Abstract
Carboplatin produces an unusual pattern of damage in the chinchilla inner ear, characterized by early destruction of type I afferent fibers and preferential loss of type I hair cells in the vestibular end organs and inner hair cells (IHCs) in the cochlea. In the present study, we investigated a potential role of calpains, a family of calcium-activated proteases, in carboplatin ototoxicity. Chinchillas received carboplatin (100 mg/kg IP) and were sacrificed 12, 24, 48, or 72 h later for morphological evaluation or immunocytochemistry. Nerve fibers and myelin were the initial sites of increased calpain immunoreactivity (IR) and morphological damage. At 12 h, granular immunoreactive puncta were present within nerve fibers and their myelin sheaths in the spiral ganglion. In the habenula perforata, dense reaction product was present in large vacuoles in the myelin surrounding the nerve fibers. At 24 h, nerve fibers and myelin were destroyed in the habenula, and those in the spiral ganglion showed increased calpain IR and morphological damage. At 72 h, nerve fibers and myelin were completely destroyed. Calpain IR was not a prominent feature of IHCs, type I vestibular hair cells, or ganglion cells at any time after carboplatin. The results show a correlation between calpain IR and carboplatin-induced axon and myelin degeneration. We propose that calpain-induced axonopathy and myelinopathy are primary features of carboplatin ototoxicity in chinchilla.
Keywords: carboplatin, myelinopathy, axonopathy, calpain, ototoxicity, myelin
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Acknowledgements
This work was supported by NIDCD grant P01 DC03600-01A1 (RJS and SLM).
References
- 1.Aggarwal SK. A histochemical approach to the mechanism of action of cisplatin and its analogues. J. Histochem. Cytochem. 1993;41:1053–1073. doi: 10.1177/41.7.8515048. [DOI] [PubMed] [Google Scholar]
- 2.Aleu FP, Katzman R, Terry RD. Fine structure and electrolyte analyses of cerebral edema induced by alkyl tin intoxication. J. Neuropathol. Exp. Neurol. 1963;22:403–413. doi: 10.1097/00005072-196307000-00003. [DOI] [PubMed] [Google Scholar]
- 3.Banik NL, McAlhaney WW, Hogan EL. Calcium-stimulated proteolysis in myelin: evidence for a Ca2+-activated neutral proteinase associated with purified myelin of rat CNS. J. Neurochem. 1985;45:581–588. doi: 10.1111/j.1471-4159.1985.tb04026.x. [DOI] [PubMed] [Google Scholar]
- 4.Bartus RT, Elliott PJ, Hayward NJ, Dean RL, Harbeson S, Straub JA, Li Z, Powers JC. Calpain as a novel target for treating acute neurodegenerative disorders. Neurol. Res. 1995;17:249–258. doi: 10.1080/01616412.1995.11740322. [DOI] [PubMed] [Google Scholar]
- B.Bartus RT. The calpain hypothesis of neurodegeneration: Evidence for a common cytotoxic pathway. The Neurosci. 1997;3:314–327. [Google Scholar]
- 5.Besser R, Kramer G, Thumler R, Bohl J, Gutmann L, Hopf HC. Acute trimethyltin limbic–cerebellar syndrome. Neurology. 1987;37:945–950. doi: 10.1212/wnl.37.6.945. [DOI] [PubMed] [Google Scholar]
- C.Brana C, Benham CD, Sundstrom L. Calpain activation and inhibition in organotypic rat hippocampal slice cultures deprived of oxygen and glucose. Eur. J. Neurosci. 1999;11:2375–2384. doi: 10.1046/j.1460-9568.1999.00653.x. [DOI] [PubMed] [Google Scholar]
- 6.Cheng AG, Huang T, Stracher A, Kim A, Liu W, Malgrange B, Lefebvre PP, Schulman A, Van de Water TR. Calpain inhibitors protect auditory sensory cells from hypoxia and neurotrophin-withdrawal induced apoptosis. Brain Res. 1999;850:234–243. doi: 10.1016/S0006-8993(99)01983-6. [DOI] [PubMed] [Google Scholar]
- 7.Clerici WJ, Ross Jr B, Fechter LD. Acute ototoxicity of trialkyltins in the guinea pig. Toxicol. Appl. Pharmacol. 1991;109:547–556. doi: 10.1016/0041-008x(91)90017-9. [DOI] [PubMed] [Google Scholar]
- 8.Ding D, Wang J, Salvi RJ. Early damage in the chinchilla vestibular sensory epithelium from carboplatin. Audiol. Neurootol. 1997;2:155–167. doi: 10.1159/000259238. [DOI] [PubMed] [Google Scholar]
- 9.Ding D, Wang J, Zheng XY, Salvi RJ. Histochemical changes in the cochlea of chinchillas with carboplatin induced inner hair cell loss. Abstr. Assoc. Res. Otolaryngol. 1999a;613:155. [Google Scholar]
- 10.Ding DL, Wang J, Salvi R, Henderson D, Hu BH, McFadden SL, Mueller M. Selective loss of inner hair cells and type-I ganglion neurons in carboplatin-treated chinchillas. Mechanisms of damage and protection. Ann. N. Y. Acad. Sci. 1999b;884:152–170. doi: 10.1111/j.1749-6632.1999.tb08640.x. [DOI] [PubMed] [Google Scholar]
- 11.Faddis BT, Hasbani MJ, Goldberg MP. Calpain activation contributes to dendritic remodeling after brief excitotoxic injury in vitro. J. Neurosci. 1997;17:951–959. doi: 10.1523/JNEUROSCI.17-03-00951.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Gemba M, Nakatani E, Teramoto M, Nakano S. Effect of cisplatin on calcium uptake by rat kidney cortical mitochondria. Toxicol. Lett. 1987;38:291–297. doi: 10.1016/0378-4274(87)90011-7. [DOI] [PubMed] [Google Scholar]
- 13.Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J. Clin. Oncol. 1999;17:409–422. doi: 10.1200/JCO.1999.17.1.409. [DOI] [PubMed] [Google Scholar]
- A.Goll DE, Thompson VF, Taylor RG, Zalewska T. Is calpain activity regulated by membranes and autolysis or by calcium and calpastatin? BioEssays. 1992;14:549–556. doi: 10.1002/bies.950140810. [DOI] [PubMed] [Google Scholar]
- 14.Hoeffding V, Fechter LD. Trimethyltin disrupts auditory function and cochlear morphology in pigmented rats. Neurotoxicol. Teratol. 1991;13:135–145. doi: 10.1016/0892-0362(91)90003-F. [DOI] [PubMed] [Google Scholar]
- 15.Hofstetter P, Ding D, Powers N, Salvi RJ. Quantitative relationship of carboplatin dose to magnitude of inner and outer hair cell loss and the reduction in distortion product otoacoustic emission amplitude in chinchillas. Hear. Res. 1997a;112:199–215. doi: 10.1016/s0378-5955(97)00123-8. [DOI] [PubMed] [Google Scholar]
- 16.Hofstetter P, Ding D, Salvi R. Magnitude and pattern of inner and outer hair cell loss in chinchilla as a function of carboplatin dose. Audiology. 1997b;36:301–311. doi: 10.3109/00206099709071981. [DOI] [PubMed] [Google Scholar]
- 17.Jortner BS. Mechanisms of toxic injury in the peripheral nervous system: neuropathologic considerations. Toxicol. Pathol. 2000;28:54–69. doi: 10.1177/019262330002800108. [DOI] [PubMed] [Google Scholar]
- 18.Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH. Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature. 2000;405:360–364. doi: 10.1038/35012636. [DOI] [PubMed] [Google Scholar]
- 19.Mount RJ, Takeno S, Wake M, Harrison RV. Carboplatin ototoxicity in the chinchilla: lesions of the vestibular sensory epithelium. Acta Otolaryngol. Suppl. 1995;519:60–65. doi: 10.3109/00016489509121871. [DOI] [PubMed] [Google Scholar]
- 20.Obermaier G, Kretzschmar HA, Hafner A, Heubeck D, Dahme E. Spongiform central nervous system myelinopathy in African dwarf goats. J. Comp. Pathol. 1995;113:357–372. doi: 10.1016/s0021-9975(05)80121-5. [DOI] [PubMed] [Google Scholar]
- 21.Piccart MJ, Nogaret JM, Marcelis L, Longree H, Ries F, Kains JP, Gobert P, Domange AM, Sculier JP, Gompel C. Cisplatin combined with carboplatin: a new way of intensification of platinum dose in the treatment of advanced ovarian cancer. Belgian Study Group for Ovarian Carcinoma. J. Natl. Cancer Inst. 1990;82:703–707. doi: 10.1093/jnci/82.8.703. [DOI] [PubMed] [Google Scholar]
- 22.Reedijk J. Medicinal applications of heavy-metal compounds. Curr. Opin. Chem. Biol. 1999;3:236–240. doi: 10.1016/S1367-5931(99)80037-4. [DOI] [PubMed] [Google Scholar]
- 23.Roelofs RI, Hrushesky W, Rogin J, Rosenberg L. Peripheral sensory neuropathy and cisplatin chemotherapy. Neurology. 1984;34:934–938. doi: 10.1212/wnl.34.7.934. [DOI] [PubMed] [Google Scholar]
- 24.Schweitzer VG. Ototoxicity of chemotherapeutic agents. Otolaryngol. Clin. North Am. 1993;26:759–789. [PubMed] [Google Scholar]
- 25.Shields DC, Banik NL. Putative role of calpain in the pathophysiology of experimental optic neuritis. Exp. Eye Res. 1998;67:403–410. doi: 10.1006/exer.1998.0537. [DOI] [PubMed] [Google Scholar]
- 26.Shields DC, Tylor WR, Deibler GE, Banik NL. Increased calpain expression in experimental demyelinating optic neuritis: an immunocytochemical study. Brain Res. 1998;784:299–304. doi: 10.1016/S0006-8993(97)01381-4. [DOI] [PubMed] [Google Scholar]
- 27.Stracher A. Calpain inhibitors as neuroprotective agents in neurodegenerative disorders. Int. Tinnitus J. 1997;3:71–75. [PubMed] [Google Scholar]
- 28.Takeno S, Harrison RV, Ibrahim D, Wake M, Mount RJ. Cochlear function after selective inner hair cell degeneration induced by carboplatin. Hear. Res. 1994a;75:93–102. doi: 10.1016/0378-5955(94)90060-4. [DOI] [PubMed] [Google Scholar]
- 29.Takeno S, Harrison RV, Mount RJ, Wake M, Harada Y. Induction of selective inner hair cell damage by carboplatin. Scanning Microsc. 1994b;8:97–106. [PubMed] [Google Scholar]
- 30.Thompson SW, Davis LE, Kornfeld M, Hilgers RD, Standefer JC. Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies. Cancer. 1984;54:1269–1275. doi: 10.1002/1097-0142(19841001)54:7<1269::aid-cncr2820540707>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
- 31.Trautwein P, Hofstetter P, Wang J, Salvi R, Nostrant A. Selective inner hair cell loss does not alter distortion product otoacoustic emissions. Hear. Res. 1996;96:71–82. doi: 10.1016/0378-5955(96)00040-8. [DOI] [PubMed] [Google Scholar]
- 32.Wake M, Takeno S, Ibrahim D, Harrison R. Selective inner hair cell ototoxicity induced by carboplatin. Laryngoscopy. 1994;104:488–493. doi: 10.1288/00005537-199404000-00016. [DOI] [PubMed] [Google Scholar]
- 33.Wang J, Ding D, Shulman A, Stracher A, Salvi RJ. Leupeptin protects sensory hair cells from acoustic trauma. Neuroreport. 1999;10:811–816. doi: 10.1097/00001756-199903170-00027. [DOI] [PubMed] [Google Scholar]
- 34.Yamashima T. Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates. Prog. Neurobiol. 2000;62:273–295. doi: 10.1016/S0301-0082(00)00006-X. [DOI] [PubMed] [Google Scholar]