U0126 pretreatment inhibits cisplatin-induced apoptosis and autophagy in HEI-OC1 cells and cochlear hair cells.

Deafness is the most common sensory disorder in the world. Ototoxic drugs are common inducing factors of sensorineural hearing loss, and cochlear hair cell (HC) damage is the main concern of the present studies. Cisplatin is a widely used, highly effective antitumor drug, but some patients have experienced irreversible hearing loss as a result of its application. This hearing loss is closely related to HC apoptosis and autophagy. U0126 is a specific inhibitor of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signaling pathway and has neuroprotective effects. For example, the neuroprotective effect of U0126 on ischemic stroke has been widely recognized. In neural cells, U0126 can prevent death due to excess glutamate, dopamine, or zinc ions. However, no studies of U0126 and ototoxic drug-induced injury have been reported to date. In the present study, we found that U0126 pretreatment significantly reduced the apoptosis and autophagy of HCs in auditory House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear HCs. In addition, U0126 reduced the cisplatin-induced production of reactive oxygen species as well as the cisplatin-induced decrease in the mitochondrial membrane potential. These findings suggest that U0126 may be a potential therapeutic candidate for the prevention of cisplatin-induced ototoxicity.

Knockdown of sorcin increases HEI-OC1 cell damage induced by cisplatin in vitro.

Hearing loss caused by ototoxic drugs is a kind of acquired hearing loss. Cisplatin is one of the most commonly used drugs and its main action sites are hair cells (HCs). Sorcin is a drug-resistant calcium-binding protein belonging to the small penta-EF-hand protein family. Sorcin is highly expressed in many tissues, including bone, heart, brain, lung, and skin tissues. Single-cell RNA sequencing showed that sorcin was expressed in the outer HCs of mice, but its role remained unknown. We also found that sorcin was highly expressed in the cytoplasm of cochlear HCs and HEI-OC1 cells. After cisplatin injury, the expression of sorcin in HCs and HEI-OC1 cells decreased significantly. SiRNA transfection technology was used to knock down the expression of sorcin. The results showed that the number of apoptotic cells, the expression of cleaved caspased-3, and the expression of Bax increased while the anti-apoptotic factor Bcl-2 decreased in the siRNA-Sorcin + CIS group. The observed increase in apoptosis was related to the increase of reactive oxygen species (ROS) and the destruction of the mitochondrial membrane potential (MMP). Finally, we found that the downregulated sorcin worked by activating the P-ERK1/2 signaling pathway. Overall, this study showed that sorcin can be used as a new target to prevent the ototoxicity of platinum drugs.

PD-L1 and PD-1 expressed in trigeminal ganglia may inhibit pain in an acute migraine model.

BACKGROUND: Neurogenic inflammation, mediated by the activation of primary neurons, is thought to be an important factor in migraine pathophysiology. Programmed cell death ligand-1 (PD-L1) can suppress the immune response through the Programmed cell death-1 receptor. However, the role of PD-L1/PD-1 in migraine remains unclear. In this study we evaluated the expression and role of PD-L1/PD-1 in the trigeminal ganglia in an animal model of acute migraine. METHODS: Acute nitroglycerin induces acute mechanical hyperalgesia that can be used as a readout of migraine-like pain. We investigated the expression of PD-L1 and PD-1 in the trigeminal ganglia in a mouse model by means of immunofluorescence labeling, quantitative reverse transcription-polymerase chain reaction and western blotting. We explored the effects of PD-1 in a migraine model by the von Frey test and by analyzing the expression of calcitonin gene-related peptide, interleukin-1ß (IL-1ß), interleukin-18 (IL-18), Tumor Necrosis Factor-α (TNF-α), interleukin-6 (IL-6) and transient receptor potential vanilloid (TRPV4) after the intravenous injection of a PD-1 inhibitor. RESULTS: PD-L1 and PD-1 immunoreactivity were present in healthy trigeminal ganglia neurons. The mRNA levels of PD-L1 and PD-1 were significantly elevated 2 h, 4 h and 6 h after acute nitroglycerin treatment (p < 0.05). The protein levels of PD-L1 were significantly increased 2 h, 4 h and 6 h after treatment, and PD-1 was significantly increased at 2 h and 6 h. The blockade of PD-1 increased acute nitroglycerin-induced hyperalgesia, and this effect was accompanied by a more significant increase in calcitonin gene-related peptide, IL-1ß, TNF-α, IL-6 and IL-18 in the trigeminal ganglia. CONCLUSION: These findings suggest that PD-L1 and PD-1 might inhibit migraine-like pain by downregulating CGRP and inflammatory factors in the trigeminal ganglia. The use of PD-L1 and PD-1 as analgesics should be further studied.

3D-real IR MRI of Meniere's disease with partial endolymphatic hydrops.

OBJECTIVES: A three-dimensional inversion-recovery sequence with real reconstruction (3D-real IR) sequence 4 h after intravenous gadolinium injection (IV) has been used to visualize the endolymphatic hydrops (ELH) in Meniere's disease (MD). This study was designed to explore the pathology of MD with partial ELH. METHODS: We collected 338 patients with definite MD, all of whom underwent the IV method. Patients who were found to have partial ELH (vestibular or cochlear) were enrolled. The hearing thresholds of the enrolled patients were analyzed, the regions of interest of the cochlear perilymph and the cerebellum white matter were determined, and the signal intensity ratio in the former to the latter (CC ratio) for both sides in the patients was subsequently evaluated. RESULTS: Of the 338 collected patients with definite MD, 19 patients (5.6%) had unilateral vestibular ELH (N = 18) or cochlear ELH (N = 1), and 4 patients (1.2%) with bilateral ELH had contralateral cochlear ELH. The CC ratio of the affected side (1.44 ±â€¯0.46) was higher than that of the unaffected side (1.15 ±â€¯0.33, P < 0.05) in the 19 patients with unilateral ELH. Conversely, there was no difference between the ratio of the contralateral side (1.18 ±â€¯0.16) and the unaffected side (P > 0.05) in the 4 patients with bilateral ELH. CONCLUSIONS: Partial vestibular ELH was more common than partial cochlear ELH in MD. Moreover, vestibular ELH, rather than cochlear ELH, may correlate with the elevated contrast effect in the affected side, which may better reflect the pathologic mechanism of MD.

Quantitative evaluation of endolymphatic hydrops with MRI through intravenous gadolinium administration and VEMP in unilateral definite Meniere's disease.

PURPOSE: To help clinicians to further understand the significance of vestibular-evoked myogenic potential (VEMP) examinations to diagnose MD and the quantitative relationship between VEMP and MRI in assessing the location and degree of endolymphatic hydrops (EH) in definite Meniere's disease (MD) patients. METHODS: Fifty-six patients with unilateral definite MD participated in this study, which used MRIs through intravenous gadolinium administration (IV-Gd), audiometry, caloric tests and VEMP tests. The VEMP results of 26 healthy volunteers were used as a normal reference value. RESULTS: The participants were found through MRI to have differing degrees of vestibular and cochlear EH. Quantitative comparison of MRI and VEMP results found that the response rates of oVEMP decreased with cochlear EH increasing; the asymmetry ratio (AR) of oVEMP can be used to find whether cochlear EH or not, and the P1-N1 amplitude was lower in the extreme cochlear EH group (P < 0.01). The AR of cVEMP was larger in severe vestibular EH group than that of the mild or no vestibular EH group (P < 0.01). The correlation between the degree of cochlear EH and the mean PTA threshold was statistically significant (P < 0.05). The duration of MD correlated positively with vestibular EH (P < 0.05). The abnormal rate of caloric tests was higher in severe vestibular EH group than that of the mild or no vestibular EH group (P < 0.05). CONCLUSIONS: The advantages of MRIs by IV-Gd administration were obvious in assessing the location and degree of EH. oVEMP and PTA can be indirectly used to evaluate the extent of cochlear EH, cVEMP and caloric tests can be used to assess the extent of vestibular EH on the condition of absent MRIs.

Gut microbiota and metabolite variations in a migraine mouse model.

Migraine is a prevalent clinical disorder characterized by recurrent unilateral throbbing headache episodes accompanied by symptoms such as nausea, vomiting, photophobia, and phonophobia. Despite its common occurrence, the diagnosis, pathophysiology, and treatment of migraine remain controversial. Extensive research has implicated the gut microbiota in various central nervous system disorders, including anxiety disorders, depression, and Parkinson's disease. Some studies have also suggested that migraine may stem from disruptions to neurohormones and metabolism. This study aimed to investigate the disparities in gut microbiota and metabolites between migraine mice model and normal mice to shed light on the underlying mechanisms and potential therapeutic approaches. Distinct differences in gut microbial composition were observed between the migraine mouse model and normal mouse, indicating a potential correlation between these variations and the pathogenesis of migraine. This study provides evidence of differences in gut microbiota composition and metabolites between a migraine mouse model and normal mice, which showed that Akkermansiaceae constituted the most abundant taxon in the sham injection mouse group, while Lachnospiraceae constituted the most prevalent group in the migraine mouse model group. The associations between the abundances of Akkermansia muciniphila and Lachnospiraceae bacteria and metabolites suggested their potential roles in the pathogenesis of migraine. The altered abundance of Lachnospiraceae observed in migraine-afflicted mice and its correlations with changes in metabolites suggest that it may affect the host's health. Thus, probiotic therapy emerges as a possible treatment for migraine. Moreover, significant disparities in gut metabolites were observed between the migraine mouse model and normal mice. These alterations encompass multiple metabolic pathways, suggesting that metabolic disturbances may also contribute to the development of migraines.

Auditory Manifestations of Vestibular Migraine.

Objectives: To investigate the auditory features of patients with vestibular migraine (VM) and to analyze the possible relevant factors of hearing loss. Methods: A total of 166 patients with VM were enrolled. Demographic variables, age of onset, disease course, distribution of vestibular attacks, characteristics of hearing loss, and the coexistence of related disorders, such as visual aura, familial history, motion sickness, nausea, headache, photophobia, otalgia, tinnitus, aural fullness, and phonophobia, were analyzed and compared. Results: Patients with VM can manifest otalgia (8.4%), tinnitus (51.8%), aural fullness (41%), and phonophobia (31.9%). Of 166 patients, the prevalence of VMw was 21.1% (n = 35). Patients with VMw mainly manifested mild and easily reversible low-frequency hearing loss. The proportions of tinnitus and aural fullness were significantly larger in patients with VMw than that in patients with VMo (P < 0.05). The duration of vestibular symptoms was significantly shorter in patients with VMw (P < 0.05). However, the age of onset, disease course, gender, frequency of vestibular attacks, the coexistence of visual aura, familial history, motion sickness, nausea, headache, photophobia, otalgia, and phonophobia had no significant difference between the two groups. Conclusion: Auditory symptoms were common in patients with VM. The hearing loss of VM was characterized by a mild and easily reversible low-frequency hearing loss, accompanied by higher proportions of tinnitus and aural fullness, and a shorter duration of vestibular symptoms compared with patients with VMo.

Characteristics of clinical details and endolymphatic hydrops in unilateral and bilateral Ménière's disease in a single Asian group.

Objectives: To elucidate the characteristics of the clinical details and endolymphatic hydrops (EH) in bilateral Ménière's disease (BMD). Methods: A total of 545 patients with definite MD were enrolled. Demographic variables; the age of onset; disease course; inner ear function; the coexistence of related disorders such as migraine, delayed MD, drop attacks, and autoimmune diseases; familial history; and characteristics of EH were analyzed. Results: In the study population, the prevalence of BMD was 15.4%. The disease duration of BMD (84.0 ± 89.6 months) was significantly longer than that of unilateral MD (UMD, 60.1 ± 94.0 months) (P = 0.001). As evaluated by hearing thresholds and cervical and ocular vestibular evoked myogenic potentials, inner ear functions were more deteriorated in BMD (P < 0.05) than in UMD. The proportions of delayed MD and a family history of vertigo were significantly larger in BMD (P < 0.05). EH was observed in 100% of cases on the clinically affected side and 6.1% of cases on the unaffected side. Conclusion: A low prevalence of BMD, longer disease duration, higher frequencies of delayed MD, and family history of vertigo in patients with BMD were significant findings observed in the present study. All affected ears presented with EH, and a low percentage of unaffected sides presented with EH.

Intracranial pressure, lateral sinus patency, and jugular ultrasound hemodynamics in patients with venous pulsatile tinnitus.

The clinical and hemodynamic characteristics of venous pulsatile tinnitus (PT) patients with normal or elevated cerebrospinal fluid pressure (CSFP) have not been clearly differentiated. This study aimed to explore CSFP among patients with PT as the solitary symptom, as well as quantitatively and qualitatively assess the role of the degree of transverse sinus (TS) stenosis and jugular hemodynamics in venous PT patients. A total of 50 subjects with venous PT with or without sigmoid sinus wall anomalies (SSWAs) were enrolled in this study. In addition to radiologic assessments for TS stenosis and invagination of arachnoid granulation (AG) in TS, CSFP and jugular hemodynamics were measured via cerebrospinal fluid (CSF) manometry and Doppler ultrasound. Apart from group comparisons and correlation analyses, multivariate linear regression, and receiver operating characteristic (ROC) models were used to identify the sensitivity and specificity of the index of transverse sinus stenosis (ITSS) and hemodynamic variables with inferential significance. The mean CSFP of all cases was 199.5 ± 52.7 mmH2O, with no statistical difference in CSFP between the diverticulum and dehiscence groups. Multivariate linear regression analysis demonstrated that CSFP was linearly correlated with ITSS and pulsatility index (PI). ROC analysis showed that the area under the ROC curve of PI was 0.693 at 200 mmH2O threshold, and the best PI cut-off value was 0.467, with a sensitivity of 65.7% and specificity of 81.8%. For 250 mmH2O threshold, the area under the ROC curve of PI was 0.718, and the best PI cut-off value was 0.467 with a sensitivity of 68.4% and specificity of 75.0%. Additionally, the area under the ROC curve of ITSS was 0.757, and the best ITSS cutoff value was 8.5 (p = 0.002, 95% CI = 0.616-0.898) with a sensitivity of 72.4% and specificity of 75.0% at 200 mmH2O threshold. In conclusion, patients with venous PT as the only presenting symptom should be suspected of having borderline or increased CSFP when they present with high ITSS, BMI and low PI. Further, AG in TS without encephalocele and empty sellae are not limiting findings for differentiating the level of CSFP in patients with venous PT.

3D Real IR MR Findings in Acoustic Neuromas: Altered Perilymph Metabolism.

OBJECTIVES: This study aimed to investigate the perilymph metabolism by analyzing the 3D real IR MR findings in acoustic neuroma (AN) after intravenous administration of gadolinium (Gd). METHODS: Eleven patients (6 men and 5 women) diagnosed with AN were included, and 3D real IR MRI was performed 4 hours after intravenous Gd injection. The signal intensity and details of inner ear, tumor, and internal auditory canal (IAC) by MRI were analyzed. RESULTS: Four patients had tumors confined to the IAC, and 5 had tumors that extended to the cerebellopontine angle cistern. The signal intensity of the cochlea, vestibule, and IAC fundus was conspicuously enhanced in 3D real IR images than the control side. One patient had a tumor in the cochlea, in which the signal intensity of the semicircular canal and vestibule was increased. One patient had an intravestibular tumor in which the signal intensity of the semicircular canal was increased and the cochlea had endolymphatic hydrops in the affected ear. CONCLUSIONS: The synchronously increased signal intensity in the inner ear and IAC may indicate that IAC may serve as a channel for removal of the perilymph in the inner ear; the blockage by the tumor may have changed the hydrodynamics of the perilymph to cause a longer retention of Gd in the inner ear.

MR imaging and clinical characteristics of Lermoyez syndrome.

Background: Lermoyez syndrome (LS) is a rare auditory disorder, the details of LS remain unclear.Objectives: To investigate the grades of endolymphatic hydrops (ELH) and clinical characteristics of clinically diagnosed LS.Material and methods: Nine patients with clinically diagnosed LS were included. three-dimensional-real-infra red imaging characteristics were analyzed. ELH grades and detailed clinical characteristics were evaluated.Results: The group consisted of two women and seven men with an age at presentation of 48.4 ± 10.9 (28-61) years, an onset age of 40.9 ± 12.0 (23-58) years, and a disease duration of 7.6 ± 7.5 years. Of the nine patients, ELH was observed in 100% of the patients on the clinically affected side. In addition, 22.2% of vestibular ELH and 77.8% of cochlear ELH were classified as mild or moderate in grade.Conclusions and significance: The patients with LS had Meniere's triad, fluctuation of hearing that occurred in a reverse relationship to that of the vertiginous attack, and vestibular and cochlear ELH, which may suggest that LS is a variant of MD. However, the sex difference and milder cochlear ELH in LS compared with those in typical MD may indicate an underlying intrinsic difference in the mechanism of LS.

Clinical Features and Endolymphatic Hydrops in Patients With MRI Evidence of Hydrops.

OBJECTIVES:: The purpose of this study was to investigate the correlation between grades of endolymphatic hydrops (ELH) and clinical characteristics and determine the detailed clinical characteristics of Ménière's disease (MD) patients with evidence of hydrops based on magnetic resonance imaging (MRI). METHODS:: One hundred ninety-eight MD patients (396 ears) with MRI evidence of hydrops were included. ELH grades were evaluated using the Nakashima grading standard. Correlations between the extent of ELH and clinical features were evaluated. Detailed clinical characteristics were analyzed to assess the clinical diagnostic criteria. RESULTS:: Of 198 patients, ELH was observed in 100% of cases on the clinically affected side and 8.6% of cases on the asymptomatic side. In addition, 98.5% of ELH was classified as moderate or significant grade. Low-frequency hearing loss was significantly correlated with the extent of both vestibular and cochlear hydrops, whereas the vertigo attack frequency showed no significant correlation with ELH grades. The disease duration of MD with bilateral ELH was longer than that with unilateral ELH. The clinical characteristics were variant and did not completely fit the proposed diagnostic criteria. CONCLUSIONS:: MRI findings have relevance to the clinical severity, to a certain extent, but not vestibular symptoms. The proposed diagnostic criteria based on clinical characteristics may be partially effective; analysis of the detailed clinical characteristics of MD was meaningful. Diagnosis of MD based on both MRI and clinical symptoms could facilitate an early diagnosis.

Magnetic Resonance Imaging of Ménière's Disease After Intravenous Administration of Gadolinium.

OBJECTIVES: A three-dimensional (3D) inversion-recovery (IR) sequence with real reconstruction (3D-real IR) sequence 4 hours after intravenous (IV) gadolinium injection has been used to visualize the endolymphatic hydrops (ELH) in Ménière's disease (MD). This study was designed to investigate the ELH characteristics in clinically diagnosed definite MD and to explore the pathology of MD with magnetic resonance imaging (MRI). METHODS: One hundred fifty-four patients with definite MD were included in this study. All patients underwent the IV method. The grades of ELH were analyzed on each image, regions of interest of the cochlear perilymph and the cerebellum white matter were determined, and the signal intensity ratio of the former to the latter (CC ratio) on both sides in patients with unilateral MD was subsequently evaluated. RESULTS: Endolymphatic hydrops was observed in 148 patients (96.1%) on the clinically affected side; the remaining 6 patients (3.9%) had no apparent ELH. One hundred fifteen patients (74.7%) had unilateral ELH, and 33 patients (21.4%) had bilateral ELH. Eighteen patients (11.7%) had ELH on the clinically silent side. Patients with moderate and significant grades of ELH in the vestibule and cochlea accounted for 88.3% and 90.3%, respectively. The CC ratio of the affected side (1.39 ± 0.37) was higher than that of the unaffected side (1.18 ± 0.29) ( P < .01) in 115 patients with unilateral MD. CONCLUSIONS: Moderate and significant grades of ELH are common in MD; however, the proposed diagnostic criteria are not fully consistent with ELH. The elevated contrast effect in the affected side in patients with unilateral MD may better reflect the pathologic condition of MD.

Effect of Epineurial Neurorrhaphy on Restoration of Facial Nerve Injuries with Different Levels of Neurotmesis in a Rat Model: A Pilot Study.

BACKGROUND: Different degrees of neurotmesis of the peripheral facial nerve frequently are encountered in clinic, for which the epineurial neurorrhaphy is the preferred technique. However, because of the capability of self-restoration of nerves and the side effects of surgery, neurorrhaphy may not be an optimal choice for various degrees of neurotmesis. In this study, we explored the necessity of epineurial neurorrhaphy for different degrees of neurotmesis, in addition to investigating factors that impact neural functional recovery. METHODS: Rat models were divided into 6 groups: intact, noninjured controls; A, one-third cross-sectional facial nerve disconnected injury after epineurial neurorrhaphy; B, one-third cross-sectional facial nerve disconnected injury without epineurial neurorrhaphy; C, two-thirds cross-sectional facial nerve disconnected injury after epineurial neurorrhaphy; D, two-thirds cross-sectional facial nerve disconnected injury without epineurial neurorrhaphy; and E, two-thirds cross-sectional facial nerve disconnection followed by complete transection and neurorrhaphy. Facial functional recovery was assessed with the use of behavioral assessments and electrophysiologic tests. The morphologic changes of trunk of the facial nerve were analyzed by osmium-toluidine blue staining and immunofluorescence. The modification of central nervous system was evaluated by retrograde labeling and Nissl's staining of facial nerve nuclei. RESULTS: Concerning morphologic and functional assessments, there were no statistically significant differences between one-third facial nerve disconnected injury with or without epineurial neurorrhaphy and the intact model. For two-thirds facial nerve disconnected injury, direct neurorrhaphy was superior to complete transection followed by neurorrhaphy. For two-thirds facial nerve disconnected injury, the nerves can largely self-restore in neural structure and function without the use of epineurial neurorrhaphy. For the facial nerve nuclei, the number of neurons decreased in the more than two-thirds nerve disconnected models, and models with two-thirds disconnection and without neurorrhaphy had the least number of neurons. For the distribution of neurons in different facial nerve subnuclei, both models with two-thirds nerve disconnection without neurorrhaphy and models with two-thirds nerve disconnection after complete transection and neurorrhaphy demonstrated disorganization of neurons, in which the latter was more serious. CONCLUSIONS: For one-third disconnected facial nerve injury, there's no need to suture the nerve stump, although for residual one-third connected nerve injury, direct suture is preferable if permitted than pre-performing a complete transection to trim the stump. Residual one-third connected nerve fibers largely can self-restore. The results from this study indicate that neural functional defect may be attributed to the damage and misdirection of peripheral nerve fibers and central neurons.

Different discharge properties of facial nucleus motoneurons following neurotmesis in a rat model.

Facial nucleus motoneurons innervating the facial expressive muscles are involved in a wide range of motor activities, however, the types of movement related neurons and their electrophysiological transformation after peripheral facial nerve injury haven't been revealed. This study was designed to elucidate the types of facial nucleus motoneurons and their alterations of discharge parameters following peripheral facial nerve injury in vivo. Here we set up a rat model by implanting electrode arrays into the brainstem and recorded the electrophysiological signals of facial nucleus neurons in the intact rats for 5 days, then transected the trunk of facial nerve (TF), and continued the record for 4 weeks. At the 4th week post-surgery, the morphological changes of TFs were analyzed. In this paper, we described two types of putative facial nucleus motoneurons based on their electrophysiological properties and their firing frequency adaptation. Type I motoneurons (n=57.6%) were characterized by a sustained spike adaptation, Type II motoneurons (n=26.2%) were identified by a phasic fast spike firing. Facial palsy and synkinesia, caused by neurotmesis of TF, were accompanied by firing rates reduction and firing pattern alteration of motoneurons. Our findings suggest the presence of two types of facial nucleus motorneurons, and their response patterns after neurotmesis support the notion that the discharge pattern of motorneurons may play an important role in the facial nerve function.