Inhibition of mTOR by Rapamycin Results in Auditory Hair Cell Damage and Decreased Spiral Ganglion Neuron Outgrowth and Neurite Formation In Vitro.
Rapamycin is an antifungal agent with immunosuppressive properties. Rapamycin inhibits the mammalian target of rapamycin (mTOR) by blocking the mTOR complex 1 (mTORC1). mTOR is an atypical serine/threonine protein kinase, which controls cell growth, cell proliferation, and cell metabolism. However, less is known about the mTOR pathway in the inner ear. First, we evaluated whether or not the two mTOR complexes (mTORC1 and mTORC2, resp.) are present in the mammalian cochlea. Next, tissue explants of 5-day-old rats were treated with increasing concentrations of rapamycin to explore the effects of rapamycin on auditory hair cells and spiral ganglion neurons. Auditory hair cell survival, spiral ganglion neuron number, length of neurites, and neuronal survival were analyzed in vitro. Our data indicates that both mTOR complexes are expressed in the mammalian cochlea. We observed that inhibition of mTOR by rapamycin results in a dose dependent damage of auditory hair cells. Moreover, spiral ganglion neurite number and length of neurites were significantly decreased in all concentrations used compared to control in a dose dependent manner. Our data indicate that the mTOR may play a role in the survival of hair cells and modulates spiral ganglion neuronal outgrowth and neurite formation.
Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland ; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
Katharina
K
Leitmeyer
Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland ; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
Andrea
A
Glutz
Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland ; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
Vesna
V
Radojevic
Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland ; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
Cristian
C
Setz
Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland ; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
Nathan
N
Huerzeler
Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland ; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
Helen
H
Bumann
Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland ; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
Daniel
D
Bodmer
Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland ; Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
Yves
Y
Brand
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D006198:Hair Cells, Auditory / Q000201:enzymology* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D016501:Neurites / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000009:adverse effects* / Q000494:pharmacology; D013136:Spiral Ganglion / Q000201:enzymology* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D046912:Multiprotein Complexes; C546845:mTOR protein, rat; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus