Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig.
Glutamate excitotoxicity is implicated in both the genesis of neural injury and noise-induced hearing loss (NIHL). Acoustic overstimulation may result in excessive synaptic glutamate, resulting in excessive binding to post-synaptic receptors and the initiation of a destructive cascade of cellular events, thus leading to neuronal degeneration and NIHL. The purpose of this study was to determine whether this apparent excitotoxicity can be attenuated by kynurenic acid (KYNA), a broad-spectrum glutamate receptor antagonist, and protect against noise-induced temporary threshold shifts (TTS). Guinea pigs were randomly assigned to three separate groups. Base-line compound action potentials (CAP) thresholds and cochlear microphonics (CM) were recorded. Group I was treated with physiologic saline as a vehicle control applied to the round window membrane that was followed by 110 dB SPL wide-band noise for 90 min. Group II received 5 mM KYNA followed by noise exposure, and group III received 5 mM KYNA alone without noise exposure. Post-drug and noise levels of CAP thresholds and CM were then obtained. Noise exposure in the control group caused a significant temporary threshold shift (TTS) of 30-40 dB across the frequencies tested (from 3 kHz to 18 kHz). Animals that received 5 mM KYNA prior to noise exposure (group II) showed statistically significant protection against noise-induced damage and demonstrated a minimal TTS ranging between 5 and 10 dB at the same frequencies. Animals in group III receiving KYNA without noise exposure showed no change in thresholds. Additionally, cochlear microphonics showed no considerable difference in threshold shifts when controls were compared to KYNA-treated animals. These results show that antagonizing glutamate receptors can attenuate noise-induced TTS, suggesting that glutamate excitotoxicity may play a role in acoustic trauma.
Khan
M J
MJ
Department of Otorhinolaryngology Head and Neck Surgery, Henry Ford Hospital, Detroit, MI 48202, USA.
Seidman
M D
MD
Quirk
W S
WS
Shivapuja
B G
BG
D000818:Animals; D001309:Auditory Threshold / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006168:Guinea Pigs; D007736:Kynurenic Acid / Q000494:pharmacology*; D008297:Male; D009622:Noise / Q000009:adverse effects; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000378:metabolism; D012405:Round Window, Ear / Q000187:drug effects / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D007736:Kynurenic Acid