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Author: admin | 25.01.2016 | Category: Ginkgo Biloba Tinnitus

Independent of the type of ringing in the ears, the fine hair cells participate in the constant sound and the hearing process.
The so-called hair cells perceive the sound waves and relay them directly to the auditory nerve. However, tiny deposits in the fine blood vessels around the cochlea can limit the cellsa€™ supply.
Often the ringing in the ears appears after a sudden deafness being described as a suddenly appearing deafness of the inner ear. The later specialist treatment is carried out the more increases the risk of a permanent tinnitus. Before the initiation of treatment it is important to check whether there is a specific cause of the ringing in the ears. Depending on the diagnosis, a specific treatment or the combination of several measures can be initiated then. Important: Take action in due time to avoid that an acute tinnitus develops into a chronic one. In particular with chronic tinnitus, measures adding to the reduction of the ringing in the ears and coping with the disease make good sense. If stress cannot be avoided in everyday life it should be reduced and decreased deliberately in your leisure time. Lorem ipsum dolor sit amet, consectetuer adipiscing elit praesent vestibulum molestie lacus.
This article reviews the importance of the round-window membrane in exposing the labyrinth to or protecting it from the toxic effects of otitis media. Only in the last decades have the middle ear and the inner ear been recognized as valid and important immunocompetent structures [1]. The purpose of this article is to review the interrelations between the middle ear and the inner ear in otitis media and the role of bacteria, bacterial products, and inflammatory mediators as toxic agents acting through the roundwindow membrane. The middle-ear space is lined by a mucous membrane that in turn is covered by a layer of mucin (mucus) through which microorganisms must pass before they reach the mucosa itself (Table 1).
Once the microorganisms have reached the epithelial surface of the mucous membrane, they must overcome the rapidly dividing mucosal cells and the superficial specific mucosal immune system [4]. If bacteria are able to overcome the mucus and epithelial layers of the mucosa, they must meet with both nonspecific and specific defense systems in the lamina propria. Once bacteria overcome the defense mechanisms of the middle-ear mucosa, damage to the inner ear can occur. The conditions caused in the middle ear by bacteria - acute otitis media, chronic suppurative otitis media, and middle-ear effusion - now are accepted as representing different phases in the spectrum of the same pathological continuum of otitis media [11]. Bacteria that cause acute otitis media are predominantly aerobic, particularly Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis [13- 15]. Also related to inner-ear damage caused by otitis media is the role of inflammatory mediators. Round-window membrane anatomy and structural studies disclose three basic layers: an outer epithelium, a middle core of connective tissue, and an inner epithelium (Figs.
Under normal conditions, the inner ear possesses remarkably stable homeostatic mechanisms for the maintenance of functional integrity of the inner ear fluid. Maintenance of a constant volume and composition of the inner ear fluids is essential for the functional integrity of the inner ear [1]. Maintenance of inner ear fluid ion homeostasis is essential for signal transduction and proper function of the inner ear. Other mechanisms involved in the regulation of inner ear fluid composition include the BLB. It was demonstrated that glucose levels in perilymph parallel the levels in blood when experimental hyperglycemia or hypoglycemia was induced [10].
The composition of both endolymph and perilymph also is maintained by active homeostatic mechanisms located within the stria vascularis contained within the membranous labyrinth [6, 12].
Hair cells are specialized sensory mechanoreceptors that transduce specific mechanical energy into a change in membrane potential by opening and closing, or gating, of ion channels. Ion channels, including the delayed rectifier K+ channel, Ca2+-dependent K+ channel, Ca2+ voltage-sensitive channel, and receptors such as NMDA and nicotinic acetylcholine receptors (nAchRs) have been localized to the stria vascularis, IHCs, and OHCs and are the primary factors responsible for maintaining the electrical potential of the hair cells and the process of auditory transduction (Table 2). At rest, channel-mediated ion influx by passive diffusion is balanced by active flux that requires energy. Proper regulation of ion channel conductance is mediated by protein phosphorylation and is essential to opening or closing ion channels such as the K+ channel [19] and to maintaining ionic homeostasis in the inner ear.
Ca2+ is an important second messenger and is a final common pathway essential for many processes in neurons and cells. Hormonal modulation of inner ear fluids through alteration of membrane permeability to ions and water has been reported [22]. Ion channels compose the largest component of inner ear disease most likely to be affected by changes in inner ear fluid composition.
Oxidative stress caused by free radical damage is perhaps the most fundamental cause of age-related pathology in the biological aging of cells.
The effects of NO on ion homeostasis may also be attributed to the modulation of intracellular Ca2+. Aminoglycosides also act as iron chelators and promote the formation of reactive oxygen species [43]. A vailable data suggest that after exposure to ototoxic drugs, hair cells die by apoptosis.
Evidence suggests that inner ear diseases such as Meniere's disease, tinnitus, and sensorineural hearing loss may be treated by selective systemic administration of drugs [49]. Aminoglycosides used to treat vestibular disorders can be toxic to other inner ear structures. The available evidence, based on electrophysiological studies, suggests that tinnitus is associated with disturbances in spontaneous neural activity in the auditory system [53]. In general, it is known that stress-related hormones such as epinephrine, norepinephrine, vasopressin, aldosterone, and cortisol are released into the systemic circulation in response to stress.
The major symptoms of Meniere's disease are sensorineural hearing loss, vertigo, and tinnitus. Our previous studies have observed an elevation of K+, Na+, and osmolality in perilymph after epinephrine infusion [3, 6]. An elevation of prostaglandin levels (prostaglandin E2 or I2) in perilymph by cathecholamines and antidiuretic hormone has also been reported [8] and indicates another possible mechanism of altering membrane permeability in the inner ear. Acoustic trauma causes a severe sensorineural hearing loss, which is associated with tinnitus-a functional disorder of the auditory system and a major symptom of Meniere's disease.
Presbycusis refers to the gradual loss of hearing associated with various types of auditory system dysfunction that accompany aging. The cells of the inner ear and associated structures sustain damage throughout life and are presumably subject to biological aging as well. The large individual variability in the age of onset and the severity of certain types of age-related hearing loss suggest involvement of a genetic mechanism in presbycusis. Animal models have been developed using C57BL mice that show progressive auditory decline with age, decline that resembles certain types of hereditary hearing loss in humans [71].
Under normal conditions, the inner ear possesses remarkably stable homeostatic mechanisms for the maintenance of the functional integrity of the inner ear. Several substances have been found to penetrate inner ear fluids and induce functional changes.
Further studies are necessary to identify the mechanisms responsible for disturbances to the remarkable homeostasis normally maintained by membrane permeability between the fluid-containing compartments of the inner ear. Since not only organic diseases but also stress can cause the constant ringing, murmur, whistling or hissing in the ear. But if not enough oxygen and important nutrients are transported to the hair cells their ability to regenerate will be reduced significantly.
Physicians suspect acute perfusion disorders, virus infections or nervous disorders as possible causes. Therefore you should immediately seek professional help when a ringing in the ears lasts more than one or two days. In such situations, distraction with low music and hear books is a help to many people affected. Relaxation techniques such as yoga, biofeedback or progressive muscular relaxation can be a support. While a PubMed search for the terms "intratympanic" or "transtympanic" produces just a few "hits" for any given year back in the 1990s, [1] for 2011 already more than 40 publications on the topic are listed - and this only counting those which deal with drug injections into the human middle ear. Clinical aspects of round window membrane permeability under normal and pathological conditions.
Intratympanic dexamethasone for sudden sensorineural hearing loss after failure of systemic therapy. Oral vs intratympanic corticosteroid therapy for idiopathic sudden sensorineural hearing loss: A randomized trial.
Injection of the tympanum for chronic conductive deafness and associated tinnitus aurium: A preliminary report on the use of ethylmorphine hydrochloride.
Treatment of cochlear tinnitus with transtympanic infusion of 4% lidocaine into the tympanic cavity.
Dexamethasone inner ear perfusion for the treatment of Meniere's disease: A prospective, randomized, double-blind, crossover trial. Intratympanic dexamethasone injections as a treatment for severe, disabling tinnitus: Does it work? Treatment of subjective tinnitus: A comparative clinical study of intratympanic steroid injection versus oral carbamazepine. Topical administration of Caroverine in somatic tinnitus treatment: Proof-of-concept study. Round-window anatomical considerations in intratympanic drug therapy for inner-ear diseases. Individual differences in the permeability of the round window: Evaluating the movement of intratympanic gadolinium into the inner ear.
Analysis of gentamicin kinetics in fluids of the inner ear with round window administration.
The biology of intratympanic drug administration and pharmacodynamics of round window drug absorption. Intratympanic versus intravenous delivery of dexamethasone and dexamethasone sodium phosphate to cochlear perilymph. Dexamethasone concentration gradients along scala tympani after application to the round window membrane.
Hyaluronic acid hydrogel sustains the delivery of dexamethasone across the round window membrane. Cochlear protection by local insulin-like growth factor-1 application using biodegradable hydrogel.
Direct round window application of gentamicin with varying delivery vehicles: A comparison of ototoxicity. Distribution of dexamethasone and preservation of inner ear function following intratympanic delivery of a gel-based formulation. Dexamethasone pharmacokinetics in the inner ear: Comparison of route of administration and use of facilitating agents. Permeability of the round window membrane is influenced by the composition of applied drug solutions and by common surgical procedures.
Morphologic changes in round window membrane after topical hydrocortisone and dexamethasone treatment.
Characteristics of the immune system in the human middle ear and middle-ear mechanisms against bacteria are explained.
One of the first and most important studies pertaining to the immunological aspects of the middle ear, published in 1974 [2], concerned the role of the secretory immune system in the middle ear and otitis media.
In this article, we emphasize the importance of continued investigations into the facilitative or protective contributions of the round-window membrane in inner-ear toxicity in the several forms of otitis media. Within the mucin are found substances that can either kill the bacteria or inhibit their growth: lysozyme, lactoferrin, and lactoperoxidase [4].
This specific defense system depends on the secretory antibodies, mainly secretory immunoglobulin A (IgA). The first system is made up of a complement system, phagocytes (macrophages and polymorphonuclear neutrophils), and transferrin. Pathological events can be caused by a direct effect of the bacteria itself: Bacterial penetration of all three layers of the round-window membrane was demonstrated experimentally and resulted in bacteria entering into cochlear turns and neuronal pathways, causing nerve degeneration and edema and hemorrhage of the stria vascularis [8]. Experimentally, the same pattern of otitis media pathological changes were observed in the round-window membrane and in the mucoperiosteum of the middle ear. Even middle-ear effusion, often considered to be or described as a sterile condition, is now accepted as containing bacteria and bacterial products in a high percentage of cases [16,l7], and the predominant microorganisms are the same as those in acute otitis media [18,19].
Mediators are biochemical components produced by epithelial cells, infiltrating inflammatory cells, and endothelial cells, which mediate inflammatory reactions in a sequential manner [20].
Only after drilling the lateral edge of the round window niche is the round window membrane clearly visible.
Photomicrograph of the normal human round-window membrane, which consists of an outer low cuboidal epithelium (left side of the image) , a middle core of connective tissue, and an inner simple epithelium (right side of the image).
The inner ear fluid maintains its homeostasis by a variety of regulatory mechanisms such as an ion transport system, a blood-labyrinth barrier, and a constant blood supply. Inner ear fluids are maintained by a delicate balance of homeostatic mechanisms that include a blood-labyrinth barrier (BLB), epithelial ion transport systems, and a constant blood supply [2]. They provide an appropriate ionic environment for optimal generation of the membrane potentials that are necessary for inner ear function. Endolymph, the fluid within the membranous labyrinth of the inner ear, and perilymph, the fluid that surrounds the membranous structures, differ markedly in their composition, and both playa vital role in the physiology of the inner ear. The BLB is thought to be an important homeostatic mechanism that protects the delicate ionic balance within the labyrinth. Percentage of serum concentration or activity in perilymph after systemic administration of various biological substances. Tight junctions present in the stria vascularis contribute to the distinct ionic environment of the endolymph.
When this mechanism is functioning normally, stretch or pressure forces displace hair cell stereocilia and cause opening or closure of K+ -conducting ion channels, which in turn depolarizes and repolarizes the hair cell body. Ion channels function by gating in response to external stimuli, and they may be classified by their response to stimuli.
Substances such as neurotransmitters and some drugs bind extracellularly, whereas intracellular second messengers, signaling molecules, and enzymes such as protein kinase interact with the cytoplasmic face.
Na+K+-adenosine triphosphatase (Na+K+-ATPase) is responsible for the active transport of Na+ and K+ across the cell membrane, which maintains the K+ gradient between endolymph and perilymph essential for auditory transduction. Binding of cell signaling molecules to membrane receptors or ion channels activates an intracellular signaling pathway and is an important regulatory control point for modifying a cell's response to changes in the extracellular environment. Ionic equilibrium in perilymph and endolymph can be affected by changes in the BLB induced by ototoxic drugs. Principally implicated as a mediator of oxidative stress and inflammatory and infection-related damage in the central nervous system and other tissues is the presence of increased concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS). It is produced in neurons by conversion of L-arginine by inducible NO synthase, a process that requires calcium bound to calmodulin (Ca2+-CaM). Aminoglycoside toxicity may be attributed to the combined effects of several mechanisms resulting in a disruption of normal function and integrity of the cell membrane.
Administration of a high dose of salicylate is known to produce reversible hearing loss and tinnitus [54].
Stress hormones can act as powerful intercellular signals and are reported to have local and systemic effects on hearing. The pathology of Meniere's disease is known to include enlargement of the endolymphatic sac, endolymphatic hydrops, and bulging of Reissner's membrane into the scala vestibuli.
Possible mechanisms of inner ear disturbances (endolymphatic hydrops) by epinephrine administration. It appears that epinephrine infusion results in adrenergic receptor stimulation at the cell membrane of epithelial cells in the lateral wall of the cochlea [62].


Under physiological conditions, prostaglandin may be involved in the maintenance of stable membrane permeability to water and ions through adenylate cyclase [61]. Traumatic noise exposure has also been demonstrated histopathologically to destroy auditory hair cells, especially OHCs, to contribute to the collapse of the organ of Corti, and to impair cochlear circulation.
Four types of presbycusis have been defined on the basis of a study of audiometric data and the histological findings in the elderly [68].
In 1974, Schuknecht [68] suggested that strial presbycusis is likely to have a genetic etiology because of clinical impressions that the disorder is prevalent in certain families. Thus, it is conceivable that presbycusis may be due to a genetic predisposition for the factors that are associated with sensorineural and other types of age-related hearing loss. The BLB is composed, in part, of tissues adjoining the membranous labyrinth and has been shown to protect the inner ear from unlimited entry of substances into the inner ear fluids.
The inner ear fluid maintains its homeostasis by a variety of regulatory mechanisms such as an ion transport system, a BLB, and a constant blood supply. Free radicals, stress hormones, noise exposure, and aminoglycoside antibiotics may induce short- and long-term effects on cellular function of the auditory or vestibular system (or both). Even if the symptoms mostly decrease after a little while an acute or chronic tinnitus often remains. However, personal hobbies and other activities can help to direct your attention to positive things.
Doing without or moderate consumption of alcohol and nicotine are truly a€?music to your earsa€?. The rise in interest in this local drug delivery approach may be explained by our increased knowledge and understanding of inner-ear pharmacology and pharmacokinetics from animal studies.
The role of bacteria and bacterial products in inner-ear damage is detailed, and related pathological events are described. The concept that the inner ear is capable of mounting an immune response dates back only to the 1980s [3]. Sialic acid-containing oligosaccharides of the mucin form another defense mechanism and appear to act as mucin receptors for the bacteria, preventing their adherence to the epithelial wall, thus modulating bacterial colonization [5].
This system depends on B cells derived from mucosa-associated lymphoid tissue (MALT), which consists of lymphoepithelial structures, such as those constituting Waldeyer's pharyngeal ring [6]. Bacterial products also were important: Instillation of a suspension of Escherichia coli endotoxin into the round-window niche in rats demonstrated an inner-ear disturbance using a frequency-specific auditory brain stem response technique [9]. These changes could account for modifications of permeability, rendering the membrane an easy pathway from the middle to the inner ear [12]. In chronic otitis media, the most common isolate is Pseudomonas aeruginosa, and other isolates include such aerobic organisms as Staphylococcus aureus, S.
Besides bacterial infections, endotoxins, exotoxins, and other bacterial products, inflammatory mediators could be involved in the development of sensorineural hearing loss, the more frequent complication attributable to interaction between the middle ear and the inner ear [21].
Initially, round-window membrane alterations induced by otitis media were thought to be restricted to or predominantly centered in the outer epithelium, but subsequent ultrastructural studies demonstrated that the three layers participate in the resorption and secretion of substances to and from the inner ear [30]. For easy identification of the membrane for the image, the membrane was disrupted, and the lumen of scala tympani then is clearly visible. The entire membrane might participate in the inner-ear defense mechanism , but structural changes in otitis media were confined mainly to the inner epithelium and connective ti ssue layers. Characteristics of secretory immune system in human middle ear: Implications in otitis media. Binding between outer membrane proteins of nontypeable Haemophilus influenzae and human nasopharyngeal mucin.
Bacteriology of acute otitis media in a cohort of Finnish children followed for the first two years of life.
Bacteriological findings and persistence of middle ear effusion in otitis media with effusion. Effect of prostaglandin, leukotriene, and arachidonic acid on experimental otitis media with effusion in chinchillas. Effect of exogenous arachidonic acid metabolites applied on round window membrane on hearing and their levels in the perilymph. Cytokine profiles in a rat model of otitis media with effusion caused by eustachian tube obstruction with and without Streptococcus pneumoniae infection. Highly regulated transport of ions into and out of the inner ear provides for the maintenance of inner ear fluid composition necessary for auditory transduction.
A number of factors, such as free radicals, emotional stress, anoxia, noise exposure, and aminoglycoside antibiotics, may disrupt ionic homeostasis by interacting with ion channels and the cellular processes that regulate the dynamic fluid environment of the inner ear. Like other barrier systems (blood-brain barrier, blood-cerebrospinal fluid barrier, blood - aqueous humor barrier), tight junctions within the capillaries of the spiral ligament form the morphological site of the BLB and prevent the passage of substances from blood into the fluid of the inner ear (Fig. It appears that its entry exhibits ratelimiting saturation, and glucose transport appears to be carrier-mediated. Passive spread of depolarization due to K+ influx from endolymph throughout the stereocilia into the hair cell soma activates an inward Ca2+ current, which drives nearby Ca2+-dependent K+ channels, resulting in an outward K+ current that releases neurotransmitter from the base of the hair cell. Voltage-gated ion channels open in response to a change in electric potential that normally exists across the plasma membrane of cells at rest. Hair cells have mechanically gated ion channels that are opened by deformation of the cell membrane. Na+K+-ATPase pumps three Na+ ions out of the cell for every two K+ ions pumped in, thus balancing the Na+ influx and K+ efflux. Activation of various effector proteins can lead to the production of second messengers, components of the cell signaling pathways that are important mediators of ion channel functions, such as kinases dependent on cyclic guanosine monophosphate (cGMP-dependent kinases), nitric oxide (NO), soluble guanylyl cyclase, inositol triphosphate, diacyl glycerol, and calmodulin (CaM). Most important, intracellular Ca2+ regulates many cell functions such as modulation of ion channels, enzyme activation, and gene expression. Systemic injection of urea or glycerol has been shown to disrupt the tight junctions between pericytes, among other cells that comprise the BLB, and to induce a change in inner ear fluid osmolality by shifting water that freely moves across the BLB and inner ear membranes.
NMDA receptors are normally "plugged" by Mg2+ and are permeable to Na+ and Ca2+ only when bound by ligand. Redox reactions with gentamicin form a gentamicin-iron chelate that will produce free radicals both in vitro and in intact cells [44]. Gentamicin may induce key components of the apoptotic biopathway or stress-activated kinases that mediate apoptotic cell death in several cell types, which have been shown to be activated in hair cells in response to stressful stimuli [45].
The aminoglycosides gentamicin and kanamycin are known to be differentially ototoxic to vestibular and cochlear hair cells. Systemic administration of a stress hormone may induce shortand long-term effects on cell function by promoting transcription of target genes or through the initiation of phosphorylation signaling cascades and may exert significant effects on the delicate homeostatic mechanisms of inner ear fluid and function of the inner ear [3].
It is accepted that disturbances of the inner ear fluid homeostasis and breakdown of the integrity of the inner ear tissues can lead to endolymphatichydrops. Inamura and Salt [9] reported that the rate of tracer entry into perilymph could be increased by epinephrine-induced hypertension or by simultaneous administration of histamine and prostaglandin E2.
Tinnitus may be attributed to a leakage in the apical or lateral potassium channel, metabolic disorders affecting intracellular calcium levels, and aminoglycoside toxicity. The majority of hearing loss involves progressive sen sorineural cochlear pathology characterized by marked degeneration of OHCs and nerves, most notably in the basal end of the cochlea and resulting in the loss of high-frequency hearing.
Throughout life, our immune systems are triggered to produce intermittently toxic concentrations of free radicals that can bind indiscriminately to nearby tissues. Future research should be directed to exploring basic mechanisms of the aging processes in general as well as specific functional and clinical entities. Processes associated with the metabolic activity of the BLB allow the inner ear to respond to an altered biochemical environment of a systemic or local nature and to regulate the chemical composition of the inner ear fluids. These effects are mediated by interaction with ion channels, membrane-bound G-protein-linked receptors, and the cellular processes that promote transcription of target genes or through the initiation of phosphorylation signaling cascades that exert significant effects on the delicate homeostatic mechanisms of inner ear fluid and, consequently, on the function of the inner ear.
Permeability changes of the bloodlabyrinth barrier measured in vivo during experimental treatments. Ion transport mechanisms responsible for K+ secretion and the transepithelial voltage across marginal cells of stria vascularis in vitro. Mechanism generating endocochlear potential: Role played by intermediate cells in stria vascularis. The fine structure of spiral ligament cells relates to ion return to the stria vascularis and varies with place-frequency. An immunohistochemical and electrophysiological study on Isk protein in the stria vascularis of the guinea pig. Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Expression of a potassium current in inner hair cells during development of hearing in mice.
Membrane potential depolarization in the porcine ciliary epithelium evoked by nitric oxide.
Roles for NAD(P)H oxidases and reactive oxygen species in vascular oxygen sensing mechanisms [review].
Nitric-oxide induced mobilization of intracellular calcium via the cyclic ADP-ribose signaling pathway.
Calcium and protein kinase C mediate high-glucose-induced inhibition of inducible nitric oxide synthase in vascular smooth muscle cells.
Pertussis toxinsensitive G proteins influence nitric oxide synthase III activity and protein levels in rat heart. Alteration of the calcium content in inner hair cells of the cochlea of the guinea pig after acute noise trauma with and without application of the organic calcium channel blocker diltiazem. Suppression of hypoxia- associated vascular endothelial growth factor gene expression by nitric oxide via cGMP. Activation of soluble guanylate cyclase and potassium channels contribute to relaxations to nitric oxide in smooth muscle derived from femoral veins.
Nitric oxide directly activates calcium-activated potassium channels from rat brain reconstituted into planar lipid bilayer.
Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. Nitric oxide inhibits L-type Ca2+ current in glomus cells of the rabbit carotid body via a cGMP-independent mechanism. Biochemical aspects of inner ear fluids and possible implications for pharmacological treatment.
Intraotic administration of gentamicin: A new method to study ototoxicity in the crista ampullaris of the bullfrog. Estimation of perilymph concentration of agents applied to the round window membrane by microdialysis. Gentamicin blocks Ach-evoked K+ current in guinea-pig outer hair cells by impairing Ca2+ entry at the cholinergic receptor.
Sensorineural hearing loss owing to deficient G-protein in patients with pseudohypoparathyroidism: Results of a multicentre study. The possible roles of hormones and enzymes in the production of the acute attack in Meniere's disease. Perilymphatic fluid compartments and intercellular spaces of the inner ear and the organ of Corti. However, it probably also reflects a growing awareness among otolaryngologists of the advantages of local therapy for inner-ear disorders, and the increasing comfort level associated with its use. The hypothetical role of inflammatory mediators in bacteriainduced inner-ear toxicity is particularly emphasized. Ciliary function is also important because it promotes drainage of mucus and secretions or pus from the middle-ear cavity through the eustachian tube. These MALT-induced B cells migrate through lymph and blood to target such tissues as the middle-ear mucosa, where they differentiate after extravasation to IgA-producing plasma cells. However, a large field of knowledge remains to be elucidated about the extent to which these roundwindow otitis media-induced alterations influence the permeability of the membrane [31]. Any disturbance in one of these mechanisms can disrupt homeostasis expressed by ionic, osmotic, or metabolic imbalance between the compartments. Ion channels are essential to maintain a unique composition of inner ear fluid required for auditory transduction.
The inner ear fluids seem to serve as a means for transport of nutrients and oxygen to the outer hair cells (OHCs) and inner hair cells (lHCs) of the organ of Corti and also for the removal of metabolic waste products from the cochlea [4]. The high Na+ content and low K+ content of perilymph is controlled by local homeostatic mechanisms or by radial flow through the cochlea [5]. Therefore, the BLB seems to serve as a protective mechanism for maintenance of the constancy of the inner ear fluid composition.
It has long been accepted that marginal cells of the stria vascularis are involved in the production of potassium-rich endolymph and generation of a positive endocochlear potential of +85 mY [13]. Ligandgated ion channels are insensitive to voltage changes but are opened by the noncovalent, reversible binding of chemical ligands to extracellular or intracellular domains. These can, in turn, act on such secondary effectors as protein kinases and phosphatases that target ion channels. A shift in water out of the endolymphatic space into the blood results in an increase in endolymph osmolality, disrupting the local ionic homeostasis.
Stress hormones have been reported to have local and systemic effects on hearing by exerting significant effects on the delicate homeostatic mechanisms of inner ear fluid and function of the inner ear. NO and its metabolites do not interact with specific membraneassociated receptor proteins but instead interact with second messenger systems in the target cell to modulate secondary intracellular signaling pathways. Intracellular Ca2+ is highly regulated by NO, cGMP, and protein kinase-G pathways involving reversible modification of protein kinases and other intracellular proteins and has been shown to decrease inositol triphosphate-induced Ca2+ release but may also mobilize intracellular Ca2+ stores by a cGMP pathway or in response to increased intracellular adenosine triphosphate levels. When glutamate binds to the NMDA receptor, Mg2+ is expelled, causing an influx of Na+ and Ca2+. Furthermore, aminoglycosides bind strongly to phosphoinositides and may enhance free radical formation by bringing the drugs in close proximity to arachidonic acid, which is the preferred substrate for free radical production by gentamicin [43]. Pharmacokinetics, cellular actions, and our current understanding of the molecular mechanisms underlying ototoxicity were recently reviewed [46]. First, by binding to the plasma membrane, the aminoglycoside induces the release of calcium, which competes with normal polyamine transport and energy consumption during the uptake of the drug into the cell.
This mechanism may describe the observation that aminoglycosides block K+ current by inhibiting Ca2+ influx via nicotinic-like receptors (nAchRs). Another mechanism may be a contraction of OHCs pulling on the tectorial membrane toward the stereocilia, which increases spontaneous activity of the IHCs.
These effects are mediated by the binding of stress factors to membrane-bound G-protein-linked receptors [55].
Emotional stress or severe anxiety can precipitate or aggravate the symptoms of Meniere's disease. Prostaglandins, by altering membrane permeability in the inner ear, may play an important role in the maintenance of cochlear homeostasis [49].
However, no single theory has been posited that adequately defines the role of the BLB in the development of inner ear pathological processes. Ion channels, including Na+K+-ATPase, delayed rectifier K+, Ca2+-dependent K+ channels, and voltage-sensitive Ca2+ channels have been localized to stria vascularis as well as to IHCs and OHCs and are primarily responsible for maintaining the electrical potential of the hair cells. In R Gregor, V Windhorst (eds), Comprehensive Human Physiology- From Cellular Mechanisms to Integration. Abstract of the TwentyFourth Annual Midwinter Meeting of the Association for Research in Otolaryngology, St.
Proceedings of the Fourth International Symposium on Meniere's Disease, Paris, France, April 10-14, 2000. Abstract and poster presented at the Association for Research in Otolaryngology Midwinter Meeting, St.
With chronic tinnitus, more importance is attached to stress-reducing measures so that the persons affected learn to handle their tinnitus. Clinical conditions causing these events are detailed, and the most frequently involved microorganisms are mentioned. The round-window membrane is permeable to many substances, including inflammatory mediators, and many studies have shown that these mediators can affect inner-ear function, as seen in auditory brainstem response, cochlear microphonics, otoacoustic emissions, and cochlear blood flow studies [20]. An equally important consideration is that at least part of the response to inflammation is protective [20].
Free radicals, stress hormones, noise exposure, and aminoglycoside antibiotics may induce short- and long-term effects on cellular function of the auditory or vestibular system (or both) and serve as a triggering mechanism for abrupt functional disturbances of inner ear fluid ion homeostasis.


Knowledge of the mechanisms that regulate ion channel function provides a basis for understanding how disturbances to inner ear homeostasis can lead to cellular toxicity and hearing dysfunction.
Finally, the inner ear fluids serve as relay media for the vibrations transmitted from the footplate of the stapes to the auditory transduction centers in the inner ear.
Unlike other barriers, however, the BLB seems to be less permeable to several ions (sodium, chloride, and calcium) and differentially modulates the passage of larger substances in proportion to molecular weight [8]. The Na+K+-ATPase has been localized to marginal cells of the stria vascularis [16] and to type II fibrocytes in the inferior portion of the spiral ligament.
Ion channel disorders such as tinnitus or metabolic disorders are characterized by a leakage in the apical or lateral potassium channel, affecting intracellular calcium levels. Changes in intracellular Ca2+ concentration can affect the membrane potential of the hair cell by decreasing the apical-basal K+ gradient and result in an increase in the threshold for generation of gated response.
After systemic administration of the steroid hormone epinephrine, Juhn and Rybak [6, 23] reported a similar increase in perilymph osmolality and altered cochlear physiology (Fig. Other late-emerging factors, such as a failure of the immune system, onset of autoimmune disease, or hypoxia due to vascular insufficiency, also may contribute to disruption of inner ear fluid homeostasis (Table 3). In particular, NO has been shown to regulate the permeability of cell membranes by activation of soluble guanylyl cyclase, mobilization of intracellular Ca2+, and covalent modulation of signaling pathways [25-35]. In response to ischemic or hypoxic injury, excess glutamate causes an increase in Ca2+ influx that activates endoproteases, mitochondrial excitotoxicity, and generation of free radicals, which eventually leads to neuronal cell death.
Second, by binding to phosphatidylinositol 4,5-bisphosphate on the cytoplasmic side, the aminoglycoside may disrupt the normal function and integrity of the cell membrane. It is known that hormone receptors are desensitized by adrenoreceptor kinases in the continuing presence of an agonist [56]. Increased norepinephrine and vasopressin levels in the plasma of patients with Meniere's disease have been reported [58-60]. Other possible mechanisms of ROS-mediated presbycusis may involve the accumulation of free radical damage to mitochondrial DNA, inactivation of important regulatory proteins, and apoptosis [69, 70]. Any disturbance in one of these mechanisms can induce the disruption of homeostasis expressed by ionic, osmotic, or metabolic imbalance between the compartments. Finally, roundwindow membrane macroscopic and microscopic anatomy is discussed, and considerations about the exact role of membrane inflammation - protection versus damage of the inner earare expressed. The exact role of inflammatory consequences of otitis media in protection of versus damage to the inner ear has yet to be determined. In this article, we present a comprehensive review of the mechanisms underlying inner ear fluid homeostasis necessary for normal auditory function and factors that can disrupt homeostasis and lead to functional disturbances, namely sensorineural hearing loss, tinnitus, and vertigo. The BLB has been characterized and is believed to maintain inner ear fluid composition by protecting the inner ear from toxic substances present in the systemic circulation, selectively limiting substance entry into the inner ear.
However, the composition of endolymph is now known to be derived from transcellular diffusion of perilymph and is maintained by metabolic processes.
The existence of a tight BLB, equivalent to the blood-brain or bloodcerebrospinal fluid barriers, has been confirmed by the demonstration of slow entry of tracer into perilymph [9]. An electrochemical resonance is created in the stereocilia owing to opposing cycles of depolarization and repolarization, which reinforces the mechanical action of the tectorial membrane and produces sharp tuning of the basilar membrane. Its activity has been suggested to be hormonally regulated [17, 18] and is involved in the ion transport system in the cochlear tissues [3]. The rates of movement of these ions from blood into the perilymphatic space have been studied [8].
High-voltage, activated Ca2+ channels such as the L-type open only in response to large cellular depolarizations and are found in cardiac and skeletal muscle as well as several types of neurons. Adenosine triphosphate-sensitive Ca2+-activated K+ channels, large-conductance Ca2+-activated K+ channels, and maxi-K+ channels are known to be activated by NO-associated cGMP-dependent mechanisms [36, 37]. Smith [42] reported that there is increasing evidence to suggest that excessive NMDA receptor activation and NO production after exposure to aminoglycoside antibiotics is a critical part of hair cell death. Investigators have reported a long half-life and saturation concentration of gentamicin after intravenous administration [10, 48]. When the signal termination processes are not functioning, epinephrine may continuously activate the adenylate cyclase (adenosine 3',5'cyclic monophosphate [cAMP]) pathway, disrupt ion homeostasis, and lead to membrane displacement and functional anomalies in the inner ear (Fig.
The effects of epinephrine and steroid hormones can also lead to increased intracellular calcium by allosteric modification of calmodulin or through phosphorylation cascades such as inositol triphosphate or cAMP.
It enhances absorption in the epithelia by increasing the permeability of the luminal membrane to water and sodium.
Reissner's membrane is elastic and is able to maintain itself electrically intact despite considerable distention. This can be manifested as membrane displacement or functional disturbances of the inner ear and can serve as a triggering mechanism for abrupt functional disturbances seen in such diseases as Meniere's disease, sensorineural hearing loss, tinnitus, and presbycusis. Bacterial products generated by some of these microorganisms and involved in deleterious inner-ear effects were mentioned by Hellstrom et al. The comprehension of these mechanisms is of fundamental importance to the development of measures to counteract inner-ear consequences of otitis media, particularly sensorineural hearing loss and tinnitus.
Inner ear diseases such as Meniere's disease and associated symptoms of sensorineural hearing loss and tinnitus commonly are attributed to disruptions of inner ear fluid homeostasis, although the precise etiology is unknown. The potential difference between the endocochlear potential and the resting potential of hair cells (OHCs, - 70 mY; IHCs, - 40 mY) drives K+ into the hair cell cytoplasm. IHCs express predominantly voltage-gated L-type Ca2+ channels [20] and large conductance calciumactivated K+ channels [21]. NO may also modulate signaling pathways by inhibiting stress-induced phosphorylation of protein kinases or by stimulating cGMP-dependent kinases in parallel with protein kinases, resulting in increased phosphorylation of transcription factors [38, 39]. Pharmacokinetic studies of aminoglycosides indicate that drugs administered systemically reach the inner ear and can be found in endolymph and perilymph in equal ratios for a prolonged period [48]. Increased ion permeability due to this increase in cAMP is reflected in K+ elevation in the perilymph [61].
However, in response to extreme pressure increases associated with high-intensity sound, hyperdistention of Reissner's membrane into the scala vestibuli can result in a breakdown of normal potential and potassium intoxication of the hair cells. Free radicals that mistakenly bind to proteins and DNA in our own tissues cause significant cellular and molecular damage.
Recent data have shown that the type of changes associated with disruptions to inner ear homeostasis may also be strongly influenced by genetic factors [3].
The amino acid profile of cochlear perilymph and utricular endolymph has been reported [7]. The electrochemical gradient of ions, especially K+, produced by this process is essential for auditory transduction [15]. OHCs are known also to express cholinergic receptors that involve nAchRs permeable to Ca2+ ions and that activate nearby Ca2+ sensitive K+ channels. NO may also act as a regulatory element that modulates apoptosis by interfering with promoters or by reducing activity of caspases (Fig. Juhn and Youngs [10] reported that perilymph levels generally reach a maximum of J 0% of serum levels after a distinct time delay of up to 1 hour. Recently, adrenoreceptor and receptor kinases involved in the desensitization processes in the rat cochlear tissue have been identified [3]. These findings suggest that the distention of Reissner's membrane provides limited protection for the organ of Corti by resisting functional and structural breakdown against trauma caused by static pressure and pressure developing during moderate-intensity sound.
Protective enzymes are present in tissues that usually intercept the free radicals but, as a result of age or certain toxic conditions, the effectiveness of these enzymes may be reduced.
Thus, it is conceivable that individuals may be genetically predisposed to develop certain types of hearing loss.
Although the mechanisms for an increase of intracellular Ca2+ and outward currents have yet to be determined, it is interesting to observe that stress-related hormones can affect the biochemical as well as the electrochemical characteristics of marginal cells (Fig. Consequently, cellular repair machinery may become overwhelmed by unchecked free radical damage, so that tissues are not repaired or are repaired at a slower rate.
We will introduce possible factors and mechani sms involved in regulating inner ear fluid homeostasis, the importance of the BLB in maintaining the integrity of inner ear fluid, and the possible involvement of these factors in the pathophysiology of inner ear diseases. However, abnormal receptor kinase expression due to failure of desensitization may retain high levels of hormones and cAMP and cause disturbances in ion homeostasis. Thus, the combined effects of damage caused by repeated free radical damage and a subsequent decrease in the effectiveness of cellular repair mechanisms may be responsible for presbycusis. This suggests that β-adrenoreceptor kinases may participate in the phosphorylation of G-protein-coupled receptors for proper hormone action of epinephrine. The types of changes that accompany aging can also be strongly influenced by genetic factors that may predispose individuals to develop certain types of presbycusis. Diffusion occurs across the semi-permeable round window membrane (RWM), driven by the concentration gradient between the middle ear and the perilymph-filled scala tympani on the opposite side of the RWM. The existence of factors involved in the desensitization of stress-related hormones in cochlear tissues supports the hypothesis that disruption of the inner ear fluid homeostasis may be related to the failure of the desensitization system [64].
Certain gene defects, as seen in other neurological diseases such as episodic ataxia [65], may also occur in patients with inner ear diseases such as Meniere's disease.
This may explain the increased susceptibility of patients with Meniere's disease to the effects of stress as com pared to those without the disease. Medication is injected through the tympanic membrane into the middle ear cavity in a quantity that is sufficient to fill the round window niche. It is conceivable that molecular markers can be developed as a tool for screening patients with Meniere's disease when sufficient evidence can be collected.
The active substance is diffusing across the round window membrane into the basal turn of the perilymph filled scala tympani of the cochlea from where it is spreading furtherClick here to viewThe RWM consists of three layers: An outer epithelium facing the middle ear, a core of connective tissue, and an inner-ear epithelium bordering the inner ear. Future molecular biological studies of factors involved in stress-related hormone action and desensitization may provide basic information necessary to understand the genetic basis of disturbances of inner ear fluid homeostasis.
As sound waves enter the cochlea via the oval window and travel through the liquid-filled turns of the cochlea, their energy has to be dissipated somehow because a liquid is not compressible.
The inner ear is an end organ with regards to its blood supply, and it is protected by a blood-labyrinth barrier similar to the blood-brain barrier, [5] thus requiring considerable systemic doses.
It has been demonstrated, for example, that cortisol levels in the perilymph do not increase following intravenous administration of a high dose of prednisolone (125 mg) in comparison with a placebo. They can be performed under a microscope with the patient sitting reclined on the examination chair or lying on a stretcher. For the procedure, the patient's head is usually placed in a position tilted 45° towards the unaffected ear. Patients are asked to remain in this position for about 30 min, allowing the active substance to diffuse into the inner ear. The xylocaine pump spray has a very short induction time of about 1-3 min, while EMLA cream requires 1 h. Once the anaesthesia has taken effect, any remaining anaesthetic needs to be suctioned off prior to the injection to avoid spillage into the middle ear, and avoid vertigo or dizziness. During all these preparations, the drug can be warmed up to about body temperature to prevent caloric vertigo.For the injection, various techniques and different materials are used. Typically, 1 ml syringes are used - preferably with a luer lock to prevent uncontrolled release of the needle while injecting. Frequently, a spinal needle is used, which may be slightly bent by hand, or a microsuction cannula. Alternatively, a small paracentesis (myringotomy) is made first, and then the needle penetrates through that incision.
This other version allows the RWM patency to be verified by otoendoscopy prior to the injection, and allows air to escape during the injection, thus preventing the build-up of pressure in the middle ear; the Eustachian tube may not always be "open" for air displacement. Some flexibility in the quantity of administered drug makes sense, as the volume of the middle ear is highly variable between normal hearing ears, measuring between 0.5 ml and 1 ml.
Trowbridge had observed that tinnitus and otalgia often appeared together, and ascribed this to inflammation of the tympanic plexus. With ethylmorphine hydrochloride, an analgesic and vasoactive substance, which at that time had already been used in ophthalmology for removing inflammation products from the eyes, he sought to "calm" the tympanic plexus, thus suppressing tinnitus, and rehabilitate middle-ear tissues. Mitchell from the Royal Infirmary in Edinburgh, UK, failed to replicate Trowbridge's results shortly after their publication, reporting no improvement in the majority of subjects (seven out of 11), and only a slight and transient improvement in the others.
Firstly, lidocaine, another local anaesthetic which acts as a sodium-channel blocker, was tested by several groups in the treatment of Menière's disease by way of systemic administration. Starting in the 1990s, steroid drugs were evaluated in an increasing number of clinical studies for Menière's disease and sudden deafness, although in most cases not specifically for tinnitus control.
A clinically relevant improvement (reduction of at least 2 points on a 10-point numerical rating scale for tinnitus severity) was claimed in 57% of cases. Probably, the most important source of variability arises from the fact that the RWM is anything but a standardized "drug delivery port". Its thickness (on average 70 μm) and, especially, its size varies widely in humans [3] and in some cases, it is also covered or obstructed by an extraneous "false" membrane stretching across the opening of the niche in front of the RWM, or by fibrous or fatty plugs within the niche itself.
Temporal bone studies have revealed the presence of false membranes in more than 20% of cases, and a lower prevalence of fibrous and especially fatty plugs; overall, the prevalence of RWM obstructions is thought to be up to 32%.
False membranes are sometimes perforated or reticular, [38] thus merely impeding diffusion of a drug rather than blocking it entirely. Distribution of drugs within the perilymph-filled scala tympani of the cochlea is dominated by passive diffusion, with slow substance movement and increasing loss through distribution into adjacent fluid spaces and tissue compartments, and elimination along the length of the cochlea. While direct determination of the gradient in a human cochlea is usually not feasible, it has been estimated in a computer-based simulation for i.t. Three studies with patients undergoing cochlear implantation, labyrinthectomy or translabyrinthine surgery found that perilymph concentrations varied significantly following i.t.
Thirdly, if the target site of action is located in the middle or apical turns of the cochlea, continuous perfusion or repeated i.t. Formulations or devices that ensure retention and facilitate physical contact with the RWM are preferable to solution-based formulations, which can easily get lost through the Eustachian tube. This may be achieved by injecting viscous gel formulations, or by placing wicks, microcatheters or drug-eluting implants (stabilizing matrices) [45] into, or close to, the round window niche. They include hyaluronates [13],[46] collagens, [47] chitosans, [48] fibrins, [49] starch, celluloses, gelatines, [50] poloxamers, [51] and many others. Some of them, like hyaluronates and gelatine, are natural products frequently used in otolaryngology for other clinical purposes, and whose safety has been extensively studied. Viscosity that is too high may also result in the formation of an air bubble on the RWM [Figure 3], thus preventing effective diffusion, or temporarily impact the free movement of the ossicular chain, resulting in transient conductive hearing loss, as observed, for example, with a poloxamer gel.
Suckfuell, Munich (Germany)Click here to view It seems tempting, of course, to enhance RWM diffusion of a drug by incorporating excipients into the formulation that are known to enhance permeability, such as histamine or dimethylsulfoxide (DMSO), [53] prostaglandins or leukotrienes, [3] or to use microsphere or nanoparticle formulations.
The results are not directly comparable due to differences in treatment protocols (number of injections, inclusion of placebo, etc.), data collection and size. Usually, they are of a transient nature, and their risk of occurrence can be reduced in most cases through simple measures. Sufficient warming of the drug, the use of fine needles and appropriate local anaesthesia, a gentle rate of injection, and avoidance of excessive injection volumes seem to be key factors for good local tolerance. From discussions with otolaryngologists, it would seem that closure can be expected in the majority of cases in between 2 and 5 days. In a small study involving single-dose injection through a paracentesis (and following otoendoscopy), the tympanic membrane was found to be closed 7 days later in 21 out of 24 patients.
Where there has been repeated drug administration, subsequent injections are preferably performed at the site of the initial tympanopunction, respectively paracentesis. As long as the tympanic membrane is open, the patient should avoid exposing the treated ear to water.Following the treatment administration, the otolaryngologist should remind the patient that once he or she gets up small quantities of the study drug may drain down the Eustachian tube and the nasopharynx, and that the perception of sound, including pre-existing tinnitus, may change while the eardrum remains open. Systemic exposure is minimal, the procedure is simple and straightforward to carry out, and usually well tolerated in patients. Appropriate information prior to the procedure, the use of fine needles and adequate local anaesthetics with short induction times, a gentle flow rate and moderate injection volumes, as well as a sufficiently warmed drug, reduce the likelihood of adverse events, and enhance patient acceptance. The lack of specific effective drugs must be considered the first and foremost obstacle for a more widespread use of the i.t.
Most of the studies carried out so far also suffer from important shortcomings such as a lack of statistical power, double-blinding or placebo control: The absence of the latter is of particular importance given that tinnitus treatments may elicit substantial placebo responses.
The numerous lidocaine experiments have proved that tinnitus can indeed be modulated pharmacologically, although the mechanism of action through which tinnitus suppression is achieved still remains a mystery.



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