Aminoglycosides (AG) such as amikacin are commonly used in cystic fibrosis patients with opportunistic pulmonary infections including multi-drug resistant mycobacterium tuberculous and non-tuberculous mycobacterium. Unfortunately, this class of drugs is known to cause peripheral damage to the cochlea leading to hearing loss that can fluctuate and become permanent over time or multiple exposures. However, whether amikacin can lead to central auditory dysfunction like hyperacusis (increased sensitivity to sound) or tinnitus (perception of sound in the absence of acoustic stimulation) is not well-described in the literature. Thus, an animal model needs to be developed that documents these side effects in order to develop therapeutic solutions to reduce AG-induced auditory dysfunction. Here we present pioneer work in mice which demonstrates that amikacin can lead to fluctuating behavioral evidence of hyperacusis and tinnitus as assessed by the acoustic startle reflex. Additionally, electrophysiological assessments of hearing via auditory brainstem response demonstrate increased central activity in the auditory brainstem. These data together suggest that peripheral AG-induced dysfunction can lead to central hyperactivity and possible behavioral manifestations of hyperacusis and tinnitus. Importantly, we demonstrate that ebselen, a novel investigational drug that acts as both an antioxidant and anti-inflammatory, can mitigate AG-induced hyperacusis.

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Nutrigenomic studies were conducted to uncover the mechanism of action for the hypoglycemic and insulin sensitizing effects of UP780. From high fat diet-induced obesity mouse model for UP780, livers and white adipose tissues (WAT) from groups of lean control, high fat diet (HFD), and HFD treated with UP780 were collected for microarray study. Microarray generated gene expression changes were applied to Ingenuity Pathway Analysis for changes in canonical metabolic and signaling pathways. Microarray was validated by quantitative reverse transcriptase-polymerase chain reaction (QPCR), Western blots, liver triglyceride, liver cholesterol, liver steatosis, and insulin ELISA. UP780 treatment decreased liver gene expressions for multiple enzymes involved in fatty acid biosynthesis and triglyceride production. UP780 treatment increased gene expressions globally for the insulin receptor signaling pathway in WAT. Both liver triglyceride and liver cholesterol levels were significantly reduced by UP780 over HFD. The reduction of liver fat was confirmed by microscopic analysis of liver steatosis. Finally, UP780 significantly decreased fasting plasma insulin level over HFD. The mechanism of action for UP780 indicated a reduction of liver fat accumulation and an enhancement in adipose tissue insulin signaling pathway. This provided mechanistic explanation for the in vivo UP780 effects of enhanced insulin sensitiveity and decreased blood glucose in mouse diabetes and prediabetes models.

Aminoglycosides (AG) antibiotics are a common treatment for recurrent infections in cystic fibrosis (CF) patients. AGs are highly ototoxic, resulting in a range of auditory dysfunctions. It was recently shown that the acoustic startle reflex (ASR) can assess behavioral evidence of hyperacusis and tinnitus in an amikacin cochleotoxicity mouse model. The goal of this study was to establish if tobramycin treatment led to similar changes in ASR behavior and to establish whether ebselen can prevent the development of these maladaptive neuroplastic symptoms. CBA/Ca mice were divided into three groups: Group 1 served as a control and did not receive tobramycin or ebselen, Group 2 received tobramycin (200 mg/kg/s.c.) and the vehicle (DMSO/saline/i.p.) daily for 14 continuous days, and Group 3 received the same dose/schedule of tobramycin as Group 2 and ebselen at (20 mg/kg/i.p.). Auditory brainstem response (ABR) and ASR hearing assessments were collected at baseline and 2, 6, 10, 14, and 18 weeks from the start of treatment. ASR tests included input/output (I/O) functions which assess general hearing and hyperacusis, and Gap-induced prepulse inhibition of the acoustic startle (GPIAS) to assess tinnitus. At 18 weeks, histologic analysis showed predominantly normal appearing hair cells and spiral ganglion neuron (SGN) synapses. Following 14 days of tobramycin injections, 16 kHz thresholds increased from baseline and fluctuated over the 18-week recovery period. I/O functions revealed exaggerated startle response magnitudes in 50% of mice over the same period. Gap detection deficits, representing behavioral evidence of tinnitus, were observed in a smaller subset (36%) of animals. Interestingly, increases in ABR wave III/wave I amplitude ratios were observed. These tobramycin data corroborate previous findings that AGs can result in hearing dysfunctions. We show that a 14-day course of tobramycin treatment can cause similar levels of hearing loss and tinnitus, when compared to a 14-day course of amikacin, but less hyperacusis. Evidence suggests that tinnitus and hyperacusis might be common side effects of AG antibiotics.