Cisplatin ototoxicity involves organ of Corti, stria vascularis and spiral ganglion: modulation by alphaMSH and ORG 2766.
It has been shown that alphaMSH and the nonmelanotropic ACTH/MSH(4-9) analog ORG 2766 can ameliorate cisplatin-induced neurotoxicity and ototoxicity. Here, we investigated whether these peptides delay the occurrence of the cisplatin-induced shift in auditory threshold, and whether they affect the subsequent recovery of cochlear potentials. Chronically implanted round window electrodes were used to obtain daily recordings of auditory nerve compound action potentials (CAP) and cochlear microphonics at frequencies ranging from 2 to 16 kHz. Cisplatin (1.5 mg/kg i.p.) plus alphaMSH, ORG 2766 (75 mug/kg s.c.), or saline were injected daily until the 40-dB CAP threshold shift at 8 kHz was reached. Endocochlear potential (EP) was measured either 1-2 days or 28 days later, followed by morphometric analysis of the cochlea. Peptide cotreatment did not consistently delay the threshold shift; however, the CAP threshold recovered faster and to a greater extent, with the potency order being alphaMSH > ORG 2766 > saline. Significant recovery at the 2 highest frequencies was seen in the alphaMSH-treated animals only. CAP amplitude at high sound pressures, which depends more on nerve function than on outer hair cell (OHC) function, decreased severely in all groups but recovered significantly in the alphaMSH- and completely in the ORG-2766-cotreated group. EP was significantly lower in the first days after the threshold shift but had completely recovered at 28 days. Morphometric analysis of the spiral ganglion also indicated involvement of ganglion cells. OHC loss was most severe in the basal turn of saline-cotreated animals. These data suggest that the cisplatin-induced acute threshold shift might be due to reversible strial failure, whereas subsequent OHC survival determines the final degree of functional recovery. Both OHC loss and neuronal function were ameliorated by peptide cotreatment.
Hamers
Frank P T
FP
Hearing Research Laboratories, Department of Oto-Rhino-Laryngology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. f.p.t.hamers@med.uu.nl
Wijbenga
Jeroen
J
Wolters
Francisca L C
FL
Klis
Sjaak F L
SF
Sluyter
Steven
S
Smoorenburg
Guido F
GF
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001300:Audiometry, Evoked Response; D001309:Auditory Threshold / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D003056:Cochlear Nerve / Q000187:drug effects / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D034381:Hearing Loss / Q000139:chemically induced / Q000517:prevention & control*; D009925:Organ of Corti / Q000187:drug effects; D010446:Peptide Fragments / Q000627:therapeutic use*; D013136:Spiral Ganglion / Q000187:drug effects; D013316:Stria Vascularis / Q000187:drug effects; D000521:alpha-MSH / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D010446:Peptide Fragments; C013765:Org 2766; D000521:alpha-MSH; D000324:Adrenocorticotropic Hormone; D002945:Cisplatin