dizocilpine-maleate and Hearing-Loss

Deprivation of acoustic input during a critical period leads to abnormal auditory development in humans. The molecular basis underlying the susceptibility of auditory cortex to loss of afferent input remains largely unknown. The transcription factor early growth response-1 (EGR-1) expression in the visual cortex has been shown to be crucial in the formation of vision, but the role of EGR-1 during the process of auditory function formation is still unclear. In this study, we presented data showing that EGR-1 was expressed in the neurons of the primary auditory cortex (A1) in mice. We observed that the auditory deprivation induced by kanamycin during the auditory critical period leads to laminar-specific alteration of neuronal distribution and EGR-1 expression in A1. In addition, MK-801 administration inhibited the expression of EGR-1 in A1 and aggravated the abnormal cortical electric response caused by kanamycin injection. Finally, we showed that the expression of PI3K, the phosphorylation of Akt, as well as the phosphorylation of cAMP-responsive element-binding protein (CREB) were decreased in A1 after kanamycin-induced hearing loss. These results characterized the expression of EGR-1 in A1 in response to the acoustic input and suggested the involvement of EGR-1 in auditory function formation.

Topics: Animals; Auditory Cortex; Cyclic AMP Response Element-Binding Protein; Dizocilpine Maleate; Early Growth Response Protein 1; Evoked Potentials, Auditory, Brain Stem; Excitatory Amino Acid Antagonists; Hearing Loss; Kanamycin; Mice; Mice, Inbred CBA; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt

The use of aminoglycoside antibiotics is limited by ototoxicity that can produce permanent hearing loss. We report that concurrent administration of N-methyl-D-aspartate (NMDA) antagonists markedly attenuates both the hearing loss and destruction of cochlear hair cells in guinea pigs treated with aminoglycoside antibiotics. These findings indicate that aminoglycoside-induced hearing loss is mediated, in part, through an excitotoxic process. The high correlation (Spearman correlation coefficient: 0.928; P < 0.01) obtained between the relative cochleotoxicities of a series of aminoglycosides in humans and the potencies of these compounds to produce a polyamine-like enhancement of [3H]dizocilpine binding to NMDA receptors is consistent with this hypothesis, and provides a simple in vitro assay that can predict this aspect of aminoglycoside-induced ototoxicity.

Topics: Animals; Anti-Bacterial Agents; Cochlea; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Guinea Pigs; Hair Cells, Auditory; Hearing Loss; Hearing Tests; Kanamycin; Male; N-Methylaspartate; Neomycin; Piperidines; Prosencephalon; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

MK-801, a glutamate receptor blocker, has been reported to protect against hypoxic-ischemic neuronal degeneration. The purpose of this study was to investigate the protective effects of MK-801 on cochlear impairment induced by carbon monoxide (CO) in the guinea pig and whether the protection reflected systemic or local effects. Glutamate has been proposed to be the neurotransmitter at the inner hair cell/type I spiral ganglion cell synapse. CO (35 ml/kg ip) elevated the compound action potential threshold at high frequencies (16-40 kHz) 30 min after treatment. In the group pretreated with 1 mg/kg MK-801 ip there was no significant elevation of compound action potential threshold 30 min after CO exposure, suggesting that MK-801 provided some protection at this dosage. In the group pretreated with 0.1 mg/kg MK-801 there was protection against cochlear dysfunction 15 min after CO injection, but significant elevation of compound action potential threshold occurred 30 and 60 min after CO exposure. Data also indicated that 1 mM MK-801 applied topically on the round window membrane provided protective effects against CO hypoxia from 15 up to 60 min. This experiment suggests that cochlear impairment induced by CO hypoxia may result from excess extracellular concentrations of glutamate.

Topics: Animals; Auditory Threshold; Carbon Monoxide; Dizocilpine Maleate; Guinea Pigs; Hearing Loss; Male; Time Factors