Central Nervous Activity upon Systemic Salicylate Application in Animals with Kanamycin-Induced Hearing Loss--A Manganese-Enhanced MRI (MEMRI) Study

Abstract

This study investigated the effect of systemic salicylate on central auditory and non-auditory structures in mice. Since cochlear hair cells are known to be one major target of salicylate, cochlear effects were reduced by using kanamycin to remove or impair hair cells. Neuronal brain activity was measured using the non-invasive manganese-enhanced magnetic resonance imaging technique. For all brain structures investigated, calcium-related neuronal activity was increased following systemic application of a sodium salicylate solution: probably due to neuronal hyperactivity. In addition, it was shown that the central effect of salicylate was not limited to the auditory system. A general alteration of calcium-related activity was indicated by an increase in manganese accumulation in the preoptic area of the anterior hypothalamus, as well as in the amygdala. The present data suggest that salicylate-induced activity changes in the auditory system differ from those shown in studies of noise trauma. Since salicylate action is reversible, central pharmacological effects of salicylate compared to those of (permanent) noise-induced hearing impairment and tinnitus might induce different pathophysiologies. These should therefore, be treated as different causes with the same symptoms.

Fig 1. Examples of MEMRI-images of a mouse brain with labelled regions of interest.

Outlines show the auditory structures of: a) the dorsal and ventral cochlear nucleus (CN), b) the superior olivary complex (SOC), c) the inferior colliculus (IC), d) the medial geniculate body (MGB) and primary auditory cortex (AC). Further, the non-auditory structures of e) the amygdala (Amyg) as well as f) the preoptic area of the anterior hypothalamus (PO/AH) are indicated in the images. Masseter muscle (M) is indicated in image a) on the CN level, used for normalization of image brightness within each slice. (Images were taken from a preliminary study to establish the MEMRI method performed on untreated animals).

Fig 2. Auditory thresholds before and after damage of the auditory periphery.

Hearing thresholds (mean±S.E.) in mice 48 hours after a threefold injection (applied every 48 hours) of kanamycin (1 mg/g body weight) and bumetanide (0.05 mg/g body weight) (kanamycin-treated group, n = 7) in relation to normal hearing control animals (normal hearing group, n = 8). Graph further indicates the mean threshold shift of the experimental group. Asterisks point to significant differences between normal hearing and hearing impaired animals for all investigated frequencies between 4 and 20 kHz (p<0.001).

Fig 3. Mean MEMRI contrast of experimental groups.

Relative manganese-enhanced MRI-T1-contrast (mean±S.E.) for the investigated auditory and non-auditory brain structures in hearing-impaired control (black columns) compared to salicylate-treated (white columns) mice. Both groups had a profound hearing loss due to peripheral damage by kanamycin/bumetanide treatment before experiments. Asterisks indicate significant differences between the groups (p<0.05). Investigated structures: dorsal cochlear nucleus (DCN), ventral cochlear nucleus (VCN), superior olivary complex (SOC), inferior colliculus (IC), medial geniculate body (MGB), auditory cortex (AC), preoptic area of the anterior hypothalamus (PO/AH), Amygdala (Amyg).