Abstract
Tripterygium glycosides (TG) is isolated from an extensively used traditional Chinese medicine herb tripterygium roots and has been extensively used in the treatment of rheumatoid arthritis, nephrotic syndrome, hyperthyroidism and other diseases due to its anti-inflammatory and immunosuppressive effects. Hearing toxicity has been recently associated with TG use in human patients. In this study, authors assessed hearing toxicity and possible molecular toxic mechanisms of TG in a whole animal model. The maximum non-lethal concentration (MNLC) of TG on the zebrafish was 21 mg/L. TG induced zebrafish hair cell loss in a dose-dependent manner (p<0.001), and the saccular otolith size reduction when treated at MNLC (p<0.01). TG treatment resulted in sound-stimulated zebrafish movement reduction (p<0.001); and the rollover zebrafish percentages were elevated as TG treatment concentrations moved up. Following TG treatment, mRNA levels of the zebrafish hearing organ development genes eya1 and val were remarkably downregulated, and the expression of apoptosis-associated genes bax and caspase3 was significantly enhanced (p<0.05). These findings confirm the hearing toxicity of TG and suggest its toxic mechanisms probably are through suppressing hearing cell development and promoting hearing cell apoptosis. Authors recommend zebrafish assay as a quick and reliable screening test of hearing toxicity for drugs and health products.
Highlights
Hearing loss is one of the major health problems worldwide [1]
Tripterygium glycosides (TG)-induced death was observed in a dose-dependent manner, and no survival could be seen with TG above 50 mg/L and no death occurred with TG below 10 mg/L
The maximum non-lethal concentration (MNLC) was 21 mg/L for TG, and 4 concentrations at 2.63, 5.25, 10.5, and 21 mg/L were selected for the hearing toxicity tests
Summary
A variety of marketed drugs such as streptomycin, gentamycin and cisplatinum are known to cause hearing toxicity in humans [2, 3]. Hearing toxicity induced by Chinese medicines, plants-derived drugs and health products has been paid attention [4]. The Food and Drug Administration (FDA) does not require hearing toxicity screening in either the preclinical or clinical testing stages of drug development, and there are no Good Clinical Practice (GCP) guidelines in place for hearing toxicity identification [5]. ICH guidelines call for a core battery of nonclinical safety pharmacology studies for human pharmaceuticals, but do not include auditory testing [6]. The absence of standard testing protocols to identify ototoxic effects at the pre-clinical stage is a major reason for the incidence of these adverse effects in the clinic [7]
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