Biomedical subjects

C A Whitworth

Publications and source records attributed to C A Whitworth.

8 recordsLinked to original sources

PubMed2006

Expression of the kidney injury molecule 1 in the rat cochlea and induction by cisplatin.

Cisplatin is a widely used chemotherapeutic agent whose dose-limiting side effects include ototoxicity and nephrotoxicity. Recent evidence indicates that cisplatin induces the expression of a novel protein, kidney injury molecule-1, in the renal proximal tubular epithelium to aid in regeneration. In this study, we determined whether kidney injury molecule-1 is expressed in the cochlea and is induced by cisplatin. Using reverse transcriptase polymerase chain reaction techniques, we have now identified kidney injury molecule-1 in the rat cochlea and in three different mouse transformed hair cell lines. Administration of cisplatin to rats produced hearing loss and induced kidney injury molecule-1 mRNA in the rat cochlea. Pretreatment of rats with lipoic acid, a scavenger of reactive oxygen species, significantly reduced cisplatin-induced hearing loss and kidney injury molecule-1 expression. Cisplatin also increased the expression of cochlear NOX3 mRNA, a member of the superoxide generating NADPH oxidase family of proteins recently identified in the cochlea, inhibition of which decreased kidney injury molecule-1 expression. Polymerase chain reaction performed on different regions of the cochlea indicated the presence of kidney injury molecule-1 mRNA in the lateral wall, organ of Corti and spiral ganglion. This distribution was confirmed by immunocytochemistry. Taken together, these data identify kidney injury molecule-1 as a novel cochlear injury molecule, whose expression is regulated by reactive oxygen species generated via the NADPH oxidase pathway.

Animals↗

PubMed2001

Pharmacological antagonism of the slow-activating delayed rectifying potassium channel (I(Ks)) has no effect on cochlear structure and function in vivo.

The experimental class III antiarrhythmic drug, L-768673, prolongs the refractory period of cardiac myocytes by selectively blocking the slow-activating delayed rectifying potassium (I(Ks)) channel. The I(Ks) channel has also been identified in vestibular dark cells and in the marginal cells of the stria vascularis. In the stria vascularis, the I(Ks) channel plays an important role in cochlear homeostasis. Genetic null deletion of the I(Ks) channel in mice and man results in profound hearing loss and cochlear pathology. Therefore, the purpose of the present study was to investigate the effect of L-768673 on the auditory function and cochlear morphology in rats using auditory brainstem-evoked response and light microscopy. Auditory testing was performed one week prior to dosing, following 14 days of administration and 28 days after the completion of dosing. L-768673 (50 or 250 mg/kg/day for 14 days), had no significant effects on auditory function or cochlear morphology. The results of this study suggest that high doses of L-768673 are not toxic to the inner ear of adult rats treated for 14 consecutive days, and that the ototoxic potential of orally administered L-768673 and similar I(Ks)-selective compounds is unlikely at doses within the therapeutic range.

Acetamides↗

PubMed2000

Acute changes in cochlear potentials due to cisplatin.

The purpose of this study was to investigate how the hair cells and stria vascularis are affected at the onset of cisplatin ototoxicity. The effects on the endocochlear potential (EP) and the cochlear microphonics (CM) were observed simultaneously in two groups of adult chinchillas receiving as follows: (1) 5 microl of cisplatin (1 mg/ml) in normal saline, and (2) 5 microl of normal saline on the round window. The EP and the CM were recorded for 12-14 h after cisplatin application, and morphological changes were assessed using scanning electron microscopy. Both the EP and the CM amplitude demonstrated a profound reduction, and a very strong correlation was observed between these two values during this time period. Although the reduction of the EP and the CM was observed by 12-14 h, only very slight degeneration of outer hair cells was seen at that time. These data suggested that a reduction of the EP which was caused by the alteration of the stria vascularis might be primarily responsible for very early changes in cochlear function after topical cisplatin application, while later changes were the direct result of hair cell damage.

Animals↗

PubMed1999

The effect of combined administration of cadmium and furosemide on auditory function in the rat.

A number of heavy metals have been associated with toxic effects to the peripheral or central auditory system. These include lead, arsenic, mercury, platinum and organic tin compounds. In addition, the ototoxic effects of some metals may be potentiated by other factors. However, the auditory effects of cadmium have not previously been reported. The purpose of the present study was to investigate the potential ototoxic effects of cadmium from an acute dosage, and its potentiation by furosemide. Auditory brainstem response (ABR) thresholds were measured in adult Sprague-Dawley rats. Rats received either cadmium chloride (5 mg/kg, i.p.) followed by saline (4 ml/kg, i.p.). cadmium chloride followed by furosemide (200 mg/kg, i.p.), or furosemide alone. Follow-up ABRs were carried out 7 days post-treatment and threshold changes were compared between each treatment group. No significant threshold change was seen for the cadmium chloride plus saline treated or the furosemide treated animals. However, significant threshold elevations were observed in animals receiving cadmium chloride plus furosemide. In addition, scanning electron microscopy revealed extensive hair cell loss in animals treated with cadmium chloride and furosemide. Although functional auditory changes were not seen after the administration of cadmium alone, the potentiation of threshold changes by furosemide suggests that cadmium may be ototoxic under certain conditions.

Animals↗

PubMed1999

Effect of 4-methylthiobenzoic acid on cisplatin-induced ototoxicity in the rat.

The purpose of this study was to investigate the effectiveness of 4-methylthiobenzoic acid (MTBA) as a protection agent against cisplatin (CDDP)-induced changes in organ of Corti surface structure, compared to electrophysiological changes. Electrophysiological change was assessed using auditory brainstem response (ABR) and morphological changes were assessed using scanning electron microscopy (SEM). Male Wistar rats underwent pre-treatment ABRs in response to clicks, and tone bursts at 2, 4, 8, 16, and 32 kHz. The three groups of rats were injected as follows: (1) MTBA (250 mg/kg, i.p.), (2) CDDP (16 mg/kg, i.p.), (3) CDDP+MTBA (16 mg/kg, i.p. + 250 mg/kg, i.p.). Post-treatment ABRs were performed 3 days after drug administration and rats were sacrificed. Their cochleae were harvested and SEM was used to examine the surface of the organ of Corti, specifically the number of inner hair cells (IHCs) and outer hair cells (OHCs) in the apical, middle and basal turns of the cochlea. Animal weight was measured on the first and final days. There was a good correlation between ABR threshold changes and hair cell loss in the high frequency region of the cochlea (basal turn), while threshold changes in the lower test frequencies (middle turn) appeared to be the result of more subtle changes in the cochlea. MTBA provided effective protection against cisplatin-induced ABR threshold changes at all test frequencies as well as hair cell loss. MTBA also protected against body weight loss.

Animals↗

PubMed1998

Experimental model of cisplatin ototoxicity in chinchillas.

Cisplatin is an important antineoplastic agent. Its ototoxicity has been well defined, both in human and animal studies. However, animal models of systemic cisplatin administration have been complicated by multiple toxic effects. We studied cisplatin ototoxicity in an animal model involving topical application of cisplatin to the round-window membrane. Adult chinchillas were anesthetized with ketamine and pentobarbital, and auditory function was tested with the use of auditory brain-stem responses to various stimuli (clicks and 8-and 16-kHz tone bursts). Each animal was used as its own control. The middle-ear cavity was exposed through the bulla. In the experimental ear, a 25-microl solution of 0.25 mg cisplatin/1.0 ml normal saline solution was applied to the round-window membrane. In the control ear, 25 microl normal saline solution was applied to the round-window membrane. Follow-up auditory brain-stem response testing was conducted 7 days after treatment. A significant increase in threshold in the experimental ears was seen on comparison with the control ears. This finding suggests that application of cisplatin to the round-window membrane is a useful animal model in which to study cisplatin ototoxicity.

Animals↗

PubMed1987

Nutritional status, glutathione levels, and ototoxicity of loop diuretics and aminoglycoside antibiotics.

Chinchillas deprived of food for 48 h prior to the administration of a combined dose of ethacrynic acid (10 mg/kg) and kanamycin (100 mg/kg) suffered a profound hearing loss. Fed animals did not demonstrate any hearing loss at the same dose levels. Drug metabolism may be the common pathway by which ototoxic agents interact, by a mechanism which is common to both the cochlea and the kidney. Glutathione (GSH) is a tripeptide which is involved in several pathways in the detoxification of active oxygen and reactive species formed during xenobiotic metabolism. The enhanced auditory dysfunction was paralleled by one-third decline in hepatic glutathione levels in the food-deprived animals. Manipulation of endogenous GSH levels may mitigate the toxicities of many of these drugs, which otherwise limit their clinical usefulness. These results also indicate that nutritional status may have important clinical implications during drug therapy.

Animals↗

PubMedDate not supplied

Potentiation of ototoxicity by glutathione depletion.

The combination of 10 mg/kg ethacrynic acid (ETA) and 100 mg/kg kanamycin (KA) caused neither morphologic damage to the cochlea nor change in the auditory brain stem response of the chinchilla. However, after pretreatment with a single dose of buthionine sulfoximine (BSO; 800 mg/kg intraperitoneally) to reduce intracellular glutathione (gamma-glutamylcysteinylglycine; GSH) levels, the above single administration of ETA and KA resulted in complete deafness and severe morphologic damage. The kidney, which has a rapid GSH turnover and is therefore especially susceptible to GSH depletion by BSO, also demonstrated severe damage after this treatment. A similar rapid turnover of GSH and resulting limited capacity to detoxify reactive metabolites and free radicals may determine cochlear and renal vulnerability to this toxicity. These findings may explain the clinical observations of enhanced ototoxicity in patients administered amino-glycoside antibiotics concomitantly with loop diuretics.

Animals↗