Pathogenesis and Therapeutic Strategies for Tinnitus Based on Inflammatory and Neuroimmune Mechanisms

Tinnitus, the perception of phantom sound in the absence of an external stimulus, is increasingly understood to arise from a complex interplay of inflammatory and neuroimmune processes as well as maladaptive neural plasticity. In the periphery, cochlear insult, whether due to agerelated hearing loss, acoustic trauma, ototoxic drugs, or chronic noise exposure, triggers the release of proinflammatory cytokines such as TNF-, IL-1, and IL-6. These mediators can disrupt tight junctions in the bloodbrain barrier, permitting peripheral immune factors to infiltrate central auditory pathways. Within the CNS, activated microglia adopt an M1proinflammatory phenotype, releasing additional cytokines and reactive oxygen species, while astrocytes lose their homeostatic regulation of glutamate and calcium signaling, further promoting hyperexcitability. These glial changes drive synaptic remodeling and neuronal hyperactivity in key auditory nuclei, consolidating tinnitus percepts through aberrant cortical reorganization. Therapeutic efforts have therefore focused on attenuating inflammation with localized interventions, such as intrathecal corticosteroid injections, and systemic agents like minocycline or anti-TNF biologics. Concurrently, neuromodulation strategies (repetitive transcranial magnetic stimulation, transcranial directcurrent stimulation, and vagus nerve stimulation) aim to recalibrate cortical excitability and foster adaptive plasticity. Together, these approaches represent a multifaceted framework for targeting both the immunological and electrophysiological underpinnings of tinnitus.