d-Methionine provides excellent protection from cisplatin ototoxicity in the rat

Campbell, Kathleen C.M.; Rybak, Leonard P.; Meech, Robert P.; Hughes, Larry F.

doi:10.1016/s0378-5955(96)00152-9

Cited by 219 publications

(207 citation statements)

References 48 publications

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“…D-Met has been shown to prevent or ameliorate peripheral cisplatininduced hearing threshold shifts, outer hair cell loss, loss of hair cell function, loss of spiral ganglion cell neurons, and damage to the stria vascularis in animals (Campbell et al, 1996(Campbell et al, , 1999(Campbell et al, , 2007Gabaizadeh et al, 1997;Wimmer et al, 2004). However, to our knowledge, this investigation is the first evidence of direct cisplatin damage to the cortical neurons, in vitro, and the amelioration of this damage by an over-thecounter supplement -D-Met.…”

Section: Discussionmentioning

confidence: 69%

“…Studies of cisplatin-induced hearing loss have generally focused on damage to the peripheral auditory system, with morphological alterations in the organ of Corti of the cochlea, loss of and damage of cochlear hair cells, damage to the stria vascularis and degeneration of spiral ganglion neurons (Campbell et al, 1996(Campbell et al, , 1999Meech et al, 1998;Hoistad et al, 1998). Cisplatin has been shown to enhance the formation of reactive oxygen species, and the free radicalinduced cell damage is thought to play an important role in cisplatin neurotoxicity (Dehne et al, 2001;Poirrier et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…These adverse effects from cisplatin exposure have led to the search for preventative treatments (Campbell et al, 1996(Campbell et al, , 1999Rybak et al, 2007). Sulfur containing compounds such as sodium thiosulfate (STS) and diethyl-dithiocarbamate (DDTC) were reported to provide good otoprotection against cisplatin (Otto et al, 1988), but had significant side effects and/or interference with antitumor activity (Jones et al, 1991;Church et al, 1995;Gandara et al, 1995;Muldoon et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…D-Methionine (D-Met), also a sulfur-containing nucleophilic antioxidant, has shown to provide effective nephroprotection against cisplatin without interfering with antitumor action (Jones and Basinger, 1989). Cisplatin-induced hearing loss, and subsequent outer hair cell loss and stria vascularis damage, is protected by D-Met (Campbell et al, 1996(Campbell et al, , 1999. In the cochlea, D-Met partially protected cisplatin-induced decreases in antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione a reductase (GR), and prevented increases in malondialdehyde levels, a measure of lipid peroxidation (Campbell et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…In the cochlea, D-Met partially protected cisplatin-induced decreases in antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione a reductase (GR), and prevented increases in malondialdehyde levels, a measure of lipid peroxidation (Campbell et al, 2003). Several animal studies have shown that D-Met prevented oxidative-stress induced ototoxicity and nephrotoxicity from cisplatin treatment (Campbell et al, 1996;Reser et al, 1999). Hamstra et al (2010) evaluated the safety of the MRX-1024 -the bioavailable suspension of D-Met -in cancer patients.…”

Section: Introductionmentioning

confidence: 99%

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d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks

Gopal

Shrestha

et al. 2012

Neurotoxicology and Teratology

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Cisplatin is a platinum-based chemotherapeutic agent widely used for the treatment of various types of cancer. Patients undergoing cisplatin treatment often suffer from a condition known as "chemobrain", ototoxicity, peripheral neuropathy, weight loss, nausea, vomiting, nephrotoxicity, seizures, hearing loss and tinnitus.D-Methionine (D-Met), a sulfur-containing nucleophilic antioxidant, has been shown to prevent cisplatininduced side effects in animals without antitumor interference. In this study, we have used an in vitro model of cortical networks (CNs), enriched in auditory cortex cells; to quantify cisplatin neurotoxicity and the protective effects of D-Met. Dissociated neurons from auditory cortices of mouse embryos were grown on microelectrode arrays with 64 transparent indium-tin oxide electrodes, which enabled continuous optical and electrophysiological monitoring of network neurons. Cisplatin at 0.10-0.25 mM induced up to a 200% increase in spontaneous spiking activity, while concentrations at or above 0.5 mM caused irreversible loss of neuronal activity, accompanied by cell death. Pretreatment with D-Met, at a concentration of 1.0 mM, prevented the cisplatin-induced excitation at 0.10-0.25 mM, caused sustained excitation without occurrence of cell death at 0.5 mM, and delayed cell death at 0.75 mM cisplatin. L-Methionine, the optical isomer, showed lower potency and less efficacy than D-Met, was less protective against 0.1 mM cisplatin, and proved ineffective at a concentration of 0.5 mM cisplatin. Pre-exposure time of D-Met was associated with the protective effects at 0.1 and 0.5 mM cisplatin, with longer pre-exposure times exhibiting better protection. This study quantifies as a function of concentration and time that D-Met protects central nervous system tissue from acute cisplatin toxicity.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks

Gopal

Shrestha

et al. 2012

Neurotoxicology and Teratology

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Ototoxicity

Forge¹,

Taylor²,

Harpur³

2009

General, Applied and Systems Toxicology

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Ototoxicity is the process by which chemicals cause damage to the end organs of hearing (the cochlea) or balance (the vestibular system). Hearing loss is the common effect of ototoxins, although many also affect the vestibular system. Some cause temporary hearing loss (e.g. the ‘loop’ diuretics or salicylates). However, the most significant group of ototoxic agents cause death of the sensory hair cells (HCs) and permanent hearing loss, for example aminoglycoside antibiotics, cis ‐platinum and organic solvents. In mammalian species the HC losses caused by these agents are permanent because, unlike the sensory epithelia in the inner ear in birds and other nonmammalian vertebrates, there is no capacity for HC regeneration. The effects generally develop only after repeated administration, but in some cases a single administration is sufficient (e.g. trimethyltin). Drug interactions can result in much greater damage than would be expected from the single agents. Excess noise can also cause HC death and can act synergistically with ototoxic chemicals. The most characteristic pattern of damage is predominantly death of outer HCs initially at the base of the cochlea (affecting high frequency hearing). Among humans, some individuals may be genetically predisposed to ototoxic damage.

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Review: Ototoxic Characteristics of Platinum Antitumor Drugs

Ding

Allman

Salvi

2012

The Anatomical Record

120

104

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Cisplatin, carboplatin, nedaplatin, and oxaliplatin are widely used in contemporary oncology; however, their ototoxic and neurotoxic side effects are quite different as discussed in this review. Cisplatin is considered the most ototoxic, but despite its reputation, the magnitude of hair cell loss that occurs with a single, large drug bolus is limited and confined to the base of the cochlea. For all of these platinum compounds, a major factor limiting damage is drug uptake from stria vascularis into the cochlear fluids. Disrupting the blood-labyrinth barrier with diuretics or noise exposure enhances drug uptake and significantly increases the amount of damage. Combined treatment with ethacrynic acid (a loop diuretic) and cisplatin results in rapid apoptotic hair cell death characterized by upregulation of initiator caspase-8 and membrane death receptor, TRADD, followed by downstream executioners, caspase-3 and caspase-6. Unlike cisplatin, nedaplatin and oxaliplatin are highly neurotoxic when applied to cochlear cultures preferentially damaging auditory nerve fibers at low concentrations and hair cells at high concentrations. Carboplatin, considered far less ototoxic than cisplatin, is paradoxically highly toxic to chinchilla inner hair cells and type I spiral ganglion neurons; however, at high doses it also damages outer hair cells. Hair cell death from cisplatin and carboplatin is characterized in its early stages by upregulation of p53; blocking p53 expression with pifithrin-a prevents hair cell death. Major differences in the toxicity of these four platinum compounds may arise from several different metal transporters that selectively regulate the influx, efflux, and sequestration of these drugs.

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d-Methionine provides excellent protection from cisplatin ototoxicity in the rat

Cited by 219 publications

References 48 publications

d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks

d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks

Ototoxicity

Review: Ototoxic Characteristics of Platinum Antitumor Drugs

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