Dextromethorphan To Investigate the Effect and Mechanism of

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 • 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) Potential Therapeutic Uses • 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 The association between DXM and Noise-induced Hearing Loss and Tinnitus DXM Hearing loss Tinnitus Noise

Materials and Methods • Noise exposure & Dextromethorphan injection or delivery - Mice：CBA/Ca. J ( 8 weeks ) - Noise： 118 d. B SPL wide band noise, 3 h - 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

將滴有藥物之gelfoam塞入round window + 7~8 ul dextromethorphan fluid Round window Gelfoam 0. 05～ 0. 1 cm Stapedial artery Cochlea Abs orbe n t pa per poin ts Tympanic bulla • 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 d. B Vs 48 d. B

30 days post-noise Normal PBS Detromethorphan Middle turn Mice：CBA/Ca. J Noise： 118 d. B 3 hrs

Ct. BP 2: ribbon; PSD 95: 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(Ct. BP 2)和postsynaptic receptor(PSD 95) 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 (MK 801) and DXM – Cochlear NMDA receptors as a therapeutic target of noiseinduced tinnitus (AM-101). Cell Physiol Biochem 2015 – Effect of ketamine, DXM, and MK 801 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 noiseinduced animal model. • Further human clinical trials are expected to be applied in noise-induced hearing loss.

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