NMDA Receptors: Next therapeutic targets for Tinnitus?

Abstract

Tinnitus, a common otological symptom, lacks clinically approved pharmacological treatments, highlighting an urgent unmet need. This review explores the potential role of NMDARs, key glutamate receptors in the auditory system, in tinnitus pathophysiology, including excitotoxicity, synaptic plasticity, and neuropathic pain. Alterations in NMDAR variants with different subunit compositions during development have also been implicated in the onset of tinnitus. Clinical trials of NMDAR antagonists, such as acamprosate, caroverine, neramexane, and AM-101, have shown promising results, though none are yet approved. These findings highlight the need for further research on NMDARs to advance the development of next-generation targeted pharmacological therapies for tinnitus.

Keywords: Drug therapy; Glutamate receptor; NMDAR antagonist; Tinnitus; Tinnitus pathology.

Graphical abstract

Fig. 1

SGN excitotoxicity is induced by the hyperactivation of NMDARs by prolonged exposure to glutamate triggers excessive Ca²⁺ influx into SGNs [41]. Besides, intracellular Ca²⁺-overload is of cardinal significance in the formation of SGN excitotoxicity, which activates Ca²⁺ -dependent enzymes including phospholipases, NO synthases, and endonucleases, resulting in cytoskeleton breakdown, free radical production, and DNA breakdown. These activities eventually cause SGN injury or even death, i.e., SGN excitotoxicity [35,42,43].

Fig. 2

NMDAR feed-forward mechanism, upon activation by acute and chronic injury, leads to two opposite outcomes respectively [44]. (A) Under acute insult, short-time activation of the feed-forward regulation exerts neurotrophic effects of NMDAR and protects SGNs from damage. (B) However, under chronic injury, the prolonged feed-forward regulation leads to hyperactivation of NMDARs evoking excessive Ca²⁺ influx, which further causes SGN excitotoxicity and contributes to tinnitus development [45].

Fig. 3

Synaptic plasticity evokes spontaneous firing originating at the cochlea nucleus (CN) for compensation of the input loss from cochlea and propagate this increased activity to superior auditory pathway. (a) When the cochlea is injured by some harmful factors, auditory nerve fiber input from cochlea to cochlear nucleus is attenuated [50]. (b) Frequency-specific spontaneous firing rates occur in CN and is transmitted to the inferior colliculus (IC) via the superior olivary complex (SOC) or not [51]. (c) In IC, it induces increased bursting and cross-fiber synchrony. (d) In the medial geniculate body (MGB), increased synchronization and burst firing as well as hyperpolarization of the neurons are discovered. (e) The propagation of the increased discharge triggers dysrhythmia in the auditory cortex (AC) and produces the perception of tinnitus in the brain [58].