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1.
CNS Oncol ; 9(1): CNS50, 2020 03 01.
Article in English | MEDLINE | ID: mdl-32141326

ABSTRACT

Endolymphatic sac tumors (ELSTs) are rare, locally invasive, vascular tumors of the temporal bone. These lesions are associated with von Hippel-Lindau syndrome but may arise sporadically. Early surgical intervention is recommended to prevent permanent neurologic deficits; however, many ELSTs are unresectable or are subtotally resected due to neurovascular compromise. Chemotherapeutic salvage therapy in trials of neoplasms of associated syndromes has targeted angiogenesis with variable response. We present the case of a sporadic ELST, previously minimally responsive to bevacizumab, treated with pazopanib, a multi-kinase inhibitor and antiangiogenic, with good response. Cases such as our patient may demonstrate the utility of novel antiangiogenics in the treatment of these rare neoplasms, particularly when the tumor is unresectable or necessitates subtotal resection.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Ear Neoplasms/drug therapy , Endolymphatic Sac/drug effects , Adult , Bevacizumab/administration & dosage , Ear Neoplasms/pathology , Endolymphatic Sac/pathology , Humans , Indazoles/administration & dosage , Male , Prognosis , Pyrimidines/administration & dosage , Sulfonamides/administration & dosage , von Hippel-Lindau Disease/pathology
2.
PLoS One ; 13(11): e0207467, 2018.
Article in English | MEDLINE | ID: mdl-30440019

ABSTRACT

INTRODUCTION: Middle ear application of gentamicin is a common medical treatment for uncontrolled Ménière's disease. The objective of the study was to evaluate the impact of endolymphatic hydrops on inner ear delivery. METHODS: Perilymph gentamicin concentrations and correlation with endolymphatic hydrops in an animal model were assessed. A group of 24 guinea pigs was submitted to surgical obstruction of the endolymphatic sac and duct of the right ear. Gentamicin was applied either to the right ear's round window niche or through a transtympanic injection. Perilymph specimens were collected at different times. Histologic morphometry was used to evaluate both turn-specific and overall hydrops degree. RESULTS: In animals with endolymphatic hydrops, lower concentrations of gentamicin were observed after 20 or 120 minutes of exposure and in both types of administration, when compared to controls. This difference reached statistical significance in the round window niche application group (Mann-Whitney, p = 0,007). A negative correlation between perilymphatic gentamicin concentration and hydrops degree could be observed in both groups, after 120 minutes of exposure (Spearman correlation, round window niche p<0,001; TT p = 0,005). CONCLUSIONS: The study indicates that the endolymphatic hydrops degree has a negative interference on the delivery of gentamicin into the inner ear following middle ear application.


Subject(s)
Ear, Inner/drug effects , Endolymphatic Hydrops/drug therapy , Gentamicins/administration & dosage , Meniere Disease/drug therapy , Animals , Auditory Threshold/drug effects , Contrast Media/administration & dosage , Disease Models, Animal , Ear, Inner/physiopathology , Ear, Middle/drug effects , Endolymphatic Hydrops/physiopathology , Endolymphatic Sac/drug effects , Endolymphatic Sac/physiopathology , Gentamicins/adverse effects , Guinea Pigs , Humans , Meniere Disease/physiopathology , Perilymph/drug effects
3.
Otol Neurotol ; 39(5): 616-621, 2018 06.
Article in English | MEDLINE | ID: mdl-29738389

ABSTRACT

OBJECTIVE: Endolymphatic sac decompression surgery (ELSD) may be used to treat patients who have Menière's 's disease refractory to medical therapy. In this study, we investigated whether or not the injection of steroid into the endolymphatic sac at the time of ELSD provides additional benefit to patient outcomes. STUDY DESIGN: Randomized prospective single-blinded placebo-controlled study. SETTING: Tertiary center. PATIENTS: Patients with Menière's disease with poorly controlled vertigo despite medical therapy and serviceable hearing that were offered ELSD. INTERVENTION(S): Patients randomized into two groups, with control group (n = 17) undergone ELSD without steroid injection and experimental group undergone ELSD with steroid injection (n = 18) MAIN OUTCOME MEASURE(S):: Audiogram, dizziness handicap inventory, tinnitus handicap inventory, frequency of vertigo spells, functional level scale, and quality of life were obtained at multiple intervals from preoperatively to 24 months postoperatively. RESULTS: ELSD resulted in a statistically significant improvement in vertigo control whether or not steroid was injected into the endolymphatic sac at the time of surgery. However, no additional benefit was observed with the addition of intra-sac steroid injection. No statistical difference in pure-tone average, tinnitus handicap inventory, dizziness handicap inventory, or quality of life was observed between the steroid and nonsteroid surgical groups up to 24 months postoperatively. CONCLUSION: ELSD is an effective treatment for Menière's disease refractory to medical therapy; however, the addition of intra-sac steroid injection at the time of surgery does not seem to result in a further improvement in patient outcomes.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Decompression, Surgical/methods , Dexamethasone/administration & dosage , Endolymphatic Sac/drug effects , Endolymphatic Sac/surgery , Meniere Disease/therapy , Adult , Aged , Female , Humans , Male , Middle Aged , Neurosurgical Procedures/methods , Prospective Studies , Quality of Life , Treatment Outcome
4.
Sci Rep ; 7: 42217, 2017 02 06.
Article in English | MEDLINE | ID: mdl-28165045

ABSTRACT

The endolymphatic sac (ES) is a cystic structure of the inner ear connected to the cochlea and vestibule, which plays a role in regulating ion homeostasis in inner ear fluid. Disruption of ion homeostasis can cause inner ear disorders with hearing loss and dizziness, such as Meniere's disease. Herein, we found, for the first time, functional evidence for the involvement of ß1- and ß2-adrenergic receptors in apical electrogenic ion transport by human ES epithelium by using electrophysiological/pharmacological and molecular biological methods, which were dependent on K+ and Cl- ion transport. The apical electrogenic transport was absent or very weak in ES epithelia of patients with Meniere's disease. These results suggested that adrenergic stimulation via ß1- and ß2-adrenergic receptors in the human ES was involved in regulation of inner ear fluid ion homeostasis and impairment of this response could be a pathological mechanism of Meniere's disease.


Subject(s)
Endolymphatic Sac/metabolism , Epithelium/metabolism , Receptors, Adrenergic, beta-1/metabolism , Receptors, Adrenergic, beta-2/metabolism , 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology , Adrenergic beta-1 Receptor Antagonists/pharmacology , Adrenergic beta-2 Receptor Antagonists/pharmacology , Barium/pharmacology , Biological Transport/drug effects , Endolymphatic Sac/drug effects , Endolymphatic Sac/pathology , Epithelium/drug effects , Epithelium/pathology , Female , Humans , Isoproterenol/pharmacology , Male , Meniere Disease/pathology , Middle Aged , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Adrenergic, beta-1/genetics , Receptors, Adrenergic, beta-2/genetics
5.
Otol Neurotol ; 38(4): 599-605, 2017 04.
Article in English | MEDLINE | ID: mdl-28072656

ABSTRACT

OBJECTIVE: The correlation between the isosorbide-induced decompression effect on the endolymphatic space and plasma osmolality (p-OSM) or plasma arginine vasopressin (p-AVP) was investigated on comparing two different dosages of isosorbide (2.8 and 1.4 g/kg) to elucidate why the decompression effect is delayed with a large dose of isosorbide. MATERIALS AND METHODS: Two experiments were performed using 80 guinea pigs. Experiment 1 was designed to morphologically investigate the sequential influence of the oral intake of 1.4- and 2.8-g/kg doses of isosorbide on the endolymphatic volume. The animals used were 50 guinea pigs (control: 10, experimental: 40). All animals underwent surgical obliteration of the endolymphatic sac of the left ear. One month after the surgery, control animals were sacrificed 3 hours after the intake of distilled water, and experimental animals were sacrificed 3 and 6 hours after the isosorbide intake. All of the left temporal bone served for the quantitative assessment of changes in the endolymphatic space, and the cross-sectional area of the scala media was measured from the mid-modiolar sections of the cochlea.Experiment 2 was designed to investigate changes in p-OSM and p-AVP levels 3 hours after the oral intake of isosorbide. Animals used were 15 guinea pigs (control: 5, experimental: 10). The control group received the oral administration of distilled water (4 ml/kg), and the experimental animals were subdivided into two groups consisting of 10 animals each by the dosage of isosorbide (1.4 or 2.8 g/kg). All animals were sacrificed for the measurement of p-OSM and p-AVP concentrations 3 hours after the intake of water or 70% isosorbide solution. RESULTS: Morphologically, an isosorbide-induced decompression effect was noted in animals with both 1.4- and 2.8-g/kg doses of isosorbide. According to the regression analysis, however, the volumetric decrease of the endolymphatic space was more evident in cases with the small dose (1.4 g/kg) 3 hours after the intake (analysis of covariance [ANCOVA], p < 0.001). Six hours after, the decompression effect was significantly greater in cases with the large dose (2.8 g/kg) (ANCOVA, p < 0.001).Isosorbide intake caused a rise in p-OSM levels dose-dependently. The Cochran-Cox test revealed that the differences in the mean values among control and isosorbide groups were significant (p < 0.01). Regarding the p-AVP level, a significant increase was evident in cases with the large dose (2.8 g/kg) (p < 0.01, Cochran-Cox test), and not in cases with the small dose (1.4 g/kg). CONCLUSION: An isosorbide-induced decompression effect of the endolymphatic space was evident in spite of two different dosages of isosorbide (2.8 and 1.4 g/kg). Three hours after the isosorbide intake, however, the decompression effect was more marked in the group with the small dose (1.4 g/kg). Since significant rises in p-OSM and p-AVP were evident in the group with the large dose, this early rise of p-AVP due to dehydration seems to be the major reason for the delayed decompression effect in cases with a large isosorbide intake.


Subject(s)
Arginine Vasopressin/blood , Cochlear Duct/drug effects , Diuretics, Osmotic/pharmacology , Isosorbide/pharmacology , Administration, Oral , Animals , Dose-Response Relationship, Drug , Endolymphatic Sac/drug effects , Guinea Pigs , Osmolar Concentration
6.
Hear Res ; 332: 151-159, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26719142

ABSTRACT

We investigated the influence of vasopressin type 2 receptor antagonist (OPC-41061; Tolvaptan) on experimentally induced endolymphatic hydrops (EH) in guinea pigs. In the first series, the endolymphatic sac (ES) of the left ear of all animals was electrocauterized. Four weeks after surgery, the animals were allocated to four groups: three systemic applications groups (saline, OPC 10 and 100 mg/kg) and a local round window (RW) OPC 1 mg/body application group. We examined the histopathology of the temporal bones and assessed volumetric changes of the endolymphatic space in the cochlea and saccule. In the second series, we investigated the effects of systemic and topical applications of OPC on plasma vasopressin (p-VP) concentrations and plasma osmolality (p-OSM). In the first series, we found that EH was reduced in the OPC 10 mg/kg systemic and OPC RW application groups. In contrast, EH increased in the OPC 100 mg/kg systemic application group. In the second series, neither p-VP levels nor p-OSM were significantly different among the non-OPC, OPC 10 mg/kg systemic, and OPC RW application groups. However, in the OPC 100 mg/kg systemic application group, the p-VP level was significantly higher than that in other groups, and p-OSM was higher than that in the non-OPC group. The systemic application of a low dose of OPC and topical application of OPC resulted in reduced EH in the face of minimal systemic effects (p-VP and p-OSM). These findings suggest that OPC-41061 may be one useful treatment option for EH.


Subject(s)
Antidiuretic Hormone Receptor Antagonists/pharmacology , Benzazepines/pharmacology , Endolymphatic Hydrops/drug therapy , Endolymphatic Sac/drug effects , Receptors, Vasopressin/drug effects , Water-Electrolyte Balance/drug effects , Administration, Oral , Administration, Topical , Animals , Antidiuretic Hormone Receptor Antagonists/administration & dosage , Benzazepines/administration & dosage , Disease Models, Animal , Endolymphatic Hydrops/blood , Endolymphatic Hydrops/physiopathology , Endolymphatic Sac/metabolism , Endolymphatic Sac/physiopathology , Female , Guinea Pigs , Meniere Disease/blood , Meniere Disease/drug therapy , Meniere Disease/physiopathology , Osmolar Concentration , Receptors, Vasopressin/metabolism , Tolvaptan , Vasopressins/blood
7.
Acta Otolaryngol ; 134(10): 990-1004, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25131393

ABSTRACT

CONCLUSION: A new murine model of Ménière's disease has been developed, based on long-term administration of vasopressin. Induction of vestibular dysfunction in the present animal model can cause additional stress, by reducing inner ear blood flow. Latanoprost, a selective agonist for the FP prostanoid receptor, may become a new remedy for Ménière's disease. OBJECTIVE: The purpose of this study was to develop a more suitable animal model, with a closer resemblance to the pathophysiological process in Ménière's disease. METHODS: Adult CBA/J or ICR mice were treated by subcutaneous injection of vasopressin for 5 days up to 8 weeks. Morphological analyses were performed of the cochlea, vestibular end organs and endolymphatic sac. The effect of latanoprost on the development of endolymphatic hydrops was also examined. RESULTS: All experimental animals showed mild to moderate endolymphatic hydrops, increasing in severity as the vasopressin treatment was prolonged. Animals treated with vasopressin for 8 weeks showed severe endolymphatic hydrops with partial loss of outer hair cells and spiral ganglion cells. These animals also had a reversible vestibular dysfunction following intratympanic injection of epinephrine. Latanoprost inhibited the development of endolymphatic hydrops caused by vasopressin.


Subject(s)
Meniere Disease/chemically induced , Meniere Disease/pathology , Vasopressins/administration & dosage , Vasopressins/adverse effects , Animals , Biopsy, Needle , Cochlea/drug effects , Cochlea/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Endolymphatic Sac/drug effects , Endolymphatic Sac/pathology , Immunohistochemistry , Injections, Subcutaneous , Latanoprost , Meniere Disease/drug therapy , Mice , Mice, Inbred CBA , Mice, Inbred ICR , Prostaglandins F, Synthetic/pharmacology , Random Allocation , Reference Values , Risk Assessment , Time Factors
8.
Otol Neurotol ; 33(5): 886-90, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22699994

ABSTRACT

OBJECTIVE: To investigate allergic endolymphatic hydrops (EH) and the effect of leukotriene receptor antagonist (LTRA). METHODS: Experiment 1: Thirty-six guinea pigs were actively sensitized with DNP-ascaris twice and were provoked with DNP-bovine serum albumin 1 week after the second sensitization. Alterations in the inner ear were investigated histologically at 1, 12, 24, and 36 hours after the provocation, and changes of the endolymphatic space were quantitatively assessed. The animals in the control group received no sensitization but only distilled water. Experiment 2: Twenty-four guinea pigs were actively sensitized and provoked in the same manner. Animals received oral administration of LTRA 1 hour before the provocation. Alterations in the inner ear were investigated as same manner as in Experiment 1. Experiment 3: Eleven of 19 guinea pigs were actively sensitized and provoked in the same manner. Eight animals in the control group received distilled water. One hour after these procedures, the changes in p-AVP levels were investigated. RESULTS: Experiment 1: EH was observed 12, 24, and 36 hours after the last sensitization. In these groups, their cross-sectional areas of the scala media were significantly larger than that of the control group. Degranulation of mast cells was observed in the endolymphatic sac. Experiment 2: In animal groups with LTRA, EH was not observed at all. Experiment 3: P-AVP levels were significantly elevated in animals with the sensitization. CONCLUSION: The sensitization with DNP-Ascaris produced allergic EH and elevation of p-AVP, and allergic EH was inhibited by LTRA.


Subject(s)
Chromones/therapeutic use , Ear, Inner/drug effects , Endolymphatic Hydrops/drug therapy , Hypersensitivity/complications , Leukotriene Antagonists/therapeutic use , Animals , Chromones/pharmacology , Ear, Inner/pathology , Endolymphatic Hydrops/etiology , Endolymphatic Hydrops/pathology , Endolymphatic Sac/drug effects , Endolymphatic Sac/pathology , Guinea Pigs , Hypersensitivity/pathology , Leukotriene Antagonists/pharmacology
9.
Am J Physiol Regul Integr Comp Physiol ; 297(5): R1610-4, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19793958

ABSTRACT

To clarify the role of the endolymphatic sac (ES) in the regulation of endolymphatic pressure, the effects of isoproterenol, a beta-adrenergic receptor agonist, and acetazolamide, a potent carbonic anhydrase inhibitor, both of which decrease ES direct current potential on cochlear hydrostatic pressure, were examined in guinea pigs. When isoproterenol was applied intravenously, hydrostatic pressures of cochlear endolymph and perilymph were significantly increased with no change in endocochlear potential or the hydrostatic pressure of cerebrospinal fluid. Acetazolamide produced no marked change in the hydrostatic pressure of cochlear endolymph. In ears with an obstructed ES, the action of isoproterenol on the hydrostatic pressure of cochlear endolymph and perilymph was suppressed. These results suggest that the ES may regulate the hydrostatic pressure of the endolymphatic system via the action of the agents such as catecholamines on the ES.


Subject(s)
Cochlea/physiology , Endolymph/physiology , Endolymphatic Sac/physiology , Acetazolamide/pharmacology , Adrenergic beta-Agonists/pharmacology , Animals , Carbonic Anhydrase Inhibitors/pharmacology , Cochlea/drug effects , Endolymph/drug effects , Endolymphatic Sac/drug effects , Guinea Pigs , Hydrostatic Pressure , Isoproterenol/pharmacology , Models, Animal
10.
Acta Otolaryngol ; 128(11): 1187-95, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18607967

ABSTRACT

CONCLUSIONS: That the endolymphatic sac (ES) reacts to changes in inner ear blood flow may be important for homeostasis of the inner ear fluid volume and pressure. OBJECTIVES: To elucidate the effect of changes in inner ear blood flow on the ES and to learn more about the volume and pressure regulatory function of the ES. MATERIALS AND METHODS: Epinephrine or sodium nitroprusside (SNP) was injected into the middle ear cavity of adult CBA/J mice. The ES were analyzed morphologically by light microscopy. RESULTS: Epinephrine reduced the luminal size of the ES leading to an accumulation of intraluminal homogeneous substance. Injection of SNP increased the size of the ES lumen, accompanied by a collapse of the lateral intercellular space (LIS) and dense perisaccular tissue. These changes were almost reversed 4 h after injection.


Subject(s)
Ear, Inner/blood supply , Endolymphatic Sac/cytology , Animals , Cochlea/blood supply , Endolymphatic Duct/cytology , Endolymphatic Duct/drug effects , Endolymphatic Sac/drug effects , Endolymphatic Sac/physiology , Epinephrine/pharmacology , Mice , Mice, Inbred CBA , Nitroprusside/pharmacology , Regional Blood Flow/drug effects , Stria Vascularis/cytology , Stria Vascularis/drug effects , Vasoconstrictor Agents/pharmacology , Vasodilator Agents/pharmacology
11.
Laryngoscope ; 118(5): 854-61, 2008 May.
Article in English | MEDLINE | ID: mdl-18520184

ABSTRACT

OBJECTIVE: Meniere's disease is a common inner ear disease with an incidence of 15 to 50 per 100,000 population. Since Meniere's disease is thought to be triggered by an immune insult to the inner ear, we examined intraendolymphatic sac application of steroids as a new therapeutic strategy for intractable Meniere's disease. STUDY DESIGN: Prospective randomized controlled study. METHODS: Between 1996 and 2005, we enrolled and assigned 197 intractable Meniere's patients to three groups in a randomized controlled trial: Group I (G-I)- patients who underwent endolymphatic sac drainage and steroid-instillation; Group II (G-II)-those who underwent endolymphatic sac drainage without steroid-instillation; and Group III (G-III)-those who declined endolymphatic sac drainage. Definitive spells and hearing in all three groups were determined for 2 to 7 years after treatment. RESULTS: According to the 1995 American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) criteria, 2-year results demonstrated that vertigo was completely controlled in 88.0% of patients in G-I (n = 100), 85.1% of patients in G-II (n = 47), and 8.0% in G-III (n = 50). Statistically, G-I = G-II>G-III. Hearing was improved in 49.0% of patients in G-I, 31.9% in G-II, and 6.0% in G-III (G-I>G-II>G-III). Results after 7 years showed that vertigo was completely controlled in 78.8% of patients in G-I, 79.2% in G-II, and 25.0% in G-III (G-I = G-II>G-III). Hearing improved in 36.5% of patients in G-I, 8.3% in G-II, and 0.0% in G-III (G-I>G-II = G-III). CONCLUSIONS: From non-surgical observation in G-III for at least 7 years after treatment, steroids instilled into endolymphatic sac in G-I patients significantly improved hearing in intractable Meniere's patients, more so than endolymphatic sac drainage without steroids in G-II patients.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Dexamethasone/pharmacology , Dexamethasone/therapeutic use , Diazepam/pharmacology , Diazepam/therapeutic use , Dimenhydrinate/pharmacology , Dimenhydrinate/therapeutic use , Diuretics/pharmacology , Diuretics/therapeutic use , Endolymphatic Sac/drug effects , Histamine H1 Antagonists/pharmacology , Histamine H1 Antagonists/therapeutic use , Meniere Disease/drug therapy , Piperidines/pharmacology , Piperidines/therapeutic use , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies
12.
Acta Otolaryngol ; 128(3): 263-71, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17851960

ABSTRACT

CONCLUSION: A new murine model for the study of Ménière's disease has been developed by treatment with both lipopolysaccharide (LPS) and aldosterone. Induction of vestibular dysfunction in the hydropic animal model may entail additional stress such as reduced inner ear blood flow, and sudden acute changes in endolymph volume and/or pressure. OBJECTIVE: The purpose of this study was to develop a more suitable animal model, showing closer resemblance to the pathophysiological process in Ménière's disease. MATERIALS AND METHODS: Adult CBA/J mice were treated by intratympanic injection of LPS, intraperitoneal injection of aldosterone, or injection of both LPS and aldosterone. Morphological analyses were performed in the cochlea and endolymphatic sac. RESULTS: All experimental animals showed mild to moderate endolymphatic hydrops. Those treated with both LPS and aldosterone showed reversible vestibular dysfunction after the intratympanic injection of epinephrine.


Subject(s)
Aldosterone/pharmacology , Disease Models, Animal , Endolymphatic Hydrops/physiopathology , Escherichia coli , Lipopolysaccharides/pharmacology , Meniere Disease/physiopathology , Animals , Ear, Middle , Endolymph/physiology , Endolymphatic Duct/drug effects , Endolymphatic Duct/pathology , Endolymphatic Duct/physiopathology , Endolymphatic Hydrops/chemically induced , Endolymphatic Hydrops/pathology , Endolymphatic Sac/drug effects , Endolymphatic Sac/pathology , Endolymphatic Sac/physiopathology , Epinephrine/pharmacology , Homeostasis/drug effects , Homeostasis/physiology , Injections , Injections, Intraperitoneal , Meniere Disease/chemically induced , Meniere Disease/pathology , Mice , Mice, Inbred CBA , Postural Balance/drug effects , Postural Balance/physiology , Sodium-Potassium-Exchanging ATPase/metabolism , Stria Vascularis/drug effects , Stria Vascularis/pathology , Stria Vascularis/physiology
13.
Acta Otolaryngol Suppl ; (553): 13-8, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15277029

ABSTRACT

The aquaporins (AQPs) are a family of small transmembrane water transporters. It has recently been revealed that they play a role in regulating homeostasis in the inner ear fluids. Steroid therapy is usually administered to patients with inner ear disorders; however, the mechanism of steroid effects has not been clearly determined. To elucidate the points of action of steroids in the inner ear, we recently examined the distributions of AQP isoform mRNAs in the rat inner ear and identified AQP1-6 mRNAs in the rat cochlea and AQP1, 3, 4, 5 and 6 mRNAs in the rat endolymphatic sac by means of reverse transcriptase polymerase chain reaction (PCR). In this study, we investigated changes in expression of AQP mRNAs in the rat inner ear after i.p. injections of steroids using real-time quantitative PCR and found that AQP3 mRNA in the endolymphatic sac was significantly upregulated in both dose- and time-dependent manners. This result suggests that steroids may effect water homeostasis in the rat inner ear via AQPs.


Subject(s)
Aquaporins/metabolism , Ear, Inner/metabolism , Steroids/pharmacology , Animals , Aquaporins/drug effects , Aquaporins/genetics , Cochlea/drug effects , Cochlea/metabolism , Dexamethasone/administration & dosage , Dexamethasone/pharmacology , Dose-Response Relationship, Drug , Ear, Inner/drug effects , Ear, Inner/physiology , Electrophysiology , Endolymphatic Sac/drug effects , Endolymphatic Sac/metabolism , Gene Expression , Glucocorticoids/administration & dosage , Glucocorticoids/pharmacology , Injections, Intraperitoneal , Male , RNA, Messenger/metabolism , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Steroids/administration & dosage
14.
Neurol Res ; 25(8): 865-70, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14669532

ABSTRACT

The final aim of the present study is to see if the endolymphatic sac is really available as a drug delivery system to have effect on the inner ear organs. In the present study, we examined effects of a single insertion of dexamethasone into the rat unilateral endolymphatic sac on mRNA expression of the inner ear aquaporin (AQP) family, transmembrane water transporters and putative endolymphatic fluid modulators, by means of real-time quantitative PCR. Only AQP-3 mRNA expression in the ipsilateral cochlea was significantly up-regulated in comparison with controls and the up-regulation was demonstrated both in dose-dependent and time-dependent manners. These findings suggest that the intra-endolymphatic sac steroids could make regulatory effects on the inner ear AQP-3 expression via vestibular aqueduct and modulate the homeostasis of endolymphatic fluids, encouraging the possibility that the endolymphatic sac could be a therapeutic window for the inner ear disease.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Aquaporins/genetics , Cochlea/drug effects , Dexamethasone/pharmacology , Endolymphatic Sac/drug effects , Gene Expression Regulation/drug effects , Acoustic Stimulation , Animals , Aquaporin 3 , Aquaporins/metabolism , Brain Stem/drug effects , Brain Stem/physiology , Cochlea/metabolism , Dose-Response Relationship, Drug , Endolymphatic Sac/metabolism , Evoked Potentials, Auditory , Functional Laterality , Male , RNA, Messenger/metabolism , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction/methods , Time Factors , Up-Regulation
15.
Hear Res ; 182(1-2): 9-18, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12948596

ABSTRACT

In the present study, two experiments were performed to investigate the influence of OPC-31260 on experimentally induced endolymphatic hydrops in guinea pigs and the regulation of aquaporin-2 (AQP2) mRNA expression in the rat inner ear. In morphological studies, the increases in the ratios of the length of Reissner's membrane (IR-L) and the cross-sectional area of the scala media (IR-S) were quantitatively assessed among normal guinea pigs (normal ears) and three groups with hydropic ears: hydropic ears with no infusion (non-infusion hydropic ears), hydropic ears with an infusion of physiological saline into the scala tympani (saline-infused hydropic ears) and hydropic ears with infusion of 0.3% OPC-31260 into the scala tympani (OPC-infused hydropic ears). IR-Ls in the experimental groups were markedly larger than in the normal ear group, but there was no significant difference among the groups of non-infusion hydropic ears, saline-infused hydropic ears and OPC-infused hydropic ears. The IR-Ss of non-infusion hydropic ears and saline-infused hydropic ears (48.8-49.3%) were statistically different from that of normal ears (6.5%) (Dunnet multiple comparison test, P<0.01). However, IR-S of the OPC-infused hydropic ears (-14.8%) was significantly smaller than those of non-infusion hydropic ears and saline-infused hydropic ears (one-way ANOVA, P<0.01). In the quantitative polymerase chain reaction study, a comparison of the ratio of AQP2 and beta-actin mRNA (MAQP2/Mbeta-actin) was made between water-injected and OPC-31260-injected rats. An intravenous injection of OPC-31260 resulted in a significant decrease in MAQP2/Mbeta-actin both in the cochlea and in the endolymphatic sac (t-test, P<0.001). These results indicate that water homeostasis in the inner ear is regulated via the vasopressin-AQP2 system, and that the vasopressin type-2 antagonist OPC-31260 is a promising drug in the treatment of Meniere's disease.


Subject(s)
Antidiuretic Hormone Receptor Antagonists , Aquaporins/metabolism , Benzazepines/therapeutic use , Endolymphatic Hydrops/drug therapy , Endolymphatic Sac/drug effects , Analysis of Variance , Animals , Aquaporin 2 , Aquaporins/genetics , Benzazepines/pharmacology , Endolymphatic Hydrops/chemically induced , Endolymphatic Sac/blood supply , Gene Expression Regulation/drug effects , Guinea Pigs , Male , Osmotic Pressure , RNA, Messenger/metabolism , Rats , Reverse Transcriptase Polymerase Chain Reaction , Vasopressins/adverse effects
16.
Acta Otolaryngol ; 122(6): 600-6, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12403121

ABSTRACT

Although steroid treatment is generally administered for patients with inner ear disorders, including Meniere's disease, the mechanism via which steroids exert their effects remains to be clarified. The aquaporins (AQPs) are a family of small transmembrane water transporters, and it has recently been revealed that they play a role in regulating homeostasis in the inner ear fluids. In order to elucidate the action points of steroids in the inner ear, we firstly identified AQPI, 2, 3, 4, 5 and 6 mRNAs in the rat cochlea and AQP1, 3, 4, 5 and 6 in the rat endolymphatic sac by means of reverse transcription-polymerase chain reaction. Subsequently, we found that intratympanic injections of steroids upregulated AQPI mRNA of the rat cochlea in a dose-dependent manner. These results suggest that steroids may affect water homeostasis in the rat inner ear mainly via AQP1.


Subject(s)
Aquaporins/metabolism , Cochlea/metabolism , Dexamethasone/pharmacology , Endolymphatic Sac/metabolism , Glucocorticoids/pharmacology , Animals , Aquaporins/genetics , Cochlea/drug effects , Cochlea/pathology , Dexamethasone/administration & dosage , Endolymphatic Sac/drug effects , Endolymphatic Sac/pathology , Gene Expression , Glucocorticoids/administration & dosage , Injections , Male , RNA, Messenger/metabolism , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Tympanic Membrane
17.
Article in English | MEDLINE | ID: mdl-11359093

ABSTRACT

Immunohistochemical study for inducible nitric oxide synthase (iNOS or NOS II) in the cochlea of guinea pigs was performed after the injection of keyhole limpet hemocyanin (KLH) into the endolymphatic sac. Morphological changes were observed in the cochlea of all animals after the injection of KLH. Increased iNOS expression was detected in the lateral wall, organ of Corti and ganglion cells. It is known that high levels of nitric oxide can lead to inner ear dysfunction. Our results suggest that iNOS may mediate the inner ear disturbance as seen in endolymphatic hydrops.


Subject(s)
Cochlea/enzymology , Cochlea/physiopathology , Endolymphatic Sac/metabolism , Nitric Oxide Synthase/metabolism , Adjuvants, Immunologic/pharmacology , Animals , Cochlea/drug effects , Endolymphatic Sac/drug effects , Guinea Pigs , Hemocyanins/pharmacology , Immunohistochemistry , Nitric Oxide Synthase/drug effects
18.
Neurosci Lett ; 303(3): 189-92, 2001 May 11.
Article in English | MEDLINE | ID: mdl-11323117

ABSTRACT

Expression of p-glycoprotein (p-gp) and multidrug resistance protein 1 (MRP1) was detected in the vestibular labyrinth and endolymphatic sac (ES) of the guinea pig by immunohistochemical staining using anti-p-gp monoclonal antibody (mAb) C219 and anti-MRP mAb MRPr1. P-gp was detected in capillary endothelial cells of the crista ampullaris, utricle, saccule and ES. MRP1 was detected in the epithelial lining of the crista ampullaris, utricle, saccule, and epithelial cells of the ES. Since p-gp and MRP1 act as extrusion pumps, they may coordinate with each other in vestibular organs and ES and play an important role in the blood-labyrinth barrier.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP-Binding Cassette Transporters/metabolism , Endolymph/metabolism , Endolymphatic Sac/metabolism , Vestibule, Labyrinth/metabolism , Animals , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/physiology , Capillaries/cytology , Capillaries/drug effects , Capillaries/metabolism , Carrier Proteins/drug effects , Carrier Proteins/metabolism , Cerebrospinal Fluid/drug effects , Cerebrospinal Fluid/metabolism , Endolymph/drug effects , Endolymphatic Sac/blood supply , Endolymphatic Sac/drug effects , Guinea Pigs , Immunohistochemistry , Vestibule, Labyrinth/blood supply , Vestibule, Labyrinth/drug effects
19.
Ann Otol Rhinol Laryngol ; 110(2): 109-12, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11219515

ABSTRACT

To enhance the effect of treatment for intractable Meniere's disease, we exposed the opened endolymphatic sac to high concentrations of steroids. This technique--endolymphatic sac drainage and steroid instillation surgery--involves the application of a mass of prednisolone followed by absorbable gelatin sponges soaked in a high concentration of dexamethasone into a sac lumen opened and expanded with a bundle of absorbable gelatin film. These sponges are also placed around the sac and coated with biochemical adhesive so that the medicine is slowly delivered into the sac over a prolonged period of time by means of a natural sustained-release vehicle. The short-term results (6 to 14 months) in 12 patients with Meniere's disease, including those in stage IV, treated by the above techniques showed that definitive spells were completely controlled in all cases. Hearing was improved, and annoyance due to tinnitus was decreased in all cases except one.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Dexamethasone/therapeutic use , Drainage/methods , Endolymphatic Sac/drug effects , Endolymphatic Sac/surgery , Endolymphatic Shunt/methods , Meniere Disease/therapy , Prednisolone/therapeutic use , Adult , Aged , Anti-Inflammatory Agents/pharmacology , Delayed-Action Preparations , Female , Follow-Up Studies , Gelatin , Humans , Instillation, Drug , Male , Meniere Disease/classification , Meniere Disease/diagnosis , Middle Aged , Severity of Illness Index , Time Factors , Treatment Outcome
20.
Am J Physiol Regul Integr Comp Physiol ; 279(5): R1695-700, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11049851

ABSTRACT

The aim of the present work was to assess the effect of various drugs applied locally on the pH of the luminal fluid (pH(lum)) in guinea pig endolymphatic sac. pH(lum) and transepithelial potential, when measured in vivo by means of double-barrelled pH-sensitive microelectrodes, were 7.06 +/- 0.08 and +6.1 +/- 0.34 mV (mean +/- SE; n = 84), respectively, which is consistent with a net acid secretion in the luminal fluid of the endolymphatic sac. Bafilomycin and acetazolamide increased and decreased, respectively, pH(lum). Amiloride, ethylisopropylamiloride, ouabain, and Schering 28080 had no effect on pH(lum). Results obtained with inhibitors of anionic transport systems were inconclusive; e.g., DIDS reduced pH(lum), whereas neither SITS nor triflocin had any effect. We conclude that bafilomycin-sensitive H(+)-ATPase activity accounts for the transepithelial acid gradient measured in the endolymphatic sac and that intracellular and membrane-bound carbonic anhydrase probably participates in regulating endolymphatic sac pH(lum). The relationship between acid pH, endolymph volume, and Ménière's disease remains to be further investigated.


Subject(s)
Body Fluids/chemistry , Endolymphatic Sac/drug effects , Macrolides , 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology , Acetazolamide/pharmacology , Animals , Anti-Bacterial Agents/pharmacology , Carbonic Anhydrase Inhibitors/pharmacology , Endolymphatic Sac/physiology , Enzyme Inhibitors/pharmacology , Epithelium/physiology , Guinea Pigs , Hydrogen-Ion Concentration , Imidazoles/pharmacology , Male , Membrane Potentials , Microelectrodes , Ouabain/pharmacology , Proton Pump Inhibitors , Proton-Translocating ATPases/antagonists & inhibitors , Proton-Translocating ATPases/metabolism , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors
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