The effect of prednisolone and non-steroidal anti-inflammatory agents on the normal and noise-damaged guinea pig inner ear

Abstract

The effect of anti-inflammatory agents, such as the synthetic glucocorticoid prednisolone, diclofenac sodium, and histamine H1-receptor antagonist, was studied in unexposed and noise-exposed (broad-band noise, bandwidth 1–12 kHz, 106 dB SPL, 30 min) guinea pigs. The results were compared with the results obtained from no treatment and with isotonic saline (placebo) therapy. The cochlear blood flow (CoBF) and the partial oxygen pressure in the perilymph (PL-pO₂) were continuously and simultaneously recorded over a period of 210 min. In addition, cochlear microphonics (CMs), compound action potentials of the auditory nerve (CAPs), and auditory brain stem responses (ABRs) were registered. Noise-induced hearing loss paralleled a decrease of PL-pO₂. Both were found to occur before evidence of reduced CoBF. PL-pO₂ and CoBF progressively declined post-exposure, while CMs, CAPs, and ABRs did not further deteriorate nor showed signs of recovery up to 180 min after cessation of noise. Treatment started 60 min post-exposure, or after 90 min without manipulation and was then further studied for 120 min. In the unexposed animals, diclofenac sodium and prednisolone induced a significant decline of PL-pO₂, while CoBF, CMs, CAPs, and ABRs revealed no change. Isotonic saline did not influence the measured parameters. After infusion of the histamine H1-receptor antagonist, a significant decrease of CoBF together with blood pressure and CMs was observed, while PL-pO₂, CAPs, and ABRs showed no change. In the noise-exposed animals, diclofenac sodium induced partial restoration of CM and CAP amplitudes and full restoration of ABRs. Following a high dose of prednisolone (25 mg), partial restoration of CMs and full restoration of CAPs and ABRs were registered. This effect was significantly less pronounced following a low dose of prednisolone (2.5 mg). Restoration of CMs, CAPs, and ABRs was immediate (i.e. 50 min after infusion) and remained stable for another 60 min until the end of the recording period. The histamine H1-receptor antagonist and isotonic saline did not influence CMs, CAPs, and ABRs. None of the applied drugs resulted in relief of progressive noise-induced cochlear hypoxia and post-traumatic ischemia. These findings indicate direct cellular effects of prednisolone and diclofenac sodium in the cochlea taking into account no blood flow and oxygenation. The possible mechanisms involved are discussed.

Introduction

Clinical studies on the effect of corticosteroids, classified as glucocorticoids (e.g. prednisolone), in sudden sensorineural hearing loss (SNHL) using untreated or placebo-treated controls have revealed conflicting results (Mattox and Simmons, 1977; Wilson et al., 1980; Moskowitz et al., 1984; Veldman et al., 1993). Therefore, it is still to be seen whether glucocorticoids are more effective than no treatment, placebo, blood flow promoting drugs or hyperbaric oxygen therapy (see reviews in Lamm, 1992, Lamm, 1995a, Lamm, 1995b; Lamm and Arnold, 1993; Lamm et al., 1997a, Lamm et al., 1997b). However, progressive SNHL can be successfully treated with glucocorticoids (Kanzaki and O-Uchi, 1981, Kanzaki and O-Uchi, 1983; Kanzaki et al., 1993; Kunihiro et al., 1990; Vischer and Arnold, 1991; Veldman et al., 1993).

Clinical results on the effect of glucocorticoids or other anti-inflammatory agents in noise-induced hearing loss (NIHL) have not yet been published. Prednisolone brought about a more pronounced recovery of VIIIth nerve compound action potential thresholds in guinea pigs compared with untreated controls after repeated exposure to low-level noise (Michel et al., 1993). In another study, following repeated exposure to low-level noise, a decrease of glucocorticoid receptor protein levels was observed in the organ of Corti region of rats (Rarey et al., 1995).

The rationale for administration of anti-inflammatory agents in NIHL is based on the following considerations. Inflammatory tissue alterations are not only elicited by bacterial, viral or other immunopathological processes but also by physically induced cellular damage, tissue hypoxia, and ischemia (Insel, 1990). Acoustic overstimulation may induce a variety of intracochlear ultrastructural cell damages indicating that there are numerous factors that can cause compromised cellular function, resulting in NIHL. Recent studies undertaken in our laboratory have demonstrated that NIHL paralleled cochlear hypoxia, and that both were found to occur before evidence of reduced cochlear blood flow (Lamm and Arnold, 1996). It was assumed, therefore, that noise-induced cochlear hypoxia is not brought about by a decreased delivery but reflects an increased oxygen consumption, and hence, increased oxygen extraction rate from cochlear fluids. Both noise-induced intracochlear cell damages and/or hypoxia could explain the significance of the delayed effect on cochlear blood flow. In non-cochlear tissues, biosynthesis and release of membrane phospholipid-derived autacoids, such as the eicosanoids (prostaglandins, prostacyclin, thromboxanes, and leucotrienes), are enhanced in damaged cells and/or hypoxic tissue (Todd and Sorkin, 1988; Insel, 1990; Campbell, 1990; Brooks and Day, 1991). In addition, an abnormal histamine liberation occurs in non-cochlear mechanically injured and/or hypoxic tissue (Garrison, 1990). Both eicosanoids and histamine induce a number of vascular effects, such as local arteriolar dilation and/or constriction, capillary dilation and/or constriction, and increased permeability of postcapillary venulae due to contraction of endothelial cells (Garrison, 1990). After noise exposure under various experimental conditions, similar vascular alterations, particularly increased vessel lumen irregularities and abnormal red cell distribution, were observed in cochlear tissue sections (Hawkins, 1971, Hawkins, 1976; Hawkins et al., 1972; Lipscomb and Roettger, 1973; Lipscomb et al., 1977; Vertes et al., 1979; Vertes and Axelsson, 1981; Axelsson and Vertes, 1982; Dengerink et al., 1985; Axelsson and Dengerink, 1987). Recently, capillary constrictions were also seen in vivo with intravital microscopy (Quirk et al., 1991, Quirk et al., 1992). In this respect, an abnormal liberation of eicosanoids and/or histamine may be involved in the development of progressive cochlear ischemia beginning 30 min after termination of broad-band noise exposure (Lamm and Arnold, 1996). It was assumed, therefore, that anti-inflammatory drugs such as glucocorticoids, diclofenac sodium, and histamine H1-receptor antagonists can relieve post-traumatic cochlear ischemia and potentiation, and progression of noise-induced cochlear hypoxia. Furthermore, it was assumed that the drugs can relieve intracochlear damages that were found after noise exposure due to their direct cellular effects. Glucocorticoid receptors were detected in various cochlear and vestibular tissues (Rarey and Luttge, 1989; Rarey et al., 1993; ten Cate et al., 1992, ten Cate et al., 1993; Pitovski et al., 1994; Zuo et al., 1995a; Erichsen et al., 1996a), as well as the enzyme which degrades corticosteroids (ten Cate et al., 1994a; Pitovski, 1996). Binding to glucocorticoid receptors results in an alteration of transcription or expression of specific genes. Thereby, the formation and liberation of inflammatory mediators, such as eicosanoids and cytokines are inhibited, regardless of whether the inciting agent is mechanic, hypoxic, ischemic, infectious or immunological (Baulieu and Mester, 1989; Haynes, 1990; Munck et al., 1990; Barnes and Adcock, 1993). In addition, glucocorticoids influence carbohydrate (McMahon et al., 1988) and protein metabolism resulting in an increased amount of specific mRNA (Baulieu and Mester, 1989; Haynes, 1990; Munck et al., 1990; Barnes and Adcock, 1993). Finally, glucocorticoids also influence cellular osmolarity (Haynes, 1990; Barnes and Adcock, 1993). Diclofenac sodium inhibits cyclo-oxygenase und lipoxygenases, the enzymes involved in the synthesis of eicosanoids (Todd and Sorkin, 1988; Insel, 1990; Campbell, 1990; Brooks and Day, 1991). In addition, the drug interferes with a number of different plasma membrane-associated processes, including transmembrane ion flux, and influences the activity of enzymes involved in oxidative phosphorylation processes (Brooks and Day, 1991). Histamine H1-receptor antagonists inhibit the arteriolar vasoconstrictor effect of histamine, the vasodilator effect that is mediated by the endothelial cells of capillaries and the increased permeability of postcapillary venulae (Garrison, 1990).

The purpose of the present study was to determine whether noise-induced hearing loss and epiphenomena, such as the cochlear hypoxia and post-traumatic progressive ischemia (Lamm and Arnold, 1996), are influenced by glucocorticoids, such as prednisolone, or non-steroidal anti-inflammatory agents, such as diclofenac sodium and histamine H1-receptor antagonist. The results were compared with the results obtained from no treatment or with isotonic saline (placebo) therapy.