Activation of the GABAA Receptor Ameliorates the Cochlear Excitotoxicity Caused by Kainic Acid in the Guinea Pig

Abstract

Excitotoxicity is a major neurotoxic mechanism in cochlear disorders, including cochlear ischemic injury and acoustic injury. Kainic acid (KA), an excitatory amino acid, can damage glutamatergic neurons. The application of KA to the round window membrane, an opening of the cochlear bony labyrinth to the middle ear, induces excitotoxicity of cochlear afferent dendrites and significantly decreases the amplitude of compound action potential of the cochlea (CAP), a cochlear potential generated by activation of the auditory nerve fibers. On the other hand, muscimol, a gamma-aminobutyric acid (GABA) A receptor agonist, is neuroprotective in excitotoxicity in the central nervous system. Here we studied whether activation of GABA receptor decreased the excitotoxicity of the cochlea caused by KA. KA (10 mM) was applied to the round window membrane of guinea pigs for 30 minutes. Muscimol, bicuculline, a GABA A receptor antagonist, or baclofen, a GABA B receptor agonist, was given at the onset of KA application. The threshold shift of CAP was examined with chronically implanted electrodes. Application of KA significantly elevated the CAP threshold on day 1 and day 3 as compared with the pre-application level. Muscimol significantly decreased the KA-induced CAP threshold shifts. Furthermore, this protective effect of muscimol was inhibited by the application of bicuculline, a GABA A receptor antagonist. However, baclofen, a GABA B receptor agonist, did not affect the CAP threshold shifts caused by KA. These results suggest that activation of GABA A receptor could prevent cochlear excitotoxicity. GABA A rececptor activation may represent an effective treatment of cochlear ischemc injury and acoustic injury.

The use of animal models to study cell transplantation in neuropathic hearing loss

“…Overstimulation of the cochlea with kainic acid has been used as a model for glutamatergic damage. Although at lower doses, the loss of neural responses has been found to be reversible in the guinea pig (Sakai et al, 2008) and chinchilla (Zheng et al, 1997;Zheng et al, 1999)…”

Ischemia-Reperfusion Injury of the Cochlea: Pharmacological Strategies for Cochlear Protection and Implications of Glutamate and Reactive Oxygen Species

“…It is now considered that the excitotoxicity of cochlear afferent neurons often induces temporary hearing threshold shifts [24]. However, Sun et al .…”

“…There are several agents reported to reduce cochlear excitotoxicity including a GABA(A) agonist (muscimol [24]), dopamine [42, 43], riluzole [44], ebselen [45], and pituitary adenyl cyclase-activating polypeptide (PACAP) [46]. Because the excitotoxicity of cochlear afferent neurons often induces temporary hearing threshold shifts [24], these agents are potential therapeutic targets to prevent temporary hearing deterioration.…”

“…Because the excitotoxicity of cochlear afferent neurons often induces temporary hearing threshold shifts [24], these agents are potential therapeutic targets to prevent temporary hearing deterioration.…”