Co-administration of the neurotrophic ACTH(4-9) analogue, ORG 2766, may reduce the cochleotoxic effects of cisplatin.
In this study the effect of the neurotrophic ACTH(4-9) analogue, ORG 2766, on cisplatin cochleotoxicity was investigated with both light- and transmission electron microscopy. Guinea pigs were treated with either cisplatin+ORG 2766 (n = 11) or cisplatin + physiological saline (n = 9). All animals treated with cisplatin + physiological saline showed complete loss of outer hair cells (OHC) and degeneration of the organ of Corti in the basal cochlear turns, while partial OHC loss was found in the middle and apical turns. The inner hair cells (IHC) and other cochlear tissues were not affected. Eight animals from the group treated with cisplatin + ORG 2766 demonstrated similar pathological changes, but to a lesser degree, especially in the middle turns. The three remaining animals demonstrated no cochlear alterations at all, light-microscopically, and only minor subcellular changes in the OHCs at the ultrastructural level. Electrophysiologically, these three animals showed normals compound action potential (CAP) amplitudes at stimulus frequencies from 0.5 to 16 kHz and normal cochlear microphonics (CM) in the frequency range from 0.5 to 8 kHz. The other animals treated with cisplatin + ORG 2766 showed a severe loss in their CAPs and CM, except for one showing intermediate loss. All animals from the group treated with cisplatin alone showed a severe loss in their CAPs and CM. Endolymphatic hydrops was present in all animals from the cisplatin- and the cisplatin + ORG 2766-treated groups. These data indicate that daily, concomitant administration of ORG 2766 may reduce OHC loss and subsequent degeneration of the organ of Corti in cisplatin-treated guinea pig cochleas.
de Groot
J C
JC
Department of Otorhinolaryngology, University Hospital Utrecht, The Netherlands. j.c.m.j.degroot@kmb.azu.nl
Hamers
F P
FP
Gispen
W H
WH
Smoorenburg
G F
GF
D000161:Acoustic Stimulation; D000200:Action Potentials / Q000187:drug effects; D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002452:Cell Count; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D004347:Drug Interactions; D004594:Electrophysiology; D018870:Endoplasmic Reticulum, Rough / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006056:Golgi Apparatus / Q000187:drug effects; D006168:Guinea Pigs; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D012462:Saline Solution, Hypertonic / Q000008:administration & dosage; D016610:Tissue Embedding; D003689:Vestibular Nucleus, Lateral / Q000166:cytology / Q000187:drug effects
D000927:Anticonvulsants; D000970:Antineoplastic Agents; D010446:Peptide Fragments; D012462:Saline Solution, Hypertonic; C013765:Org 2766; D000324:Adrenocorticotropic Hormone; D002945:Cisplatin