Prophylactic and therapeutic functions of drug combinations against noise-induced hearing loss

Abstract

Noise is the most common occupational and environmental hazard. Noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit, after age-related hearing loss (presbycusis). Although promising approaches have been identified for reducing NIHL, currently there are no effective medications to prevent NIHL. Development of an efficacious treatment has been hampered by the complex array of cellular and molecular pathways involved in NIHL. We turned this difficulty into an advantage by asking whether NIHL could be effectively prevented by targeting multiple signaling pathways with a combination of drugs already approved by U.S. Food and Drug Administration (FDA). We previously found that antiepileptic drugs blocking T-type calcium channels had both prophylactic and therapeutic effects for NIHL. NIHL can also be reduced by an up-regulation of glucocorticoid (GC) signaling pathways. Based on these findings, we tested a combination therapy for NIHL that included ethosuximide and zonisamide (anticonvulsants) and dexamethasone and methylprednisolone (synthetic GCs) in mice under exposure conditions typically associated with dramatic permanent threshold shifts (PTS). We first examined possible prophylactic effects for each drug when administered alone two hours before noise, and calculated the median effective dose (ED50). We then tested for synergistic effects of two-drug combinations (anticonvulsant + GC), and identified combinations with the strongest synergy against NIHL, based on a previously established combination index (CI) metric. We repeated similar tests to determine their therapeutic effects when administered the same drugs 24 hours after the noise exposure. Our study shows the feasibility of developing pharmacological intervention in multiple pathways, and discovering drug combinations with optimal synergistic effects in preventing permanent NIHL.

Cisplatin‐Induced Ototoxicity and the Effects of Intratympanic Diltiazem in a Mouse Model

“…A recent study demonstrated that calciumblocking anticonvulstants can be protective against noiseinduced hearing loss. 24 Together these results provide strong support for use of CCBs as otoprotective agents against ototoxicity. In this study, diltiazem was used because it is an antagonist of L-type calcium channels, which provided a targeted approach to prevent calcium-mediated apoptosis of cisplatin ototoxicity.…”

Protection from noise-induced hearing loss with Src inhibitors

“…Antioxidant compounds [20][21][22][23][24][25][26][27][28], glutamate antagonists [56], calcium channel blockers [57], JNK inhibitors [58,59] and glucocorticoid compounds [57,60] have all demonstrated protective or therapeutic effects against NIHL, and do not represent an exhaustive list of the classes of compounds that have been tested. Src inhibitors have clearly demonstrated a potential protective effect when the compound is delivered directly into the cochlea.…”

T-type calcium channel blockers as neuroprotective agents

“…Previously, only the L-type CCBs appeared to reduce the auditory loss [76]. Our recent studies found that trimethadione and ethosuximide were protective of auditory hair cells and spiral ganglion neurons (SGNs) [59,5]. However, similar to in vitro studies, it was unclear whether this neuroprotection in vivo was due to blocking of T-type calcium channels or regulating other signaling pathways.…”

“…As we will now discuss, blockers for T-type calcium channels have been developed to treat various diseases. These blockers show neuroprotective effects both in vitro and in vivo [59,80,42,5]. However, molecular mechanisms underlying their neuroprotective effects are still unclear.…”