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Assay for compounds that protect against sensory hair cell death and compounds identified by same

a technology of sensory hair cell death and assay, which is applied in the direction of diagnostic recording/measuring, ultrasonic/sonic/infrasonic diagnostics, vaccination/ovulation diagnostics, etc. it can prevent, inhibit or reduce the damage or death of sensory hair cells

Inactive Publication Date: 2006-08-24
FRED HUTCHINSON CANCER RES CENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods for identifying compounds that can protect against sensory hair cell damage or death caused by noxious stimuli. The methods involve labeling the lateral line hair cells of zebrafish with a non-toxic label, and then contacting the zebrafish with a test compound and a noxious stimulus. The compounds that decrease, inhibit or prevent sensory hair cell damage or death are identified based on the number of live lateral line hair cells compared to a control group. The invention also includes several compounds that have been identified as protective against ototoxic drugs, which can cause damage or death of sensory hair cells. These compounds can be administered to prevent ototoxicity.

Problems solved by technology

The incidence of vestibulotoxic effects of such drugs on patient populations has been less well studied.
None of the foregoing references disclose using zebrafish for screening for compounds that inhibit or prevent ototoxicity induced by one or more noxious stimuli.

Method used

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  • Assay for compounds that protect against sensory hair cell death and compounds identified by same
  • Assay for compounds that protect against sensory hair cell death and compounds identified by same
  • Assay for compounds that protect against sensory hair cell death and compounds identified by same

Examples

Experimental program
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example 1

Methods for Identifying Protective Compounds

Animals

[0139] Zebrafish embryos were produced by paired matings of adult fish maintained at 28.5° C. in the University of Washington zebrafish facility. Beginning at 4 days post fertilization (dpf), larvae were fed live paramecia. Larvae were maintained at a density of 50 per 100 mm2 petri dish in embryo medium (1 mM MgSO4, 120 μM KH2PO4, 74 μM Na2 HPO4, 1 mM CaCl2, 500 μM KCl, 15 μM NaCl, and 500 μM NaHCO3 in dH2O) in a tissue incubator at 28.5° C. All animal procedures were approved by the University of Washington Institutional Animal Care and Use Committee.

Vital Dye Staining

[0140] Larvae were placed in a transfer device fashioned from a 50 ml conical tube with one end cut off and a mesh cover at the bottom. FM 1-43 (n-(3-triethylammoniumpropyl)-4-(4-dibutylamino]-styryl)pyridinium dibromide; Molecular Probes, Eugene, Oreg.) labeling of lateral line neuromasts was achieved by immersing free swimming larvae in 3 μM FM 1-43 in embryo...

example 2

Identification of Long-Lasting Protective Compounds that Do Not Inhibit Mechanotransduction-Dependent Activity

Use of Small Molecule Screens to Identify Otoprotective Compounds Using the Lateral Line Hair Cells of Zebrafish

[0144] In order to identify compounds that protect hair cells of the lateral line from the toxic effects of the aminoglycoside neomycin, 10,960 small molecules were screened. 5 dpf larvae were double labeled with the fluorescent dyes FM 1-43 and Yo-Pro-1, pretreated with the compounds at a dose of 10 μm, exposed to 200 mM neomycin, and their hair cells evaluated after 1 hour, FIG. 1.

[0145] Two (2) of 10,960 compounds were identified in the screen to protect hair cells from neomycin induced hair cell death, 2-({[(4-chlorophenyl)amino]carbonyl}amino)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (C17H19ClN4O2S) (F5) and 2-{[({2,2,2-trichloro-1-[(4-methoxybenzoyl)amino]ethyl}amino)carbonothioyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxami...

example 3

FDA-Approved Protective Compounds Identified Via High-Throughput Screening

[0151] A library of 1040 FDA approved compounds (NINDS Custom Collection II, Microsource, Inc.) were screened using a high-throughput assay. This screen identified seven drugs that protect against aminoglycoside-induced hair cell death. [0152] 1. Cepharanthine is a biscoclaurine alkaloid from Stephania cepharantha. It is thought to have membrane-stabilizing activity and has been used for the treatment of nasal allergy and snake venom-induced hair cell death. [0153] 2. Amsacrine is an acridine dye derivative that is thought to inhibit topoisomerase II and cause DNA strand breaks. [0154] 3. Drofenine is an anticholinergic drug that acts on smooth muscles and is used as an antispasmodic. It acts on M1 and M2 muscarinic receptors and also has been shown to have inhibitory effects on butyrylcholinesterase. [0155] 4. Phenoxybenzamine is an alpha-adrenergic blocker used for hypertension. [0156] 5. N,N-hexamethylenea...

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Abstract

The present invention provides methods of identifying compounds that protect against ototoxicity induced by one or more noxious stimuli, and methods of treating an individual with compounds identified using the present screening methods. Also provided are compounds demonstrated to have otoprotective effects.

Description

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0001] This invention was made with government support under grant numbers F32 DC007224 and R01 DC005987 awarded by the National Institutes of Health. The government may have certain rights in this invention.BACKGROUND OF THE INVENTION [0002] Aminoglycosides are clinically used drugs that cause dose-dependent sensorineural hearing loss (Smith et al., New Engl J Med, (1977) 296:349-53) and are known to kill hair cells in the mammalian inner ear (Theopold, Acta Otolaryngol (1977) 84:57-64). In the U.S, over 2,000,000 people receive treatment with aminoglycosides per year. The clinical efficacy of these drugs in treating resistant bacterial infections and their low cost globally account for their continued use and need. Cisplatin, a chemotherapeutic agent, is also used for its benefit to life despite its toxic effects on the hair cells of the inner ear. High frequency hearing loss (>8 kHZ) h...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K49/00
CPCA61K49/0006
Inventor OU, HENRY C.SANTOS, FELIPERUBEL, EDWIN W.RAIBLE, DAVID W.SIMON, JULIAN A.
Owner FRED HUTCHINSON CANCER RES CENT
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