title: Ebselen treatment reduces noise induced hearing loss via the mimicry and induction of glutathione peroxidase.
abstract: Previous studies indicate that noise induced hearing loss (NIHL) involves a decrease in glutathione peroxidase (GPx) activity and a subsequent loss of outer hair cells (OHC). However, the cellular localization of this GPx decrease and the link to OHC loss are still poorly understood. In this report, we examined the cellular localization of GPx (GPx1, GPx 3 and GPx 4) in F-344 rat before and after noise exposure and after oral treatment with ebselen, a small molecule mimic of GPx activity. Results indicate that GPx1 is the major isoform within the cochlea and is highly expressed in cells of the organ of Corti, spiral ganglia, stria vascularis, and spiral ligament. Within 5h of noise exposure (4h at 113 dB, 4-16 kHz), significant OHC loss was already apparent in regions coincident with the 8-16 kHz region of the cochlea. In addition, the stria vascularis exhibited significant edema or swelling and a decrease in GPx1 immunoreactivity or fluorescent intensity. Treatment with ebselen (4 mg/kg p.o.) before and immediately after noise exposure reduced both OHC loss and the swelling of the stria vascularis typically observed within 5h post-noise exposure. Interestingly, GPx1 levels increased in the stria vascularis after noise and ebselen treatment vs noise and vehicle-only treatment, and exceeded baseline no noise control levels. These data indicate that ebselen acts to prevent the acute loss of OHCs and reduces the acute swelling of the stria vascularis by two potential mechanisms: one, as a ROS/RNS scavenger through its intrinsic GPx activity, and two, as a stimulator of GPx1 expression or activity. This latter mechanism may be due to the preservation of endogenous GPx1 from ROS/RNS induced degradation and/or the stimulation of GPx1 expression or activity.
authors.affiliation: Sound Pharmaceuticals, Inc., Research and Development, 4010 Stone Way N Suite 120, Seattle, WA 98103, USA. jkil@soundpharmaceuticals.com
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kil
authors.forename: Carol
authors.initials: C
authors.lastname: Pierce
authors.forename: Huy
authors.initials: H
authors.lastname: Tran
authors.forename: Rende
authors.initials: R
authors.lastname: Gu
authors.forename: Eric D
authors.initials: ED
authors.lastname: Lynch
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001309:Auditory Threshold / Q000187:drug effects; D001393:Azoles / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000096:biosynthesis*; D018072:Hair Cells, Auditory, Outer / Q000201:enzymology / Q000473:pathology; D006317:Hearing Loss, Noise-Induced / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007527:Isoenzymes / Q000096:biosynthesis; D054833:Isoindoles; D008954:Models, Biological; D018716:Molecular Mimicry; D016566:Organoselenium Compounds / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000975:Antioxidants; D001393:Azoles; D016166:Free Radical Scavengers; D007527:Isoenzymes; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722069:Gpx1 protein, rat