are involved in tinnitus generation. Animal and human studies have shown that some of these neurotransmitters and the agonists or antagonists of their receptors either affect tinnitus behaviors or demonstrate some degree of treatment effects on tinnitus. However, due to the unclear biological mechanisms of tinnitus and side effects of these drugs, the value of clinical usage of such drugs in treating tinnitus is yet to be established. Revealing the relationship between tinnitus and neurotransmitter receptor functions will help identify more effective drugs for tinnitus treatment. This article reviews the literature of neurophysiological studies on tinnitus in both animal and human subject studies at various levels of the auditory pathway.
As the population is aging, the prevalence of presbycusis is increasing proportionally. The prevalence of tinnitus, which usually accompanies presbycusis, is also growing. Presbytinnitus, defined as tinnitus which accompanies presbycusis, not only influences the individual's well-being and productivity but also causes communication problems, isolation, and social withdrawal. We now need to adopt more aggressive approaches to treating presbytinnitus in the elderly population, rather than giving them discouraging comments on the course of disease progression. Although the exact mechanisms of presbytinnitus have not been revealed and the specified therapeutic methods have not yet been established, an increasing number of studies using masking, retraining therapy, psychological therapy, and some medications have shown promising outcomes for the management of presbytinnitus. Therefore, appropriate treatment with multidisciplinary modalities should be provided for patients with presbytinnitus in order to reduce a growing social burden.
Ramelteon is a melatonin receptor agonist. Melatonin, a neurohormone secreted by the pineal gland at night, helps regulate the sleep-wake cycle, although tinnitus disturbs sleep. To evaluate ramelteon in treating subjective tinnitus, we administered it internally to 42 subjects not sufficient effectively aided by usual internal treatment. Subjects took 8. 0 mg of ramelteon, nightly for 2 weeks or more. We evaluated results, using a visual analog scale (VAS) of the standardized, 1993 Tinnitus Study Group tinnitus test, the tinnitus handicap inventory (THI) for 25 subjects and symptom changes in all 42 subjects. Of the 42 (88.1%), 37 could take ramelteon. Of these 37 (64. 9%), 24 improved subjectively, after taking ramelteon. In 7 subjects with Meniere's disease (MD), 6 improved, possibly from MD melatonin deficiency 12). Mean VAS and THI decreased significantly between weeks 0 and 4-16 in Wilcoxon's signed rank test, after taking ramelteon. Ramelteon thus appears to be useful in treating subjective tinnitus, and subjects with MD are most likely to benefit from ramelteon treatment.
Purpose
The aim of our study was to determine whether the combination of intratympanic (IT) corticosteroid with melatonin could be associated with decreased tinnitus in patients with unilateral acute idiopathic tinnitus developed within 3 months.
Materials and Methods
We evaluated this hypothesis through a prospective, randomized, controlled, double-blinded trial. Patients included in the study were randomly allocated into two groups: Group A – comprising 30 patients, received melatonin and IT dexamethazone, and Group B – including 30 patients receiving melatonin alone. After 3 months, improvement in tinnitus was assessed using different outcome measures: tinnitus loudness score, tinnitus awareness score, Tinnitus Handicap Inventory (THI), Pittsburgh Sleep Quality Index (PSQI) and Beck Depression Inventory (BDI).
Results
We have demonstrated significant improvements in each of the above mentioned outcomes subsequent to treatment in both groups. However, patients in the IT dexamathazone and melatonin group attained statistically significant better outcomes. Besides, the differences in improvement rate and cure rate were highly significant between the two groups, favoring the IT dexamethazone and melatonin group.
Conclusions
Our preliminary study demonstrated that IT dexamethazone plus melatonin is efficient in improvement of idiopathic unilateral tinnitus developed within 3 months.
Melatonin, a hormone produced by the pineal gland, may be a promising treatment option for tinnitus. The primary functions of this hormone are believed to be the initiation and maintenance of sleep because its secretions coincide with circadian rhythms. Some investigators have noted that melatonin may alleviate subjective symptoms of tinnitus. Moreover, melatonin may have properties protective against ototoxic drugs such as amikacin, gentamicin, or cancer therapeutic agents that are dose dependent. In vitro, melatonin has demonstrated antioxidative properties and it has been postulated that these antioxidative properties contribute to the alleviation of tinnitus. Melatonin levels used to obtain these findings in vitro, however, are at supraphysiologic levels; therefore, it is more likely that the benefits from taking supplemental melatonin occur from minimal antioxidative properties, sleep enhancement, or other potential methods of action that are not yet understood. Melatonin offers minimal risk of toxicity with modest daily doses such as 1 to 3 mg, as well as a low cost and favorable adverse effect profile for older adults. In addition to potential benefits in the treatment of tinnitus, melatonin also may have beneficial neurogenerative properties. We recommend that melatonin be considered for use in patients with significant tinnitus.
This article discusses the use of an integrative approach to treating tinnitus. The authors begin with a discussion of their approach to tinnitus patients, followed by a detailed look at the physiology of tinnitus and several theories of its mechanism. The many viable options for tinnitus relief are discussed, including sound therapies, Western medical approaches, and herbal and traditional medicines that can be used as integrative and complementary treatments. It concludes with a reminder that a variety of treatment options are available to tinnitus patients to help them take control of their symptoms.
Background:
The important development of tinnitus research in the last few years has improved the knowledge of tinnitus mechanisms, its diagnosis and its treatment. From a peripheral point of view, tinnitus is considered today as a brain reaction to erroneous input activity from the auditory or somatosensorial systems.
Method:
An accurate diagnosis is crucial to design the best therapeutic options. Treatment should be based on tinnitus aetiology as a first step. Medical counselling is a very effective tool, and it should be mandatory for all patients. Drug treatment experiments could take a step forward in the next few years. NMDA-antagonists or GABA-agonists are some of the targets of the research. The transtympanic delivery path is a good option for cochlear fluctuant diseases and gives us the possibility of higher dosages and fewer systemic side effects. Stimulation of the somatosensory pathways can help us to control somatic modulated tinnitus and it could be done through muscular training, electro-stimulation or pharmaceutical approaches. Auditory management is based in the fact that acoustic deprivation is the most powerful engine for tinnitus generation. Patients can be treated through passive training therapies as hearing aids, retraining therapies or filtered music approaches. Active acoustic training through auditory discrimination is a new promising approach and so is the repetitive transcranial magnetic stimulation over the auditory cortex.
Conclusion:
The combination of different approaches simultaneously will bring the best results for tinnitus relief and efforts should be made towards finding the best combination for each patient.
Introduction:
Tinnitus, the phantom perception of sound, is a highly prevalent disorder and treatment is elusive.
Areas covered:
This review focuses on clinical research regarding pharmacological treatments for tinnitus. The authors searched PubMed databases for English language articles related to pharmacological treatment of tinnitus, published through August 2012. The keywords "tinnitus AND pharmacological treatment" and "tinnitus AND drugs" were used. The search focused on clinical trials, but was complemented by other articles and information from clinical trial registries.
Expert opinion:
Despite the significant unmet clinical need for a safe and effective drug for tinnitus relief, there is currently no EMA- or FDA-approved drug on the market. Even a drug that produces a small but significant effect would have a huge therapeutic impact. At present, evidence-based pharmacological approaches are limited to the treatment of comorbidities such as depression, anxiety, or insomnia. In the last few years there have been significant advances in the understanding of the pathophysiology of the different forms of tinnitus, the establishment of valid animal models, and the development of clinical trial methodology. A glimpse of hope is appearing in the horizon as an increasing number of pharmaceutical industries now have compounds targeting tinnitus in their pipeline.
We sought to report the efficacy of oral melatonin as treatment for chronic tinnitus and to determine whether particular subsets of tinnitus patients have greater benefit from melatonin therapy than others.
This was a prospective, randomized, double-blind, crossover clinical trial in an ambulatory tertiary referral otology and neurotology practice. Adults with chronic tinnitus were randomized to 3 mg melatonin or placebo nightly for 30 days followed by a 1-month washout period. Each group then crossed into the opposite treatment arm for 30 days. The tests audiometric tinnitus matching (TM), Tinnitus Severity Index (TSI), Self Rated Tinnitus (SRT), Pittsburgh Sleep Quality Index (PSQI), and Beck Depression Inventory (BDI) were administered at the outset and every 30 days thereafter to assess the effects of each intervention.
A total of 61 subjects completed the study. A significantly greater decrease in TM and SRT scores (p < 0.05) from baseline was observed after treatment with melatonin relative to the effect observed with placebo. Male gender, bilateral tinnitus, noise exposure, no prior tinnitus treatment, absence of depression and/or anxiety at baseline, and greater pretreatment TSI scores were associated with a positive response to melatonin. Absence of depression and/or anxiety at baseline, greater pretreatment TSI scores, and greater pretreatment SRT scores were found to be positively associated with greater likelihood of improvement in both tinnitus and sleep with use of melatonin (p<0.05).
Melatonin is associated with a statistically significant decrease in tinnitus intensity and improved sleep quality in patients with chronic tinnitus. Melatonin is most effective in men, those without a history of depression, those who have not undergone prior tinnitus treatments, those with more severe and bilateral tinnitus, and those with a history of noise exposure.
2-[125I]Iodomelatonin binds with high affinity to a site possessing the pharmacological characteristics of a melatonin receptor in chicken retinal membranes. The specific binding of 2-[125I]iodomelatonin is stable, saturable, and reversible. Saturation experiments indicated that 2-[125I]iodomelatonin labeled a single class of sites with an affinity constant (Kd) of 434 +/- 56 pM and a total number of binding sites (Bmax) of 74.0 +/- 13.6 fmol/mg of protein. The affinity constant obtained from kinetic analysis was in close agreement with that obtained in saturation experiments. Competition experiments showed a monophasic reduction of 2-[125I]iodomelatonin binding with a pharmacological order of indole amine affinities characteristic of a melatonin receptor: 2-iodomelatonin greater than 6-chloromelatonin greater than or equal to melatonin greater than or equal to 6,7-dichloro-2-methylmelatonin greater than 6-hydroxymelatonin greater than or equal to 6-methoxymelatonin much greater than N-acetyltryptamine greater than N-acetyl-5-hydroxytryptamine greater than 5-methoxytryptamine greater than 5-hydroxytryptamine (inactive). The affinities of these melatonin analogs in competing for 2-[125I]iodomelatonin binding sites were correlated closely with their potencies for inhibition of the calcium-dependent release of [3H]dopamine from chicken and rabbit retinas, indicating association of the binding site with a functional response regulated by melatonin. The results indicate that 2-[125I]iodomelatonin is a selective, high-affinity radioligand for the identification and characterization of melatonin receptor sites.
The possible interaction of melatonin receptors and D1 dopamine receptors was investigated in neural cells prepared from embryonic day 8 chick retinas and cultured for 6 d. Dopamine stimulated cAMP accumulation in cultured retinal cells. This effect of dopamine was antagonized by addition of dopamine receptor antagonists (haloperidol and SCH23390) or melatonin receptor agonists (melatonin, 2-iodomelatonin, and 6-chloromelatonin). The inhibition of dopamine-stimulated cAMP accumulation by melatonin was concentration dependent, with half-maximal inhibition at approximately 160 pM. Melatonin inhibited the effect of dopamine at all dopamine concentrations, suppressing the maximal response to the neurotransmitter by approximately 70%. Melatonin also inhibited the stimulation of cAMP accumulation by SKF 82958, a selective D1 dopamine receptor agonist. Pretreatment of cultures with pertussis toxin had no significant effect on dopamine-stimulated cAMP accumulation, but inhibited the response to melatonin. In contrast to its effect on cAMP accumulation, melatonin had no effect on dopamine-stimulated inositol phosphate accumulation. These results suggest that melatonin receptors are coupled to dopamine receptor-regulated adenylate cyclase via an inhibitory G protein, and demonstrate another mechanism, in addition to inhibition of dopamine release, through which melatonin can modulate dopaminergic neurotransmission.
This paper presents a neurophysiological approach to tinnitus and discusses its clinical implications. A hypothesis of discordant damage of inner and outer hair cells systems in tinnitus generation is outlined. A recent animal model has facilitated the investigation of the mechanisms of tinnitus and has been further refined to allow for the measurement of tinnitus pitch and loudness. The analysis of the processes involved in tinnitus detection postulates the involvement of an abnormal increase of gain within the auditory system. Moreover, it provides a basis for treating patients with hyperacusis, which we are considering to be a pre-tinnitus state. Analysis of the process of tinnitus perception allows for the possibility of facilitating the process of tinnitus habituation for the purpose of its alleviation. The combining of theoretical analysis with clinical findings has resulted in the creation of a multidisciplinary Tinnitus Centre. The foundation of the Centre focuses on two goals: the clinical goal is to remove tinnitus perception from the patient's consciousness, while directing research toward finding a mechanism-based method for the suppression of tinnitus generators and processes responsible for enhancement of tinnitus-related neuronal activity.
To review the interaction between melatonin and the dopaminergic system in the hypothalamus and striatum and its potential clinical use in dopamine-related disorders in the central nervous system. Medline-based search on melatonin-dopamine interactions in mammals. Melatonin. the hormone produced by the pineal gland at night. influences circadian and seasonal rhythms, most notably the sleep-wake cycle and seasonal reproduction. The neurochemical basis of these activities is not understood yet. Inhibition of dopamine release by melatonin has been demonstrated in specific areas of the mammalian central nervous system (hypothalamus, hippocampus, medulla-pons, and retina). Antidopaminergic activities of melatonin have been demonstrated in the striatum. Dopaminergic transmission has a pivotal role in circadian entrainment of the fetus, in coordination of body movement and reproduction. Recent findings indicate that melatonin may modulate dopaminergic pathways involved in movement disorders in humans. In Parkinson patients melatonin may, on the one hand, exacerbate symptoms (because of its putative interference with dopamine release) and, on the other, protect against neurodegeneration (by virtue of its antioxidant properties and its effects on mitochondrial activity). Melatonin appears to be effective in the treatment of tardive dyskinesia. a severe movement disorder associated with long-term blockade of the postsynaptic dopamine D2 receptor by antipsychotic drugs in schizophrenic patients. The interaction of melatonin with the dopaminergic system may play a significant role in the nonphotic and photic entrainment of the biological clock as well as in the fine-tuning of motor coordination in the striatum. These interactions and the antioxidant nature of melatonin may be beneficial in the treatment of dopamine-related disorders.
Although a melatonin/dopamine relationship has been well established in nonmotor systems wherein dopamine and melatonin share an antagonist relationship, less clear is the role melatonin may play in extrapyramidal dopaminergic function. Therefore, the purpose of the present experiments was to examine the relationship between melatonin and the dopaminergic D2 receptor system and behavior. Hypokinesia was induced in male Sprague-Dawley rats with fluphenazine (D2 antagonist, 0.4 mg/kg ip) and stereotypies with apomorphine (D2 agonist, 0.6 mg/kg sc) during the light (1200 h) and dark (2200 h) phases. As expected, fluphenazine induced severe hypokinesia during the light phase (482 +/- 176 s); however, unexpectedly, fluphenazine-induced hypokinesia during the dark was almost nonexistent (25 +/- 6 s). Furthermore, melatonin treatment (30 mg/kg ip) produced a strong interaction with fluphenazine in that it reduced fluphenazine-induced hypokinesia by nearly 80% in the light (112 +/- 45 s) but paradoxically increased the minimal fluphenazine-induced hypokinesia in the dark by more than 60% (70 +/- 17 s). Melatonin also reduced apomorphine-induced stereotypies by nearly 40% in the light but had no effect in the dark. Taken together, these data show (1) a strong and unexpected nocturnal effect of fluphenazine on hypokinesia and (2) provide support for an antagonistic melatonin/dopaminergic interaction in the context of motor behavior and D2 receptor function which appears to be critically dependent on the light/dark status of the dopaminergic system.
: The binding sites for 2-[125I]iodomelatonin in chicken spleens were characterized. The binding was rapid, stable, saturable, reversible, and of high affinity. Both melatonin and 6-chloromelatonin strongly inhibited the binding. The dissociation constant (Kd) obtained from the Scatchard analysis was 31.4 ± 5.19 pmol/1 (3-weeks old, n = 4), which was in good agreement with the Kd (50.6 pmol/1) calculated from the kinetic study. The maximum number of binding sites (Bmax) was 1.09 ± 0.11 fmol/mg protein (3-weeks old, n = 4). Twelve 11-week-old chicks were killed in two groups at mid-light or mid-dark. Saturation studies indicated no significant difference (P > 0.05) in the Kd between mid-light (42.1 ± 3.9 pmol/1) and mid-dark (31.6 ± 4.9 pmol/1). The maximum number of binding sites (Bmax) at mid-light and mid-dark were 1.52 ± 0.16 and 1.35 ± 0.08 fmol/mg protein, respectively, with no significant variation (P > 0.05) recorded. However, when the whole spleen was taken into consideration, the Bmax per spleen protein of the mid-light samples (253 ± 36 fmol/spleen protein) was significantly greater than that (129 ± 16 fmol/spleen protein) of the mid-dark samples (P < 0.05). This indicated that in our study a diurnal rhythm of the total number of 2-[125I]iodomelatonin binding sites might exist in the chicken spleen.
Specific melatonin binding sites in the harderian gland of both rat and Syrian hamster were studied using [125I]melatonin. In both species, binding of [125I]melatonin by harderian gland membranes exhibited properties such as dependence on time, temperature, membrane concentration, saturability, and high specificity. Only one class of high-affinity binding sites was found with a Kd of 0.19 and 6.47 nM for the rat and Syrian hamster, respectively. The binding capacity in the rat harderian gland was 4.00 fmol/mg protein; in the Syrian hamster it was 7.58 fmol/mg protein. In the rat, no sex differences were found in the binding of the tracer to the membranes. However, in the Syrian hamster, binding of [125I]melatonin by the harderian gland was twice higher in the female than in the male. No changes were found in the Kd values (6.47 vs. 6.94 nM), while binding capacity was significantly increased in the female (13.50 fmol/mg protein) when compared to the male hamster (7.58 fmol/mg protein). Binding of [125I]melatonin by the harderian gland of male hamsters was modified by castration but not by melatonin treatment. Castration induced an increase of binding up to the level of females. However, chronic melatonin administration did not alter the [125I]melatonin binding in either intact or gonadectomized male hamsters. Binding studies also showed diurnal variations. There was a diurnal rhythm of [125I]melatonin binding by Syrian hamster harderian glands with the peak at the end of the light period and the trough late in the dark period. This rhythm in the binding is observed in both male and female hamsters, although binding in females was always higher than that in males. Serum melatonin levels also demonstrated a diurnal variation with a well-established nocturnal peak of melatonin at 4.00 h and a fall after light onset at 6.00 h. As it has been previously described, nocturnal levels of serum melatonin in the male Syrian hamster were higher than those of the female hamster. Results confirm the presence of melatonin binding sites in the harderian gland of rats and Syrian hamsters, suggesting that these binding sites may mediate, in addition to other effects, the regulation of melatonin in the harderian gland.
The mechanism of the ototoxicity caused by cisplatin is based in the generation of reactive oxygen species, which interferes with the antioxidant protection of the organ of Corti. Conversely, the protection of the cochlea with antioxidants ameliorates the ototoxicity by cisplatin. The ototoxicity produced by cisplatin can be reversible or persistent, depending on the age of the patient, cumulative doses, number of chemotherapy cycles, history of noise exposure, and deteriorating renal function. We have obtained in rats an ototoxic chart utilizing cisplatin (10 mg/kg body weight injected intraperitoneally, once only). Together with this treatment, the animals were treated with melatonin in the drinking water (10 mg/L) or injected subcutaneously (250 μg), and with an antioxidant mixture, injected subcutaneously, composed of 0.25 mg alpha-tocopherol acid succinate, 3 mg ascorbic acid, 1 mg glutathione, and 60 mg N-acetylcysteine. The distortion product otoacoustic emissions were determined for a prolonged period of time for each animal. The ototoxicity produced by cisplatin was maximal from days 7 to 10 post-treatment, returning to normal values in a month. When melatonin and the antioxidant mixture were present, the recovery was between days 10 and 15 post-treatment, independent of the means of administration of the pineal product. We conclude that the ototoxicity caused by cisplatin is ameliorated by melatonin and other antioxidants.
Melatonin has been shown to be an effective antioxidant in a number of experimental models both in vitro and in vivo. Considering the data available, it is now clear that the indoleamine is involved in antioxidative mechanisms more complex than originally envisaged. These range from the direct radical scavenging of a variety of radicals and reactive species to the control and/or modulation of a number of processes which may trigger a redox imbalance between antioxidant and prooxidant species. This review focuses on the direct radical scavenging activity of melatonin and provides a summary of the mechanisms of the reactions between the indoleamine and reactive species in pure chemical solutions. These actions likely account for at least some of the protective actions of melatonin under conditions of high oxidative stress.
The present paper demonstrates the effect of melatonin on cyclic AMP production in human lymphocytes from peripheral blood. Melatonin by itself did not influence cyclic AMP accumulation in these cells at any dose studied; however, the drug potentiated the effect of vasoactive intestinal peptide (VIP) on the cyclic nucleotide production. In the presence of physiological concentrations of VIP (either 1, 10 or 100 pM), melatonin potentiated cyclic AMP production. However, at high doses of VIP (either 1, 10 or 100 nM), melatonin exhibited no such effect. The results suggest that human lymphocytes are a target for melatonin and that it may participate, jointly with VIP, in the regulation of immune function.
Evaluate melatonin as a treatment for subjective tinnitus.
Randomized, prospective, double-blind, placebo-controlled crossover trial. Patients were given 3.0 mg melatonin, which was taken nightly for 30 days followed or preceded by a placebo nightly for 30 days, with a 7-day washout period between medications.
Outpatient, private, neurotology practice.
Thirty patients with subjective tinnitus.
Tinnitus matching, Tinnitus Handicap Inventory (THI), patient questionnaire and interview.
The average pretreatment THI score was 33.91 as compared with 26.43 after the placebo and 26.09 after melatonin. The difference in the THI scores between melatonin and placebo treatment were not statistically significant. The average pretreatment THI score for patients who reported overall improvement with melatonin was statistically higher (P = 0.02) than the average pretreatment THI score for patients who reported no improvement with melatonin. Among subjects reporting difficulty sleeping attributable to their tinnitus, 46.7% reported an overall improvement after melatonin compared with 20.0% for placebo (P = 0.04). There was also a statistically significant difference in improvement with melatonin for those patients with bilateral tinnitus compared with those with unilateral tinnitus (P = 0.02).
Melatonin has been shown to be useful in the treatment of subjective tinnitus. Patients with high THI scores and/or difficulty sleeping are most likely to benefit from treatment with melatonin. In light of its minimal side effects, melatonin should be a part of the physician's armamentarium in the treatment of tinnitus.
Melatonin binding sites were characterized in human blood lymphocytes. The specific binding 2-[125I]iodo-melatonin ([125I]MEL) to human lymphocytes was dependent on time and temperature, stability, saturation, and reversibility. Moreover, guanine nucleotides decreased the specific binding of [125I]MEL to crude membranes of human lymphocytes, suggesting the coupling of these binding sites to a guanosine nucleotide binding regulatory protein(s). In competition studies, the specific binding of [125I]MEL to lymphocytes was inhibited by increasing concentrations of native melatonin. Scatchard analysis showed that data were compatible with the existence of two classes of binding sites: a high-affinity site with a Kd of 5.20 +/- 0.79 nM and a binding capacity of 50.6 +/- 11.0 fmol/10(7) cells, and a low-affinity site with a Kd of 208.5 +/- 50.2 nM and a binding capacity of 2691 +/- 265 fmol/10(7) cells. However, concentration-dependent binding of [125I]MEL to lymphocytes was saturable and resulted in a linear Scatchard plot, suggesting binding to a single class of binding sites. The Kd for the single site was 1.02 +/- 0.34 nM with a binding capacity of 10.1 +/- 1.6 fmol/10(7) cells. Their affinities closely correlated with the production of cyclic nucleotides, suggesting a physiological role for the melatonin binding sites. Thus, melatonin potentiated the effect of vasoactive intestinal peptide (VIP) on cyclic AMP production (ED50 = 1.9 nM) and stimulated cyclic GMP accumulation (ED50 = 125 nM). Results demonstrate the existence of two binding sites for [125I]MEL in human blood lymphocytes, with a high-affinity binding site coupled to the potentiation of the effect of VIP on cyclic AMP production and a low-affinity binding site coupled to activation of cyclic GMP production.
The binding sites for 2-[125I]iodomelatonin in chicken spleens were characterized. The binding was rapid, stable, saturable, reversible, and of high affinity. Both melatonin and 6-chloromelatonin strongly inhibited the binding. The dissociation constant (Kd) obtained from the Scatchard analysis was 31.4 +/- 5.19 pmol/l (3-weeks old, n = 4), which was in good agreement with the Kd (50.6 pmol/l) calculated from the kinetic study. The maximum number of binding sites (Bmax) was 1.09 +/- 0.11 fmol/mg protein (3-weeks old, n = 4). Twelve 11-week-old chicks were killed in two groups at mid-light or mid-dark. Saturation studies indicated no significant difference (P greater than 0.05) in the Kd between mid-light (42.1 +/- 3.9 pmol/l) and mid-dark (31.6 +/- 4.9 pmol/l). The maximum number of binding sites (Bmax) at mid-light and mid-dark were 1.52 +/- 0.16 and 1.35 +/- 0.08 fmol/mg protein, respectively, with no significant variation (P greater than 0.05) recorded. However, when the whole spleen was taken into consideration, the Bmax per spleen protein of the mid-light samples (253 +/- 36 fmol/spleen protein) was significantly greater than that (129 +/- 16 fmol/spleen protein) of the mid-dark samples (P less than 0.05). This indicated that in our study a diurnal rhythm of the total number of 2-[125I]iodomelatonin binding sites might exist in the chicken spleen.
In the present study we investigated the synergistic effect of melatonin and vasoactive intestinal peptide (VIP) on cyclic AMP production in human blood lymphocytes. As shown by our group previously, VIP alone behaved as a potent activator of cyclic AMP production in human lymphocytes. On the other hand, melatonin alone did not affect the intracellular levels of cyclic nucleotide at any time or dose studied. However, when cells were incubated with melatonin plus VIP, melatonin potentiated the effect of the peptide. This effect can be observed in the presence of physiological doses of both melatonin (10-100 pM) and VIP (1-100 pM). The effect is specific for VIP because with other peptides belonging to the secretin-VIP family the effect was not observed. Results suggest that melatonin, in conjunction with VIP, may directly participate in the regulation of immune function in the human.
The characterization of specific melatonin binding sites in the Harderian gland (HG) and median eminence (ME) of the rat was studied using [125I]melatonin. Binding of melatonin to membrane crude preparations of both tissues was dependent on time and temperature. Thus, maximal binding was obtained at 37 degrees C after 30-60 min incubation. Binding was also dependent on protein concentration (up to 1.5 mg/ml). The specific binding of [125I]melatonin was saturable, exhibiting only one class of binding sites in both tissues. The dissociation constants (Kd) were 170 and 190 pM for ME and HG, respectively. The concentration of the binding sites in ME was 8 fmol/mg protein, and in the HG 4 fmol/mg protein. In competition studies, binding of [125I]melatonin to ME or HG was inhibited by increasing concentration of native melatonin; 50% inhibition was observed at about 702 and 422 nM for ME and HG, respectively. Additionally, the [125I]melatonin binding to the crude membranes was not affected by the addition of different drugs such as norepinephrine, isoproterenol, phenylephrine, propranolol, or prazosin. The results confirm the presence of melatonin binding sites in median eminence and show, for the first time, the existence of melatonin binding sites in the Harderian gland.
In vitro autoradiography with 125I-labeled melatonin was used to examine melatonin binding sites in human hypothalamus. Specific 125I-labeled melatonin binding was localized to the suprachiasmatic nuclei, the site of a putative biological clock, and was not apparent in other hypothalamic regions. Specific 125I-labeled melatonin binding was consistently found in the suprachiasmatic nuclei of hypothalami from adults and fetuses. Densitometric analysis of competition experiments with varying concentrations of melatonin showed monophasic competition curves, with comparable half-maximal inhibition values for the suprachiasmatic nuclei of adults (150 picomolar) and fetuses (110 picomolar). Micromolar concentrations of the melatonin agonist 6-chloromelatonin completely inhibited specific 125I-labeled melatonin binding, whereas the same concentrations of serotonin and norepinephrine caused only a partial reduction in specific binding. The results suggest that putative melatonin receptors are located in a human biological clock.
In this study, we examined the effect of the central-type benzodiazepine agonist, clonazepam, and the indoleamine hormone, melatonin, on central dopaminergic function using the 6-hydroxydopamine model of dopamine receptor supersensitivity. Unilateral lesioning of the nigrostriatal pathway with 6-hydroxydopamine was carried out in Sprague-Dawley rats. Two weeks after surgery, the animals were examined for the presence of dopaminergic supersensitivity by their response to the dopamine receptor agonist, apomorphine. Clonazepam, melatonin and its analogs, 6-chloromelatonin and 2-iodomelatonin, significantly inhibited apomorphine-induced turning behavior (P < .01). Pretreatment with a central-type benzodiazepine antagonist, flumazenil, significantly reduced the effect of melatonin and clonazepam (P < .01). The peripheral-type benzodiazepine antagonist, PK 11195, caused some attenuation of melatonin's effect (P < .05), but it was significantly less potent than flumazenil. Bicuculline, a GABAA receptor antagonist, was also found to reduce the inhibitory effect of melatonin on the induced rotational response (P < .01). These results indicate that the antidopaminergic effect of clonazepam and melatonin is mediated predominantly by central-type benzodiazepine receptors in the central nervous system, via a GABAergic mechanism.
In this paper we show the presence of 2-[125I]melatonin binding sites in human neutrophils (hN). The specific binding of melatonin to hN cells and hN membranes was dependent on time and temperature, stable, saturable, and reversible. In competition studies, the specific binding of radioactive melatonin to hN cells or hN membranes was inhibited by increasing concentrations of native melatonin. Scatchard analysis showed the existence of a single class of binding sites with a Kd of 2.1 and 7.1 microM for hN cells and hN membranes, respectively. The binding capacity was of 84 and 132 pM for hN cells and hN membranes, respectively. The affinity of the binding sites for melatonin suggests that they may be relevant in studies on the pharmacological properties of melatonin in regulating human neutrophil activity.
Melatonin binding sites were characterized in partially purified rat thymus membranes. The specific binding of 2-[125I]iodomelatonin ([125I]MEL) to thymus membranes was dependent on time and temperature, stable, saturable, and reversible. Concentration-dependent binding of [125I]MEL to thymus membranes was saturable and resulted in a linear Scatchard plot, suggesting binding to a single class of binding sites. The Kd for this single site was 0.47 nM with a binding capacity of 1.01 pM. In competition studies, the specific binding of [125I]MEL to thymus membranes was inhibited by increasing concentrations of native melatonin. Scatchard analysis showed that, unlike in saturation studies with [125I]MEL, data were compatible with the existence of two classes of binding sites: a high-affinity site with a Kd of 1.72 +/- 0.25 nM and a binding capacity of 1.40 +/- 0.18 pM, and a low-affinity site with a Kd of 1226 +/- 325 nM and a binding capacity of 460 +/- 87 pM. Interestingly, Kd and BC values of the high-affinity binding site described by competition studies are similar to those obtained by saturation studies with [125I]MEL. Binding of [125I]MEL to thymus membranes was specific as indicated by the fact no other melatonin precursor or derivative was as potent as melatonin in inhibiting the binding of [125I]MEL to membranes. Results strongly suggest that melatonin is involved in regulation of thymus activity.
The presence of specific melatonin binding sites in the Harderian gland of Syrian hamsters was studied using [125I]melatonin. Saturation binding experiments conducted with [125I]melatonin at 37 degrees C using Harderian glands of both male and female Syrian hamsters revealed a single nanomolar-affinity site. The dissociation constants (Kd) were 6.47 and 6.94 nM for males and females, respectively. The concentration of the binding sites was 7.58 fmol/mg protein for males and 13.50 fmol/mg protein for females. Castration of male hamsters resulted in a significant increase in [125I]melatonin binding sites while chronic melatonin administration did not modify the binding properties. The results confirm the presence of melatonin binding sites in the Harderian glands of rodents. The gender-associated differences found together with the effects of castration in male hamsters suggest an androgenic control in [125I]melatonin binding sites of the Syrian hamster Harderian gland.
Previously, we have demonstrated the presence of melatonin binding sites in thymus membranes of adult rats. In this paper, we show that the binding of melatonin by thymus membranes changes during postnatal development. Maximum binding was observed in newborn rats; thereafter, binding decreased progressively during the first weeks of life and exhibited the lowest values in adult animals. Stoichiometric studies showed that the decrease in melatonin binding was due to changes in the binding capacity (2.5-fold) rather than to changes in the affinity of the receptor for the ligand. The results suggest a physiological role of melatonin in regulating thymus activity early during postnatal development.
Within the normal inner ear, there are elements that belong to the immune system. Different inner ear disorders can be explained by autoimmune mechanisms, affecting both humoral and cellular immunity. Melatonin, the principal hormone of the pineal gland, modulates the immune system and extensively participates in the autoimmune processes related to type II collagen. Therefore, we have studied the presence of melatonin in rat cochlea, proving that its concentrations change depending on lighting conditions. Rats show high levels when confined to darkness and low levels when subject to continuous light exposure. The results correlate with the concentration of melatonin in peripheral circulation. Further experimental and clinical studies are necessary to clarify the role and the possible therapeutic applications of melatonin.
We have studied the behavior of peripheral blood lymphocytes in healthy controls and in patients with various hearing losses. These hearing losses were of an autoimmune origin in which type II collagen and melatonin were either present or absent, activated or not with concanavalin A (Con A). In patients with autoimmune hearing losses, the results showed lymphocytes that displayed hyporeactivity to type II collagen in terms of their proliferative activity in the presence of Con A. The hyporeactivity is specially relevant in those cells which are melatonin incubated. When different nosologic entities were studied, we observed similar lymphocyte hyporeactivity to type II collagen in bilateral sensorineural hearing loss, Ménière's disease and otosclerosis. We conclude that in the lymphocytes of patients with autoimmune hearing losses, there is hyporeactivity to type II collagen when compared to the hyporeactivity of lymphocytes in control groups. This hyporeactivity is revealed when the lymphocytes are activated in the presence of melatonin.
Rat cochleas were analysed for free oxygen radicals (FOR) and nitric oxide (NO) production by the chemiluminescent oxidation of luminol. 4Beta-phorbol-12beta-myristate-13alpha-acetate (PMA), a well-known agonist of protein kinase C, induced the release of FOR after a time lag close to 30 s and reverted to basal values in approximately 10 min. Sphingosine inhibited by nearly 50% the response to PMA, whereas staurosporine caused an inhibition of 100%. The incubation of rat cochleas with 0.5 mM arginine potentiated the chemiluminescent reaction induced by PMA causing an additional oxidation of luminol that was inhibited by the NO synthase inhibitor N-methyl-arginine (NMA). Our results show for the first time the presence in the cochlea of cell populations producing FOR and NO and the real time production following cell activation. This procedure may help to explain the mechanisms involved in ototoxicity, as in the case of streptomycin and gentamicin that enhanced PMA-dependent production of FOR and NO.
Because millions of people are self-prescribing melatonin for various indications, the safety aspects of this substance have become very important. The aim of our study was to determine whether or not melatonin impairs driving-related performance.
Twenty healthy men and women aged 21-57 years volunteered for this randomized, placebo-controlled, double-blind, crossover study. The crossover arms were separated by an interval of at least 4 weeks. On each testing day, melatonin 5 mg or placebo was taken at 1630 h; 60 minutes later a test series was performed, consisting of a medical examination, body sway measurement, and a standardized driving computer test battery to assess attention, reaction time, power of concentration, and sensomotor coordination. Subjective sleepiness was measured on three occasions during the test session using the Stanford Sleepiness Scale questionnaire.
Just one of the 16 main variables of the driving computer test battery, the selective attention tested by signal-detection, was significantly affected by melatonin (p < .05). However, even those values were still within the normal range. Subjective sleepiness was increased by melatonin, although the result was significant only after the prolonged concentration task (p < .05). Neither the clinical examination nor the body sway test showed signs of any drug influence.
The overall result of the computer test battery showed no objective adverse impact of melatonin on driving performance. However, due to the increased subjective sleepiness after administration of this hormone, caution should be exercised when driving under the influence of melatonin.
The outer hair cells of the organ of Corti transform sound into electrical signals, beginning the nervous auditive process. These cells produce acoustic emissions when working routinely, known as otoacoustic emissions. Otoacoustic emissions (OAEs) are recorded from the hearing duct through a probe which incorporates a sound source and a sensitive microphone. On the other hand, the cochlea produces oxygen-derived free radicals and nitric oxide, in addition, melatonin is present in the cochlea. The authors have studied the influence of melatonin or an antioxidant mixture (alpha-tocopherol acid succinate, ascorbic acid, glutathione, and N-acetylcysteine) on the postmortem activity of the outer hair cells of the organ of Corti of the rat, measuring distortion product otoacoustic emissions. Control rats showed postmortem distortion product otoacoustic emissions for about 2 min when sacrificed by decapitation, and for about 3 min when sacrificed by chloroform inhalation. Melatonin prolonged the postmortem activity 3.5 times when the animals were sacrificed by decapitation, and 7 times when animals were sacrificed by chloroform inhalation. Similar results were obtained with the antioxidant mixture. Results show that melatonin and other antioxidants have, in general, a protective role on the postmortem activity of the outer hair cells of the organ of Corti.
The ototoxicity of antibiotics, particularly of aminoglycosides, is a well-known undesirable side effect which may be based on a free radical mechanism. We studied the effect of different antibiotics in the production of reactive oxygen species in freshly isolated cochleas of mature and 2-10 weeks old developing rats. Phorbol myristate acetate induced the release of reactive oxygen species after a lag time close to 30 s and declined back to basal values in 10-20 min. The rate of reactive oxygen species production correlated inversely to the age in 2-10 weeks old rats. The study of a set of antibiotics showed that a very low concentration of gentamicin and streptomycin (10-100 ng/ml) enhanced the effect of phorbol myristate acetate. At the above-indicated concentrations, ciprofloxacin did not modify phorbol myristate acetate-induced activation. These results show the enhancement by aminoglycosides of reactive oxygen species production in cochlear tissues, particularly in developing rats.
The production of free radicals seems to be involved in the mechanisms of ototoxicity. Aminoglycosides produce ototoxicity, which can be determined through distortion product otoacoustic emissions (OAEs) that measure the activity of the outer hair cells of the organ of Corti. An ototoxic chart was obtained in rats using gentamicin or tobramycin. Together with this treatment, the animals ingested melatonin in the drinking water, or melatonin was injected subcutaneously or intramuscularly. The distortion product OAEs were determined over a prolonged period of time for each of the groups. The effect of melatonin on the antibiotic capacity of the aminoglycosides used was also studied. Antibiograms inoculated with Escherichia coli or Pseudomonas aeruginosa and treated with gentamicin or tobramycin in the presence or absence of melatonin at quantities from pharmacological to physiological doses were performed. The ototoxicity produced by gentamicin and tobramycin was maximal from days 3 to 5 post-treatment, returning to normal values in 2 wk. When melatonin was present, the recovery was at day 5 post-treatment, independently of the means of administration of the pineal product. The antibiograms showed that melatonin had no effect on the antibiotic capacity. It is concluded that the ototoxicity caused by gentamicin and tobramycin is ameliorated by melatonin and that the pineal hormone does not interfere with the antibiotic capacity of these antibiotics.
This study examines the effects of melatonin on dopaminergic supersensitivity induced by long-term treatment with haloperidol in rats. Enhancements of spontaneous general activity in an open-field and of stereotyped behavior induced by apomorphine after abrupt withdrawal from long-term treatment with haloperidol were used as experimental parameters for dopaminergic supersensitivity. Experiment 1 was conducted to investigate the effects of melatonin on the development of dopaminergic supersensitivity, and experiment 2 was conducted to investigate the effects of melatonin on the development as well as on expression of dopaminergic supersensitivity. Rats of both experiments were long-term treated with saline or haloperidol concomitant to saline or melatonin. In experiment 1 behavioral observations were performed after abrupt withdrawal from long-term treatment. In experiment 2 behavioral observations were performed 1 hour after an acute injection of saline or melatonin, administered after the abrupt withdrawal from long-term treatment. Both behavioral parameters used showed the development of central dopaminergic supersensitivity in rats treated with haloperidol since 24 hours after abrupt withdrawal. Concomitant treatment with melatonin intensified haloperidol-induced dopaminergic supersensitivity, observed 72 hours after withdrawal. Melatonin treatment per se also induced behavioral supersensitivity evaluated by both open-field and stereotyped behaviors, although it was more fugacious than that presented by haloperidol. Acute treatment with melatonin reverted the enhancement of the haloperidol-induced dopaminergic supersensitivity produced by concomitant long-term treatment with melatonin, as well as melatonin-induced dopaminergic supersensitivity per se. Our results support previous evidence of antidopaminergic effects of melatonin and demonstrate that repeated administration of this hormone modifies the plasticity of behaviors mediated by central dopaminergic systems.
With this study we try to find out the interaction of sulpiride in tinnitus pathology. This, could help us to control better the tinnitus through tinnitus retraining therapy.
A hundred patients with tinnitus were divided into two groups of 50. Fifty milligrams of sulpiride or placebo were administered for three months, three time per day, with monthly controls. Clinical response, audiometry, tympanometry and acufenometry were registered.
In the first month of treatment, only 58% of patients treated with sulpiride improved, and 17% of those treated with placebo, with statistical significance. In the second month, 41% and 20% respectively, and in the third month, 42% and 17% respectively.
In patients with tinnitus, treatment with sulpiride has improved more than half of them in the first month of treatment. This time is crucial to begin tinnitus retraining therapy and to obtain a greater efficacy.
Subjective tinnitus is a phantom sound sensation that does not result from acoustic stimulation and is audible to the affected subject only. Tinnitus-like sensations in animals can be evoked by procedures that also cause tinnitus in humans. In gerbils, we investigated brain activation after systemic application of sodium salicylate or exposure to loud noise, both known to be reliable tinnitus-inductors. Brains were screened for neurons containing the c-fos protein. After salicylate injections, auditory cortex was the only auditory area with consistently increased numbers of immunoreactive neurons compared to controls. Exposure to impulse noise led to prolonged c-fos expression in auditory cortex and dorsal cochlear nucleus. After both manipulations c-fos expression was increased in the amygdala, in thalamic midline, and intralaminar areas, in frontal cortex, as well as in hypothalamic and brainstem regions involved in behavioral and physiological defensive reactions. Activation of these non-auditory areas was attributed to acute stress, to aversive-affective components and autonomous reactions associated with the treatments and a resulting tinnitus. The present findings are in accordance with former results that provided evidence for suppressed activation in auditory midbrain but enhanced activation of the auditory cortex after injecting high doses of salicylate. In addition, our present results provide evidence that acute stress coinciding with a disruption of hearing may evoke activation of the auditory cortex. We interpret these results in favor of our model of central tinnitus generation.
We tested the hypothesis that melatonin acts as a powerful hydroxyl radical (*OH) scavenger in vivo in the brain, and interferes with oxidative stress caused by the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We investigated the effect of melatonin on in vitro *OH production employing a Fenton-like reaction in test tubes, and ex vivo *OH generation in isolated mitochondria induced by 1-methyl-4-phenyl pyridinium (MPP+), as well as on in vivo *OH formation in the mouse striatum following systemic administration of MPTP. We also measured reduced glutathione (GSH) levels, and superoxide dismutase (SOD) activity in the nucleus caudatus putamen (NCP) and substantia nigra (SN), 7 days following MPTP and/or melatonin administration. Melatonin caused a significant and dose-dependent inhibition of the production of *OH in the in vitro, ex vivo and in vivo experimental conditions. Melatonin caused no changes in monoamine oxidase-B activity, in vitro in mitochondrial P2 fractions or in vivo following systemic administration. MPTP treatment in mice caused a significant depletion of GSH, and increased the specific activity of SOD both in SN and NCP on the seventh day. MPTP-induced GSH depletion was dose-dependently blocked in SN and NCP by melatonin. Higher doses of melatonin exhibited a synergistic effect on MPTP-induced increase in the SOD activity in the SN. These results suggest that while GSH inhibition is a direct consequence of *OH generation following neurotoxin administration, the increase in SOD activity is a compensatory mechanism for removing superoxide radicals generated as the result of MPTP. Our results not only point to the potency of melatonin in blocking the primary insults caused by MPTP, but also provide evidence for triggering secondary neuroprotective mechanisms, suggesting its use as a therapeutic agent in neurodegenerative disorders, such as Parkinson's disease.
Antioxidant enzymes form the first line of defense against free radicals in organisms. Their regulation depends mainly on the oxidant status of the cell, given that oxidants are their principal modulators. However, other factors have been reported to increase antioxidant enzyme activity and/or gene expression. During the last decade, the antioxidant melatonin has been shown to possess genomic actions, regulating the expression of several genes. Melatonin also influences both antioxidant enzyme activity and cellular mRNA levels for these enzymes. In the present report, we review the studies which document the influence of melatonin on the activity and expression of the antioxidative enzymes glutathione peroxidase, superoxide dismutases and catalase both under physiological and under conditions of elevated oxidative stress. We also analyze the possible mechanisms by which melatonin regulates these enzymes.
We have previously shown that melatonin reduces infarct volumes and enhances neurobehavioral and electrophysiological recoveries following transient middle cerebral artery (MCA) occlusion in rats. In the study, we examined whether melatonin would display neuroprotection against neuronal, axonal and oligodendrocyte pathology after 24 hr of reperfusion following 1 hr of MCA occlusion in mice. Melatonin (5 mg/kg) or vehicle was given intraperitoneally at the commencement of reperfusion. Neurological deficits were assessed 24 hr after ischemia. Gray matter damage was evaluated by quantitative histopathology. Axonal damage was determined with amyloid precursor protein and microtubule-associated protein tau-1 immunohistochemistry to identify postischemic disrupted axonal flow and oligodendrocyte pathology, respectively. Oxidative damage was assessed by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxynonenal (4-HNE) immunohistochemistry. Relative to controls, melatonin-treated animals not only had a significantly reduced volume of gray matter infarction by 42% (P<0.001), but also exhibited a decreased score of axonal damage by 42% (P<0.001) and a reduction in the volume of oligodendrocyte pathology by 58% (P<0.005). Melatonin-treated animals also had significantly reduced immunopositive reactions for 8-OHdG and 4-HNE by 53% (P<0.001) and 49% (P<0.001), respectively. In addition, melatonin improved sensory and motor neurobehavioral outcomes by 47 and 30%, respectively (P<0.01). Thus, delayed (1 hr) treatment with melatonin reduced both gray and white matter damage and improved neurobehavioral outcomes following transient focal cerebral ischemia in mice. The finding of reduced oxidative damage observed with melatonin suggests that its major mechanisms of action are mediated through its antioxidant and radical scavenging activity.
Melatonin, or N-acetyl-5-methoxytryptamine, is a compound derived from tryptophan that is found in all organisms from unicells to vertebrates. This indoleamine may act as a protective agent in disease conditions such as Parkinson's, Alzheimer's, aging, sepsis and other disorders including ischemia/reperfusion. In addition, melatonin has been proposed as a drug for the treatment of cancer. These disorders have in common a dysfunction of the apoptotic program. Thus, while defects which reduce apoptotic processes can exaggerate cancer, neurodegenerative disorders and ischemic conditions are made worse by enhanced apoptosis. The mechanism by which melatonin controls cell death is not entirely known. Recently, mitochondria, which are implicated in the intrinsic pathway of apoptosis, have been identified as a target for melatonin actions. It is known that melatonin scavenges oxygen and nitrogen-based reactants generated in mitochondria. This limits the loss of the intramitochondrial glutathione and lowers mitochondrial protein damage, improving electron transport chain (ETC) activity and reducing mtDNA damage. Melatonin also increases the activity of the complex I and complex IV of the ETC, thereby improving mitochondrial respiration and increasing ATP synthesis under normal and stressful conditions. These effects reflect the ability of melatonin to reduce the harmful reduction in the mitochondrial membrane potential that may trigger mitochondrial transition pore (MTP) opening and the apoptotic cascade. In addition, a reported direct action of melatonin in the control of currents through the MTP opens a new perspective in the understanding of the regulation of apoptotic cell death by the indoleamine.
To date, the neurophysiological model has been used to explain the complexity of tinnitus. However from now on, the tinnitus dopaminergic pathway opens new horizons for ear noises management. Tinnitus perception takes place in prefrontal, primary temporal and temporo-parietal associative areas, as well as the limbic system. Dopaminergic neurotransmitters go through prefrontal, primary temporal, temporo-parietal associative areas and the limbic system. Tinnitus perception and dopaminergic pathway share the same cerebral structures, which control attention, stress, emotions, learning, memory and motivated behavior. Distress of tinnitus emanates from these same cerebral functions. The dopaminergic pathway can be modulated by agonists and antagonists of their receptors and can reduce the perception of tinnitus, such as sulpiride, amisulpride, olanzapine, quetiapine, ziprasidone, zuclopenthixole and aripiprazole, still under investigation, that together with sound treatment as the Sequential Sound Therapy, and a personal contact with the patient, constitute a tinnitus integral treatment.
This study aimed at investigating the in vitro protective effects of GWC22, a novel pinoline derivative [6-ethyl-1-(3-methoxyphenyl)-2-propyl-1,2,3,4-tetrahydro-beta-carboline] chlorhydrate, against radiation-induced oxidation of linoleate initiated by hydroxyl radicals ((*)OH). Using linoleate micelles (10(-2) m) as lipid model, two indexes of peroxidation have been measured, i.e. conjugated dienes and hydroperoxides. Similar determinations were performed with melatonin in order to compare the protective effects of the two compounds. It was observed that, the higher the concentration of GWC22 (or melatonin) (3 x 10(-5) to 10(-4) m), the stronger the antioxidant ability. In these in vitro assays, GWC22 showed a better antioxidant effect than melatonin for a given antioxidant concentration. A reaction scheme has been proposed to explain the inhibitory effect of an antioxidant via the propagating steps of the lipid peroxidation. Indeed, we have suggested that melatonin and GWC22 may compete with the fatty acid to scavenge lipid peroxyl radicals (LOO(*)). We have estimated a lower limit for the LOO(*) rate constant for GWC22 (>/=1.4 x 10(5)/m/s) and for melatonin (>/=2.8 x 10(4)/m/s) assuming that the k-value of the propagating step in linoleate (LOO(*) + linoleate) was 1.4 x 10(3)/m/s. The difference of reactivity between melatonin and GWC22 in this model system is assumed to be related to their relative lipophilicity.