Cisplatin Ototoxicity Involves Organ of Corti, Stria Vascularis and Spiral Ganglion: Modulation by αMSH and ORG 2766

Abstract

It has been shown that αMSH 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 αMSH, ORG 2766 (75 µg/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 αMSH > ORG 2766 > saline. Significant recovery at the 2 highest frequencies was seen in the αMSH-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 αMSH- 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.

Time course of cochlear electrophysiology and morphology after combined administration of kanamycin and furosemide

“…Recordings were performed as described in detail by Hamers et al (2003). The animal, positioned in a soundproof chamber, was awake; it was lightly restrained in a custom-made tight cloth jacket with the eyes covered and the right pinna and ear canal exposed.…”

Genetic dependence of cochlear cells and structures injured by noise

“…Melanin is produced by melanocytes, including strial intermediate cells. Eumelanin, the predominant form in B6 mice, is suggested to be protective against cochlear injury (Conlee et al, 1988;Barrenas and Lindgren, 1991;Barrenas, 1997), and alpha melanocyte stimulating hormone (αMSH), which partly mediates the production of eumelanin, may have additional protective effects within the cochlea (Hamers et al, 2002;Wolters et al, 2003). Unlike B6 mice, CBA mice carry the dominant agouti trait (A) and may produce the agouti protein within the cochlea.…”

Chemical exposure and hearing loss

“…[22][23][24] The ototoxicity induced by platinumderivates is characterized by the loss of cochlear hair cells and cells of the spiral ganglion and by degeneration of the stria vascularis. 25 As with aminoglycosides, hearing impairment induced by platinum-derivates covers the range from high to low frequencies. 26 An exacerbation of cisplatin ototoxicity was observed with exposure to concomitant moderate to high noise levels in chinchilla and guinea pigs.…”