3,6’-Dithiothalidomide Reduces Tinnitus Phenotype in Two Different Mouse Preclinical Models of Tinnitus

Abstract

Background: Tinnitus is the perception of a sound in the absence of external stimulation. Tinnitus is a common consequence of damage to the auditory periphery, affecting around 5-12% of the population and inducing intolerable discomfort. Today, no treatment exists to cure tinnitus. From an electrophysiology point of view, tinnitus leads to auditory brainstem responses (ABRs) wave modifications and spontaneous activity changes of the primary auditory cortex (PAC) in human and rodents. Moreover, plasma brain-derived neurotrophic factor (BDNF) levels vary with the severity of tinnitus, suggesting that plasma BDNF level can be used as a biomarker to objectively evaluate tinnitus in rodent and humans. Several publications suggested that tinnitus is closely related to auditory system inflammation and proinflammatory cytokine TNF-α. Results: we evaluated the efficacy of a novel thalidomide-based TNF-α lowering agent, the 3,6'-dithiothalidomide (TLD) in two different preclinical models of tinnitus. We observed that TLD treatment increased the % of startle GAP suppression, increased ABR wave I amplitude and decreased wave IV latency, decreased spontaneous activity of PAC, and significantly decrease plasma BDNF concentration in the salicylate-induced and noise-induced tinnitus mouse models. Conclusions: Our data confirm that proinflammatory cytokines are directly linked to tinnitus phenotype suggesting that inflammatory pharmacological modulators could be a promising therapy targeting tinnitus disorder.

Association of periodontitis with tinnitus: A population‐based cohort study in Taiwan

“…In a previous study, an increase in neuroglial activation in the auditory cortex and medial geniculate body was observed in animals with salicylate‐induced tinnitus (Xia et al, 2020). Furthermore, a link between tumour necrosis factor‐alpha (TNF‐α) in the behavioural phenotype associated with tinnitus was found in animal studies (Hwang et al, 2011, 2017; W. Wang et al, 2019; Gonzalez‐Gonzalez, 2020). Evidence has also shown that TNF‐α appears to play a role in the pathogenesis of periodontitis, and an increased serum level of TNF‐α was observed in patients with periodontitis (Gorska et al, 2003; Engebretson et al, 2007; Ding et al, 2014).…”

“…Contrarily, inhibition of tissue necrosis factor reduced the tinnitus phenotype in preclinical models (Hwang et al, 2017;Gonzalez-Gonzalez, 2020).…”

“…In an animal model with salicylate‐induced tinnitus, the level of proinflammatory cytokines was shown to increase in the auditory cortex and cochlea (Hwang et al, 2011; Chen & Zheng, 2017). Contrarily, inhibition of tissue necrosis factor reduced the tinnitus phenotype in preclinical models (Hwang et al, 2017; Gonzalez‐Gonzalez, 2020).…”

Associations of Tinnitus Incidence with Use of Tumor Necrosis Factor-Alpha Inhibitors among Patients with Autoimmune Conditions

“…TNFα expression is also significantly upregulated in the IC or AC of mice with salicylate-induced tinnitus [15,16]. Further, in mice, intra-ventricle infusion of recombinant TNFα resulted in tinnitus behavior and microglia alterations in the AC following noise exposure [17], and genetic knockout of TNFα or blockade of TNFα expression decreased tinnitus-associated behavior [14,18,19]. Finally, intracochlear TNFα infusion resulted in reduced auditory nerve activity and degradation of inner hair cell synapses in guinea pigs, which could be prevented via systemic TNFα blockade [20].…”