Everolimus Attenuates Salicylate-Induced Tinnitus-Like Behavior and Auditory Cortical Hyperexcitability.

Summary

Sodium salicylate was used to induce acute tinnitus-like behavior in rats, and a single 10 mg/kg dose of everolimus, an approved mTOR-inhibiting drug, was given 30 minutes later, with all measurements taken 2 hours after that. Tinnitus rats showed hyperexcitable primary auditory cortex (raised spontaneous firing rates and c-Fos), increased gamma-band power, and markedly strengthened theta-gamma phase-amplitude coupling, the same cross-frequency coupling signature that the Interacting Brain Networks hypothesis describes from human recordings. At the molecular level the mTOR pathway was activated, the synaptic proteins BDNF and PSD95 were raised, and glutamate accumulated. Everolimus reduced all of these along with the gap-detection deficit. Two limits matter for interpretation: this is an acute, reversible, pharmacological model rather than noise trauma, and the authors' own supplementary measurements show salicylate also caused mild hearing threshold shifts that everolimus partly reversed, so they state they cannot fully separate a central drug effect from a peripheral one. Everolimus is an immunosuppressant and anticancer drug, and the authors caution against reading this as a case for repurposing it for tinnitus.

Key findings

• Rats with salicylate-induced tinnitus-like behavior showed primary auditory cortex hyperexcitability, raised gamma power, and strengthened theta-gamma phase-amplitude coupling, an animal counterpart to the coupling signature reported in human tinnitus recordings.
• The mTOR pathway was activated in the auditory cortex, with BDNF and PSD95 upregulated and glutamate accumulating.
• A single 10 mg/kg dose of the mTOR inhibitor everolimus reduced the firing rates, the pathological theta-gamma coupling, the synaptic protein increases, the glutamate excess, and the gap-detection deficit.
• Interpretation is limited: the model is acute and reversible rather than noise-induced, and salicylate also shifted hearing thresholds slightly, which everolimus partly reversed, so the authors state a central effect cannot be fully separated from a peripheral one.