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Frontiers in Synaptic Neuroscience 2021Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where...
Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca permeability. Cochlear afferent synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) contain the AMPAR subunits GluA2, 3, and 4. However, the tetrameric complement of cochlear AMPAR subunits is not known. It was recently shown in mice that chronic intracochlear delivery of IEM-1460, an antagonist selective for GluA2-lacking AMPARs [also known as Ca-permeable AMPARs (CP-AMPARs)], before, during, and after acoustic overexposure prevented both the trauma to ANF synapses and the ensuing reduction of cochlear nerve activity in response to sound. Surprisingly, baseline measurements of cochlear function before exposure were unaffected by chronic intracochlear delivery of IEM-1460. This suggested that cochlear afferent synapses contain GluA2-lacking CP-AMPARs alongside GluA2-containing Ca-impermeable AMPA receptors (CI-AMPARs), and that the former can be antagonized for protection while the latter remain conductive. Here, we investigated hearing function in the guinea pig during acute local or systemic delivery of CP-AMPAR antagonists. Acute intracochlear delivery of IEM-1460 or systemic delivery of IEM-1460 or IEM-1925 reduced the amplitude of the ANF compound action potential (CAP) significantly, for all tone levels and frequencies, by > 50% without affecting CAP thresholds or distortion product otoacoustic emissions (DPOAE). Following systemic dosing, IEM-1460 levels in cochlear perilymph were ~ 30% of blood levels, on average, consistent with pharmacokinetic properties predicting permeation of the compounds into the brain and ear. Both compounds were metabolically stable with half-lives >5 h , and elimination half-lives of 118 min (IEM-1460) and 68 min (IEM-1925). Heart rate monitoring and off-target binding assays suggest an enhanced safety profile for IEM-1925 over IEM-1460. Compound potency on CAP reduction (IC ~ 73 μM IEM-1460) was consistent with a mixture of GluA2-lacking and GluA2-containing AMPARs. These data strongly imply that cochlear afferent synapses of the guinea pig contain GluA2-lacking CP-AMPARs. We propose these CP-AMPARs may be acutely antagonized with systemic dosing, to protect from glutamate excitotoxicity, while transmission at GluA2-containing AMPARs persists to mediate hearing during the protection.
PubMed: 34290596
DOI: 10.3389/fnsyn.2021.680621 -
The Journal of International Medical... Jul 2021Enhancement of the subarachnoid space after intravenous administration of gadolinium contrast agent is not common. Enhancement usually occurs in pathological conditions...
Enhancement of the subarachnoid space after intravenous administration of gadolinium contrast agent is not common. Enhancement usually occurs in pathological conditions that increase the permeability of the blood-cerebrospinal fluid barrier, most notably in meningitis. We herein describe possible subarachnoid enhancement in patients with no apparent effect on the meninges. These patients had clinical signs of Meniere's disease and underwent specific magnetic resonance imaging of the inner ear to possibly visualize endolymphatic hydrops. The endolymphatic space can be noninvasively imaged by intravenous administration of contrast agent, usually at a double dose, 4 hours before the scanning process. During this time, the contrast agent penetrates not only the perilymph but also the subarachnoid space, where the highest concentration occurs after 4 hours according to some studies.
Topics: Contrast Media; Endolymphatic Hydrops; Gadolinium; Humans; Magnetic Resonance Imaging; Meniere Disease; Subarachnoid Space
PubMed: 34250824
DOI: 10.1177/03000605211029788 -
Anatomical Record (Hoboken, N.J. : 2007) Feb 2022Since the fissula ante fenestram (FAF) is considered as a focus of otosclerotic lesion and a route of perilymph leakage, there are few description of prenatal...
Since the fissula ante fenestram (FAF) is considered as a focus of otosclerotic lesion and a route of perilymph leakage, there are few description of prenatal development of the cartilaginous canal passing though the cochlear wall. We examined the sagittal and frontal histological sections of the ear from 32 human fetuses at 8-37 weeks of gestational age. At 8-12 weeks, in the immediately anterior side of a connection between the cochlear and canalicular parts of the otic capsule cartilage, the FAF appeared as a tear of a cartilage between the basal and second turns of the cochlea. The tear became a slit opening to the scala vestibuli. At 13-15 weeks, the FAF, less than 1.2 mm in length, had the anterosuperior and postero-inferior apertures: the former was near the geniculate ganglion and became closed after 15 weeks, while the latter approached the oval window. Third trimester fetuses, the FAF, 1.5-2.0 mm in length, consistently carried a single, postero-inferior aperture extending along the anterior margin of the oval window and it contained no definite epithelium and vessel. Although it was endochondral ossification, there was no clear zonation in cartilage cells of the FAF. A mechanical stress during three-dimensional coiling of the cochlear ducts seemed to provide the FAF. After the FAF was established, the stapes footplate might use a part of the inferior aperture for the syndesmosis. A specific ossification was seen in the FAF, but it might rarely cause the pathological syndesmosis.
Topics: Cochlea; Ear, Inner; Ear, Middle; Female; Fetal Development; Humans; Pregnancy; Stapes
PubMed: 34240820
DOI: 10.1002/ar.24711 -
Frontiers in Neurology 2021
PubMed: 34220698
DOI: 10.3389/fneur.2021.704095 -
Frontiers in Neurology 2021Menière's disease microRNA (miRNA) profiles are unique and are reflected in the perilymph and serum of patients. Development of effective biomarkers for Menière's...
Menière's disease microRNA (miRNA) profiles are unique and are reflected in the perilymph and serum of patients. Development of effective biomarkers for Menière's disease are needed. miRNAs are small RNA sequences that downregulate mRNA translation and play a significant role in a variety of disease states, ultimately making them a promising biomarker. miRNAs can be readily isolated from human inner ear perilymph and serum, and may exhibit disease-specific profiles. Perilymph sampling was performed in 10 patients undergoing surgery; 5 patients with Meniere's disease and 5 patients with otosclerosis serving as controls. miRNAs were isolated from the serum of 5 patients with bilateral Menière's disease and compared to 5 healthy age-matched controls. For evaluation of miRNAs an Agilent miRNA gene chip was used. Analysis of miRNA expression was carried out using Qlucore and Ingenuitey Pathway Analysis software. Promising miRNAs biomarkers were validated using qPCR. In the perilymph of patients with Menière's disease, we identified 16 differentially expressed miRNAs that are predicted to regulate over 220 different cochlear genes. Six miRNAs are postulated to regulate aquaporin expression and twelve miRNAs are postulated to regulate a variety of inflammatory and autoimmune pathways. When comparing perilymph with serum samples, miRNA-1299 and-1270 were differentially expressed in both the perilymph and serum of Ménière's patients compared to controls. Further analysis using qPCR confirmed miRNA-1299 is downregulated over 3-fold in Meniere's disease serum samples compared to controls. Patients with Ménière's disease exhibit distinct miRNA expression profiles within both the perilymph and serum. The altered perilymph miRNAs identified can be linked to postulated Ménière's disease pathways and may serve as biomarkers. miRNA-1299 was validated to be downregulated in both the serum and perilymph of Menière's patients.
PubMed: 34220670
DOI: 10.3389/fneur.2021.646928 -
European Archives of... May 2022It is still challenging to detect endolymphatic hydrops (EH) in patients with Meniere's disease (MD) using MRI. The aim of the present study was to optimize a sensitive...
BACKGROUND
It is still challenging to detect endolymphatic hydrops (EH) in patients with Meniere's disease (MD) using MRI. The aim of the present study was to optimize a sensitive technique generating strong contrast enhancement from minimum gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) while reliably detecting EH in the inner ear, including the apex.
MATERIALS AND METHODS
All imaging was performed using a 3.0 T MR system 24 h after intratympanic injection of low-dose Gd-DTPA. Heavily T2-weighted 3-dimensional fluid-attenuated inversion recovery reconstructed with magnitude and zero-filled interpolation (hTW-FLAIR-ZFI) was optimized and validated in phantom studies and compared with medium inversion time inversion recovery imaging with magnitude reconstruction (MIIRMR). The following parameters were used in hTW-FLAIR-ZFI: repetition time 14,000 ms, echo time 663 ms, inversion time 2900 ms, flip angle 120°, echo train length 271, and field of view 166 × 196 mm.
RESULTS
MRI obtained using hTW-FLAIR-MZFI yielded high-quality images with sharper and smoother borders between the endolymph and perilymph and a higher signal intensity ratio and more homogenous perilymph enhancement than those generated with MIIRMR (p < 0.01). There were predominantly grade II EHs in the cochleae and grade III EHs in the vestibule in definite MD. EH was detected in the apex of 11/16 ipsilateral ears, 3/16 contralateral ears in unilateral definite MD and 3/6 ears in bilateral MD.
CONCLUSIONS
The novel hTW-FLAIR-MZFI technique is sensitive and demonstrates strong and homogenous enhancement by minimum Gd-DTPA in the inner ear, including the apex, and yields high-quality images with sharp borders between the endolymph and perilymph.
Topics: Cochlea; Contrast Media; Endolymphatic Hydrops; Gadolinium DTPA; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Meniere Disease; Vestibule, Labyrinth
PubMed: 34145490
DOI: 10.1007/s00405-021-06912-4 -
Frontiers in Molecular Neuroscience 2021Cochlin is the most abundant protein in the inner ear. To study its function in response to noise trauma, we exposed adolescent wild-type ( ) and cochlin knock-out ( )...
Cochlin is the most abundant protein in the inner ear. To study its function in response to noise trauma, we exposed adolescent wild-type ( ) and cochlin knock-out ( ) mice to noise (8-16 kHz, 103 dB SPL, 2 h) that causes a permanent threshold shift and hair cell loss. Two weeks after noise exposure, mice had substantially less elevation in noise-induced auditory thresholds and hair cell loss than mice, consistent with cochlin deficiency providing protection from noise trauma. Comparison of pre-noise exposure thresholds of auditory brain stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) in mice and littermates revealed a small and significant elevation in thresholds of mice, overall consistent with a small conductive hearing loss in mice. We show quantitatively that the pro-inflammatory component of cochlin, LCCL, is upregulated after noise exposure in perilymph of wild-type mice compared to unexposed mice, as is the enzyme catalyzing LCCL release, aggrecanase1, encoded by . We further show that upregulation of pro-inflammatory cytokines in perilymph and cochlear soft-tissue after noise exposure is lower in cochlin knock-out than wild-type mice. Taken together, our data demonstrate for the first time that cochlin deficiency results in conductive hearing loss that protects against physiologic and molecular effects of noise trauma.
PubMed: 34108864
DOI: 10.3389/fnmol.2021.670013 -
Frontiers in Neurology 2021Capillaries within the inner ear form a semi-permeable barrier called the blood-labyrinth barrier that is less permeable than capillary barriers elsewhere within the...
Capillaries within the inner ear form a semi-permeable barrier called the blood-labyrinth barrier that is less permeable than capillary barriers elsewhere within the human body. Dysfunction of the blood-labyrinth barrier has been proposed as a mechanism for several audio-vestibular disorders. There has been interest in using magnetic resonance imaging (MRI) with intravenous gadolinium-based contrast agents (GBCA) as a marker for the integrity of the blood labyrinth barrier in research and clinical settings. This scoping review evaluates the evidence for using intravenous gadolinium-enhanced MRI to assess the permeability of the blood-labyrinth barrier in healthy and diseased ears. A systematic search was conducted of three databases: PubMed, EMBASE, CINAHL PLUS. Studies were included that used GBCA to study the inner ear and permeability of the blood-labyrinth barrier. Data was collected on MRI protocols used and inner ear enhancement patterns of healthy and diseased ears in both human and animal studies. The search yielded 14 studies in animals and 53 studies in humans. In healthy animal and human inner ears, contrast-enhanced MRI demonstrated gradual increase in inner ear signal intensity over time that was limited to the perilymph. Signal intensity peaked at 100 min in rodents and 4 h in humans. Compared to controls, patients with idiopathic sudden sensorineural hearing loss and otosclerosis had increased signal intensity both before and shortly after GBCA injection. In patients with Ménière's disease and vestibular schwannoma, studies reported increased signal at 4 h, compared to controls. Quality assessment of included studies determined that all the studies lacked sample size justification and many lacked adequate control groups or blinded assessors of MRI. The included studies provided convincing evidence that gadolinium crosses the blood-labyrinth barrier in healthy ears and more rapidly in some diseased ears. The timing of increased signal differs by disease. There was a lack of evidence that these findings indicate general permeability of the blood-labyrinth barrier. Future studies with consistent and rigorous methods are needed to investigate the relationship between gadolinium uptake and assessments of inner ear function and to better determine whether signal enhancement indicates permeability for molecules other than gadolinium.
PubMed: 34093410
DOI: 10.3389/fneur.2021.662264 -
Metabolites May 2021In order to increase metabolite coverage in LC-MS-based untargeted metabolomics, HILIC- and RPLC-mode separations are often combined. Unfortunately, these two techniques...
In order to increase metabolite coverage in LC-MS-based untargeted metabolomics, HILIC- and RPLC-mode separations are often combined. Unfortunately, these two techniques pose opposite requirements on sample composition, necessitating either dual sample preparations, increasing needed sample volume, or manipulation of the samples after the first analysis, potentially leading to loss of analytes. When sample material is precious, the number of analyses that can be performed is limited. To that end, an automated single-injection LC-MS method for sequential analysis of both the hydrophilic and lipophilic fractions of biological samples is described. Early eluting compounds in a HILIC separation are collected on a trap column and subsequently analyzed in the RPLC mode. The instrument configuration, composed of commercially available components, allows easy modulation of the dilution ratio of the collected effluent, with sufficient dilution to obtain peak compression in the RPLC column. Furthermore, the method is validated and shown to be fit for purpose for application in untargeted metabolomics. Repeatability in both retention times and peak areas was excellent across over 140 injections of protein-precipitated blood plasma. Finally, the method has been applied to the analysis of real perilymph samples collected in a guinea pig model. The QC sample injections clustered tightly in the PCA scores plot and showed a high repeatability in both retention times and peak areas for selected compounds.
PubMed: 34063084
DOI: 10.3390/metabo11050295 -
Nystagmus in adult patients with acute otitis media or otitis media with effusion without dizziness.PloS One 2021The present study aimed to investigate the incidence and patterns of nystagmus in adult patients with acute otitis media (AOM) or otitis media with effusion (OME)...
The present study aimed to investigate the incidence and patterns of nystagmus in adult patients with acute otitis media (AOM) or otitis media with effusion (OME) without dizziness or vertigo, and discuss possible mechanisms. From February 2018 to November 2018, 34 consecutive patients with AOM or OME without dizziness were included. Nystagmus was examined with video Frenzel glasses. Of 34 adult AOM or OME patients without dizziness, nystagmus was observed in 28 patients (82%). In unilateral AOM or OME (n = 30), the most commonly observed nystagmus pattern was irritative-type direction-fixed nystagmus (n = 13), followed by paretic-type direction-fixed nystagmus (n = 8), and direction-changing positional nystagmus (n = 4). In bilateral AOM or OME (n = 4), direction-fixed nystagmus and direction-changing positional nystagmus were observed in two and one patients, respectively. Nystagmus was observed in as many as 82% of adult AOM or OME patients even though they did not complain of dizziness, and the pattern of nystagmus was either direction-fixed or direction-changing. Direct effect of inflammatory mediators penetrated from the middle ear and biochemical alteration in the inner ear fluids due to blood-perilymph barrier dysfunction may result in the presence of nystagmus in AOM or OME patients without dizziness.
Topics: Acute Disease; Adult; Age Distribution; Aged; Case-Control Studies; Dizziness; Female; Hearing Loss; Humans; Male; Middle Aged; Nystagmus, Physiologic; Otitis Media with Effusion
PubMed: 33983960
DOI: 10.1371/journal.pone.0250357