Postnatal changes in cochlear polyamine metabolism in the rat

Brock, M.; Henley, Charles M.

doi:10.1016/0378-5955(94)90203-8

Cited by 8 publications

(6 citation statements)

References 33 publications

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“…Its major toxicity is reversible sensorineural hearing loss that has been found in adult humans at moderate doses (47) and in developing animals at low doses (48). Previous studies have demonstrated that the organ of Corti and the lateral wall of rat inner ear have the highest ODC activity, which is consistent with the distribution of polyamines (49,50) and the suggestion that ODC may play a developmental role in the cochlea. Although the effects of polyamines in suppressing the outward component of Kir currents in other systems have been shown as a biophysical phenomenon (51), until now the functional and clinical significance has not been apparent.…”

Section: Kir41 In the Inner Earsupporting

confidence: 72%

Functional Consequences of Polyamine Synthesis Inhibition by l-α-Difluoromethylornithine (DFMO)

Nie

Feng

Diaz

et al. 2005

Journal of Biological Chemistry

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L-␣-Difluoromethylornithine (DFMO) is a chemopreventive agent for colon cancer in clinical trials. Yet, the drug produces an across-frequency elevation of the hearing threshold, suggesting that DFMO may affect a common trait along the cochlear spiral. The mechanism for the ototoxic effects of DFMO remains uncertain. The cochlear duct is exclusively endowed with endocochlear potential (EP). EP is a requisite for normal sound transduction, as it provides the electromotive force that determines the magnitude of the receptor potential of hair cells. EP is generated by the high throughput of K ؉ across cells of the stria vascularis, conferred partly by the activity of Kir4.1 channels. Here, we show that the ototoxicity of DFMO may be mediated by alteration of the inward rectification of Kir4.1 channels, resulting in a marked reduction in EP. These findings are surprising given that the present model for EP generation asserts that Kir4.1 confers the outflow of K ؉ in the stria vascularis. We have proposed an alternative model. These findings should also enable the rational design of new pharmaceuticals devoid of the untoward effect of DFMO.

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Section: Kir41 In the Inner Earsupporting

confidence: 72%

Functional Consequences of Polyamine Synthesis Inhibition by l-α-Difluoromethylornithine (DFMO)

Nie

Feng

Diaz

et al. 2005

Journal of Biological Chemistry

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“…The importance of Kir channels in maintaining EP was established by studies of the cloned mouse cochlear lateral wall-specific Kir4.1 channel (38). A high level of polyamines, particularly spermidine, was reported to occur in the rat cochlea (35), and spermidine levels were reduced by DFMO in the guinea pig cochlea (36).…”

Section: Discussionmentioning

confidence: 99%

“…These side effects are not observed at lower doses of DFMO (26,27). Ototoxicity has been demonstrated to occur in experimental animals treated with DFMO including rats (35), guinea pigs (36), gerbils (37), and mice (38). Using immunohistochemistry, a high level of ornithine decarboxylase was observed in the inner ear of the rat, with the highest in the organ of Corti and lateral wall followed by the cochlear nerve (39).…”

mentioning

confidence: 96%

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

Wang

Levic

Gratton

et al. 2009

Journal of Biological Chemistry

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Male gyro (Gy) mice, which have an X chromosomal deletion inactivating the SpmS and Phex genes, were found to be profoundly hearing impaired. This defect was due to alteration in polyamine content due to the absence of spermine synthase, the product of the SpmS gene. It was reversed by breeding the Gy strain with CAG/SpmS mice, a transgenic line that ubiquitously expresses spermine synthase under the control of a composite cytomegalovirus-IE enhancer/chicken ␤-actin promoter. There was an almost complete loss of the endocochlear potential in the Gy mice, which parallels the hearing deficiency, and this was also reversed by the production of spermine from the spermine synthase transgene. Gy mice showed a striking toxic response to treatment with the ornithine decarboxylase inhibitor ␣-difluoromethylornithine (DFMO). Within 2-3 days of exposure to DFMO in the drinking water, the Gy mice suffered a catastrophic loss of motor function resulting in death within 5 days. This effect was due to an inability to maintain normal balance and was also prevented by the transgenic expression of spermine synthase. DFMO treatment of control mice or Gy-CAG/SpmS had no effect on balance. The loss of balance in Gy mice treated with DFMO was due to inhibition of polyamine synthesis because it was prevented by administration of putrescine. Our results are consistent with a critical role for polyamines in regulation of Kir channels that maintain the endocochlear potential and emphasize the importance of normal spermidine:spermine ratio in the hearing and balance functions of the inner ear.Polyamines are essential for viability in mammals. Knockouts of the genes for ornithine decarboxylase and S-adenosylmethionine decarboxylase, which are enzymes needed for the synthesis of putrescine, spermidine, and spermine, are lethal at early stages of embryonic development (1, 2). There is convincing evidence that the formation of hypusine in eIF5A, which requires spermidine as a precursor, is essential for eukaryotes (3). However, the function(s) of spermine is not so well established. Yeast mutants with inactivated spermine synthase grow at a normal rate (4). Mammalian cells in culture also grow normally in the presence of inhibitors of spermine synthase (5) or after inactivation of the spermine synthase gene (SpmS) (6 -8

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“… 16 Polyamine levels are elevated in neonatal rat cochlear soft tissue. 17,18 DFMO has been shown to reduce the levels of putrescine and spermidine in rat brain, heart, and kidney tissues. 19 In humans, putrescine levels in rectal mucosal samples fell in response to DFMO therapy, with a return toward normal levels after discontinuation of the drug.…”

Section: Discussionmentioning

confidence: 97%

Difluoromethylornithine‐Induced Reversible Hearing Loss Across a Wide Frequency Range

2004

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Postnatal changes in cochlear polyamine metabolism in the rat

Cited by 8 publications

References 33 publications

Functional Consequences of Polyamine Synthesis Inhibition by l-α-Difluoromethylornithine (DFMO)

Functional Consequences of Polyamine Synthesis Inhibition by l-α-Difluoromethylornithine (DFMO)

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

Difluoromethylornithine‐Induced Reversible Hearing Loss Across a Wide Frequency Range

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