1三軍總醫院耳鼻喉頭頸外科部 2國防醫學院耳鼻喉學科 探討Dextromethorphan對於 噪音性聽損動物模式之作用及機轉研究 To Investigate the Effect and Mechanism of Dextromethorphan on Noise-Induced Hearing Loss Animal Model 陳信傑1,2 王皓1 王智弘1,2,3,4 1三軍總醫院耳鼻喉頭頸外科部 2國防醫學院耳鼻喉學科 3國防醫學院醫學科學研究所 4國軍台中總醫院

Introduction Dextromethorphan (DXM) has been a widely used non-opioid, non‑narcotic and over-the-counter (OTC) antitussive for over 50 years. DXM binds to several other receptors and transporters in the brain and acts as a low-affinity uncompetitive N-methyl-D-aspartate receptor (NMDA) antagonist a high affinity sigma-1 receptor agonist a voltage-gated calcium channel (VGCC) antagonist. DXM has significant neuroprotective properties in many in vitro and in vivo models of central nervous system injury and neurodegenerative diseases.

DXM Approved Indications Potential Therapeutic Uses Cough suppression Patented in 1954 as an antitussive Approved by the FDA in 1958 for OTC use Preferentially act within the brainstem cough network rather than at peripheral sites to suppress cough Pseudobulbar affect (假性延髓情緒) Depression Stroke Traumatic brain injury Seizure Pain Post-operative pain Neuropathic pain Methotrexate neurotoxicity Parkinson's disease Autism

Proposed molecular targets of DXM following ischemic stroke

Aim Hearing loss Tinnitus DXM The association between DXM and Noise-induced Hearing Loss and Tinnitus Hearing loss Tinnitus DXM Noise

Materials and Methods - Mice：CBA/CaJ ( 8 weeks ) Noise exposure & Dextromethorphan injection or delivery - Mice：CBA/CaJ ( 8 weeks ) - Noise：118 dB SPL wide band noise, 3h - Intervention: (1) IP injection (DXM hydrobromide, Sigma) (0.03 mg/g) (2) Round window delivery - 於噪音暴露前2天、當天、噪音暴露後2天施打DXM hydrobromide

將小鼠耳蝸鑽洞至能清楚看見Round window，使藥物較能順利透過round window membrane進入耳蝸 Gelfoam 將滴有藥物之gelfoam塞入round window Tympanic bulla Stapedial artery Round window Cochlea 0.05～0.1 cm Gelfoam + 7~8 ul dextromethorphan fluid Absorbent paper points 將小鼠耳蝸鑽洞至能清楚看見Round window，使藥物較能順利透過round window membrane進入耳蝸 將裁剪好的gelfoam滴上藥物 (使gelfoam能濕潤變形) 將含有藥物之gelfoam放入round window洞口 利用鑷子或紙針輕推gelfoam使其能直接貼在round window membrane

Results 42 dB Vs 48 dB

Middle turn 30 days post-noise Normal PBS Detromethorphan Mice：CBA/CaJ Noise：118dB 3 hrs

CtBP2: ribbon; PSD95: postsynaptic receptor 噪音DXM治療的小鼠與噪音PBS組相比呈現較多且一起出現的ribbon(CtBP2)和post-synaptic receptor(PSD95) synaptic complex (paired ribbons and glutamate receptor patches)，而在噪音PBS組這兩者在染色呈現分開的現象。

Discussion Origin of noise-induced cochlear hearing loss and tinnitus NMDA receptor activation and auditory nerve excitation Damage to the IHC synapses and deafferentation NMDA antagonist Ketamine, Esketamine (AM-101), PCP ligand (MK801) and DXM Cochlear NMDA receptors as a therapeutic target of noise-induced tinnitus (AM-101). Cell Physiol Biochem 2015 Effect of ketamine, DXM, and MK801 on cochlear dysfunction induced by transient ischemia. Ann Otol Rhinol Laryngol 2002

Conclusions DXM had a trend to attenuate the hearing loss due to restoring the synaptic complex connection after noise-induced animal model. Further human clinical trials are expected to be applied in noise-induced hearing loss.

Thanks for your attention!