Expression of Dopamine Receptor 1A and Cannabinoid Receptor 1 Genes in the Cochlea and Brain after Salicylate-Induced Tinnitus

Hwang, Juen-Haur; Chan, Yin-Ching

doi:10.1159/000449170

Cited by 8 publications

(6 citation statements)

References 25 publications

(45 reference statements)

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“…Previous studies have reported that CB2 receptors are expressed in HEI/OC1 cells 29 and in the albino rat cochlea 32 . Another study found CB1 expression in SAMP8 mice cochleae 33 . We sought to determine whether cannabinoid receptors (CB1 and CB2) are expressed in UB/OC1 cells and in the rat cochlea.…”

Section: Resultsmentioning

confidence: 96%

Capsaicin Protects Against Cisplatin Ototoxicity by Changing the STAT3/STAT1 Ratio and Activating Cannabinoid (CB2) Receptors in the Cochlea

Bhatta

Dhukhwa

Sheehan

et al. 2019

Sci Rep

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Capsaicin, the spicy component of hot chili peppers activates the TRPV1 pain receptors, and causes rapid desensitization. Capsaicin also ameliorates cisplatin-induced nephrotoxicity. Cisplatin, a commonly used anti-neoplastic agent for solid tumors causes significant hearing loss, nephrotoxicity and peripheral neuropathy. Upregulation of cochlear TRPV1 expression is related to cisplatin-mediated ototoxicity. Here we report that direct TRPV1 activation by localized trans-tympanic (TT) or oral administration of capsaicin (TRPV1 agonist) prevents cisplatin ototoxicity by sustained increased activation of pro-survival transcription factor signal transducer and activator of transcription (STAT3) in the Wistar rat. Cisplatin treatment produced prolonged activation of pro-apoptotic Ser727 p-STAT1 and suppressed Tyr705-p-STAT3 for up to 72 h in the rat cochlea. Our data indicate that capsaicin causes a transient STAT1 activation via TRPV1 activation, responsible for the previously reported temporary threshold shift. Additionally, we found that capsaicin increased cannabinoid receptor (CB2) in the cochlea, which leads to pro-survival Tyr705-p-STAT3 activation. This tilts the delicate balance of p-STAT3/p-STAT1 towards survival. Furthermore, capsaicin mediated protection is lost when CB2 antagonist AM630 is administered prior to capsaicin treatment. In conclusion, capsaicin otoprotection appears to be mediated by activation of CB2 receptors in the cochlea which are coupled to both STAT1 and STAT3 activation.

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Section: Resultsmentioning

confidence: 96%

Capsaicin Protects Against Cisplatin Ototoxicity by Changing the STAT3/STAT1 Ratio and Activating Cannabinoid (CB2) Receptors in the Cochlea

Bhatta

Dhukhwa

Sheehan

et al. 2019

Sci Rep

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“…GRK6 is a G protein-coupled receptor kinase that modulates dopamine receptors, and overexpression has been noted to attenuate neuropathic pain and rescue levodopa-induced signaling abnormalities. [49][50][51] Dopamine antagonists have shown promise in attenuating tinnitus. 52 Interestingly, MFHAS1 and XKR6 are associated with neuroticism.…”

Section: Discussionmentioning

confidence: 99%

Novel Risk Loci in Tinnitus and Causal Inference With Neuropsychiatric Disorders Among Adults of European Ancestry

Clifford

Maihofer

Stein

et al. 2020

JAMA Otolaryngol Head Neck Surg

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IMPORTANCE Tinnitus affects at least 16 million US adults, but its pathophysiology is complicated, and treatment options remain limited. A heritable component has been identified in family and twin studies; however, no large-scale genome-wide association studies (GWAS) have been accomplished. OBJECTIVETo identify genetic risk loci associated with tinnitus, determine genetic correlations, and infer possible relationships of tinnitus with hearing loss and neuropsychiatric disorders and traits. DESIGN, SETTING, AND PARTICIPANTSA GWAS of self-reported tinnitus was performed in the UK Biobank (UKB) cohort using a linear mixed-model method implemented in BOLT-LMM (linear mixed model). Replication of significant findings was sought in the nonoverlapping US Million Veteran Program (MVP) cohort. A total of 172 995 UKB (discovery) and 260 832 MVP (replication) participants of European ancestry with self-report regarding tinnitus and hearing loss underwent genomic analysis. Linkage-disequilibrium score regression and mendelian randomization were performed between tinnitus and hearing loss and neuropsychiatric disorders. Data from the UKB were acquired and analyzed from September 24, 2018, to December 13, 2019. Data acquisition for the MVP cohort was completed July 22, 2019. Data analysis for both cohorts was completed on February 11, 2020. MAIN OUTCOMES AND MEASURESEstimates of single nucleotide variation (SNV)-based heritability for tinnitus, identification of genetic risk loci and genes, functional mapping, and replication were performed. Genetic association and inferred causality of tinnitus compared with hearing loss and neuropsychiatric disorders and traits were analyzed. RESULTSOf 172 995 UKB participants (53.7% female; mean [SD], 58.0 [8.2] years), 155 395 unrelated participants underwent SNV-based heritability analyses across a range of tinnitus phenotype definitions that explained approximately 6% of the heritability. The GWAS based on the most heritable model in the full UKB cohort identified 6 genome-wide significant loci and 27 genes in gene-based analyses, with replication of 3 of 6 loci and 8 of 27 genes in 260 832 MVP cohort participants (92.8% men; mean [SD] age, 63.8 [13.2] years). Mendelian randomization indicated that major depressive disorder had a permissive effect (β = 0.133; P = .003) and years of education had a protective effect (β = −0.322, P = <.001) on tinnitus, whereas tinnitus and hearing loss inferred a bidirectional association (β = 0.072, P = .001 and β = 1.546, P = <.001, respectively). CONCLUSIONS AND RELEVANCEThis large GWAS characterizes the genetic architecture of tinnitus, demonstrating modest but significant heritability and a polygenic profile with multiple significant risk loci and genes. Genetic correlation and inferred causation between tinnitus and major depressive disorder, educational level, and hearing impairment were identified, consistent with clinical and neuroimaging evidence. These findings may guide gene-based diagnostic and therapeutic approaches to this pervasive disor...

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“…For example, gene expression and/or function of N-methyl D-aspartate (NMDA) receptor (NR) increased in the inner ear and/or auditory nervous system 2,3 . On the contrary, function and/or gene expression of the γ-amino butyric acid (GABA) receptor (GR) and cannabinoid receptor in some brain areas decreased in the condition of tinnitus [4][5][6] . In addition, oxidative stress damage and/or neural inflammation in the peripheral and central auditory system were also important mechanisms of tinnitus [7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Effects of Spirulina on GABA-Receptor Gene Expression in Salicylate-Induced Tinnitus

Chan

Wang

Hwang³

2018

The International Tinnitus Journal

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Expression of Dopamine Receptor 1A and Cannabinoid Receptor 1 Genes in the Cochlea and Brain after Salicylate-Induced Tinnitus

Cited by 8 publications

References 25 publications

Capsaicin Protects Against Cisplatin Ototoxicity by Changing the STAT3/STAT1 Ratio and Activating Cannabinoid (CB2) Receptors in the Cochlea

Capsaicin Protects Against Cisplatin Ototoxicity by Changing the STAT3/STAT1 Ratio and Activating Cannabinoid (CB2) Receptors in the Cochlea

Novel Risk Loci in Tinnitus and Causal Inference With Neuropsychiatric Disorders Among Adults of European Ancestry

Effects of Spirulina on GABA-Receptor Gene Expression in Salicylate-Induced Tinnitus

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