On Various Investigations of the Organ of Corti, from the Effects of Quinine and Quinidine on the Electrical Signature of Outer Hair Cells, to a Method to Prevent Cisplatin Ototoxicity and a New Theory of the Physiological Basis of Electromotility, and the X-Ray Crystalography of Prestin

Jorge Enrique Delgado-Hachmeister, M.D., M.P.H, M.Sc., Ph.D. 1,2, Cindy Shope 5, Daniel Chelius 3, M.D., John S. Oghalai 4, M.D., Raye L. Alford, Ph.D. 5, Bobby R. Alford† 5, M.D., Brenda Farrell, Ph.D 5, Lucy Handscomb, Ph.D. 2, Jonathan Ashmore, Ph.D. 2, Dan Jagger, Ph.D. 2, Issam Saliba, M.D. 7, Sengyoth Vilaysane, M.D. 1, Thomas Lenarz, MD 8, Anat Shahar, Ph.D. 6 Jorge E. Delgado-Hachmeister, M.D. La Salle University Mexican Faculty of Medicine Islas Marianas No. 9, Fracc. Residencial Campestre Chiluca, Atizapán de Zaragoza, C.P. 52930, Edo. de Mex., México Mobile: + 52 55 10 52 81 58 Home Phone: + 52 55 50 19 17 36 e-mail: jorgeenriquedelgadoh@hotmail.com Abstract We decided to investigate if quinine modifies the nonlinear capacitance of the mammalian outer hair cell of the hearing organ of Corti. We used isolated outer hair cells of guinea pigs and performed electrophysiological recordings. We tracked the Voltage at Peak Capacitance of the outer hair cell at different quinine concentrations and also measured the modifications of the bell-shaped curve of the outer hair cell under different quinine concentrations. We also studied if quinine induces apoptosis of the outer hair cell. We show that quinine shifts this bell-shaped curve towards depolarized potentials (>90 mV) and induces a small reduction on the gain (up to 13%). The shifts are fully reversible at low concentrations (< 1 mM) but only partially reversible at high concentrations (> 5 mM). A histological study of guinea pig OHCs confirms that quinine triggers apoptosis in a concentration dependent manner and produces large pores in the plasma membrane at high concentrations. At therapeutic concentrations of quinine that are used to treat malaria (0.04 mM) we find that quinine shifts the voltage at peak capacitance by 1.5 to 3.5 mV. This is significantly greater than observed for chloropromazine ( < 1 mV) and furosemide (no shift) at their relevant clinical concentrations. We demonstrate for the first time that the plausible mechanism by which quinine increases hearing thresholds is by partitioning into the membrane of OHCs where it affects the membrane-based motor mechanism underlying electromotility. Key Words: outer hair cells, voltage at peak capacitance, electromotility, apoptosis, quinine, amphipaths While the actions of quinine on outer hair cell physiology of mammalians have been previously investigated, it remains unknown, the precise mechanism by which quinine induces reversible tinnitus and hearing loss. Also it is unknown why quinine produces in some rare cases irreversible hearing loss. Here we provide definitive evidence that quinine at therapeutic levels for the treatment of Falciparum malaria modifies outer hair cell physiology and electromotilty and also triggers apoptosis in outer hair cells. Proving that the main mechanism by which quinine modifies hearing thresholds is by modifying outer hair cell physiology, probably by interacting with prestin. Level of Evidence: NAPlease go through this manuscript since it describes much better our findings. https://u.pcloud.link/publink/show?code=XZaSAQVZmFWjgk67A4XDbEl4wmxVKLVtlFvy