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Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.
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Canales Iónicos Sensibles al Ácido , Isquemia Encefálica , Ácido Glutámico , Animales , Femenino , Humanos , Masculino , Ratones , 2-Amino-5-fosfonovalerato/efectos adversos , 2-Amino-5-fosfonovalerato/metabolismo , 2-Amino-5-fosfonovalerato/farmacología , Canales Iónicos Sensibles al Ácido/química , Canales Iónicos Sensibles al Ácido/deficiencia , Canales Iónicos Sensibles al Ácido/efectos de los fármacos , Canales Iónicos Sensibles al Ácido/genética , Canales Iónicos Sensibles al Ácido/metabolismo , Regulación Alostérica/efectos de los fármacos , Sitios de Unión/genética , Isquemia Encefálica/inducido químicamente , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ácido Glutámico/análogos & derivados , Ácido Glutámico/metabolismo , Ácido Glutámico/farmacología , Ácido Glutámico/toxicidad , Ratones Noqueados , Mutagénesis Sitio-Dirigida , Protones , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Taurine appears to exert potent protections against glutamate (Glu)-induced injury to neurons, but the underlying molecular mechanisms are not fully understood. The possibly protected targets consist of the plasma membrane and the mitochondrial as well as endoplasmic reticulum (ER) membranes. Protection may be provided through a variety of effects, including the prevention of membrane depolarization, neuronal excitotoxicity and mitochondrial energy failure, increases in intracellular free calcium ([Ca2+]i), activation of calpain, and reduction of Bcl-2 levels. These activities are likely to be linked spatially and temporally in the neuroprotective functions of taurine. In addition, events that occur downstream of Glu stimulation, including altered enzymatic activities, apoptotic pathways, and necrosis triggered by the increased [Ca2+]i, can be inhibited by taurine. This review discusses the possible molecular mechanisms of taurine against Glu-induced neuronal injury, providing a better understanding of the protective processes, which might be helpful in the development of novel interventional strategies.
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Ácido Glutámico/toxicidad , Fármacos Neuroprotectores/uso terapéutico , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/prevención & control , Taurina/uso terapéutico , Animales , Retículo Endoplásmico/efectos de los fármacos , Humanos , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Síndromes de Neurotoxicidad/patología , Taurina/metabolismo , Taurina/farmacologíaRESUMEN
The aim of this study was to determine the associated factors affecting the outcome of uvulopharyngopalatoplasty (UPPP) in patients with severe obstructive sleep apnea hypopnea syndrome (OSAHS), and to investigate whether cephalometric measurements were predictive of the therapeutic response to UPPP in patients with severe OSAHS. We retrospectively studied 51 consecutive patients who underwent revised UPPP with uvula preservation (H-UPPP), or Z-palatopharyngoplasty (ZPPP) for severe OSAHS [apnea-hypopnea index (AHI) >30]. All patients were evaluated using physical examination, Epworth Sleepiness Scale (ESS), cephalometry, and nocturnal polysomnography (PSG) before surgery and at 6-12 months after surgery. Based on the success criteria defined as an AHI of <20 and a decrease >50 %, the overall success rate was 45.1 %. The preoperative distance from the posterior border of the uvula to the middle pharyngeal wall (U-MPW) was significantly longer in the responder group than in the nonresponder group, when considering the whole group or the H-UPPP group alone. Among all study subjects, U-MPW and change in body mass index (â³BMI) were the significant predictors of surgical success. U-MPW was the key predictor for H-UPPP surgical success, whereas mandibular plane angle (MPA) and Friedman stage were the key predictors for ZPPP surgical success. In conclusion, U-MPW was a significant predictor of UPPP surgical success. Patients with U-MPW >10 mm who are unwilling to receive nasal continuous positive airway pressure (CPAP) therapy might be suitable candidates for UPPP surgery.
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Cefalometría , Paladar Blando/cirugía , Faringe/cirugía , Apnea Obstructiva del Sueño/cirugía , Úvula/cirugía , Adulto , Índice de Masa Corporal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polisomnografía , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Apnea Obstructiva del Sueño/diagnóstico , Resultado del TratamientoRESUMEN
Quantitative assessment of endogenously synthesized and released bilirubin from brain tissue remains a challenge. Here, we present a sensitive and reproducible experimental paradigm to quantify, in real time, unconjugated bilirubin (UCB) from isolated murine brain tissue during oxygen-glucose deprivation (OGD). We describe steps for perfusion, brain dissection, brain slice preparation and incubation, glucose depletion, and OGD processing. We then detail procedures for standard calibration plotting and sample UCB measurement. For complete details on the use and execution of this protocol, please refer to Liu et al.1.
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Glucosa , Oxígeno , Ratones , Animales , Bilirrubina , Encéfalo , CabezaRESUMEN
Optimizing cell substrates by surface modification of neural stem cells (NSCs), for efficient and oriented neurogenesis, represents a promising strategy for treating neurological diseases. However, developing substrates with the advanced surface functionality, conductivity, and biocompatibility required for practical application is still challenging. Here, Ti3 C2 Tx MXene is introduced as a coating nanomaterial for aligned poly(l-lactide) (PLLA) nanofibers (M-ANF) to enhance NSC neurogenesis and simultaneously tailor the cell growth direction. Ti3 C2 Tx MXene treatment provides a superior conductivity substrate with a surface rich in functional groups, hydrophilicity, and roughness, which can provide biochemical and physical cues to support NSC adhesion and proliferation. Moreover, Ti3 C2 Tx MXene coating significantly promotes NSC differentiation into both neurons and astrocytes. Interestingly, Ti3 C2 Tx MXene acts synergistically with the alignment of nanofibers to promote the growth of neurites, indicating enhanced maturation of these neurons. RNA sequencing analysis further reveals the molecular mechanism by which Ti3 C2 Tx MXene modulates the fate of NSCs. Notably, surface modification by Ti3 C2 Tx MXene mitigates the in vivo foreign body response to implanted PLLA nanofibers. This study confirms that Ti3 C2 Tx MXene provides multiple advantages for decorating the aligned PLLA nanofibers to cooperatively improve neural regeneration.
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Nanofibras , Células-Madre Neurales , Titanio/farmacología , NeuronasRESUMEN
Stroke prognosis is negatively associated with an elevation of serum bilirubin, but how bilirubin worsens outcomes remains mysterious. We report that post-, but not pre-, stroke bilirubin levels among inpatients scale with infarct volume. In mouse models, bilirubin increases neuronal excitability and ischemic infarct, whereas ischemic insults induce the release of endogenous bilirubin, all of which are attenuated by knockout of the TRPM2 channel or its antagonist A23. Independent of canonical TRPM2 intracellular agonists, bilirubin and its metabolic derivatives gate the channel opening, whereas A23 antagonizes it by binding to the same cavity. Knocking in a loss of binding point mutation for bilirubin, TRPM2-D1066A, effectively antagonizes ischemic neurotoxicity in mice. These findings suggest a vicious cycle of stroke injury in which initial ischemic insults trigger the release of endogenous bilirubin from injured cells, which potentially acts as a volume neurotransmitter to activate TRPM2 channels, aggravating Ca2+-dependent brain injury.
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Accidente Cerebrovascular , Canales Catiónicos TRPM , Animales , Ratones , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismo , Bilirrubina/metabolismo , Ratones Noqueados , Encéfalo/metabolismo , Infarto , Calcio/metabolismoRESUMEN
Bilirubin can cause temporary or permanent sensorineural deafness in newborn babies with hyperbilirubinemia. However, the underlying targets and physiological effects of bilirubin-induced damage in the peripheral auditory system are unclear. Using cochlear functional assays and electron microscopy imaging of the inner ear in neonatal guinea pigs, we show here that bilirubin exposure resulted in threshold elevation in both compound action potential (CAP) and auditory brainstem response (ABR), which was apparent at 1 hr and peaked 8 hr after drug administration. The threshold elevation was associated with delayed wave latencies and elongated interwave intervals in ABR and CAP. At 72 hr postinjection, these measures returned to control levels, except for the CAP amplitude. Cochlear microphonics remained unchanged during the experiment. Morphological abnormalities were consistent with the electrophysiological dysfunction, revealing fewer auditory nerve fibers (ANFs) in the basal turn, myelin sheath lesions of spiral ganglion neurons (SGNs) and ANFs, and loss of type 1 afferent endings beneath inner hair cells (IHCs) without loss of hair cells at 8 hr posttreatment. Similar to the electrophysiological findings, morphological changes were mostly reversed 10 days after treatment, except for the ANF reduction in the basal turn. These results suggest that hyperbilirubinemia in neonatal guinea pigs impaired auditory peripheral neuromechanisms that targeted mainly the IHC synapses and the myelin sheath of SGNs and their fibers. Our observations indicate a potential connection between hyperbilirubinemia and auditory neuropathy.
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Nervio Coclear/ultraestructura , Pérdida Auditiva Central/etiología , Pérdida Auditiva Central/patología , Hiperbilirrubinemia/complicaciones , Ganglio Espiral de la Cóclea/ultraestructura , Potenciales de Acción/efectos de los fármacos , Animales , Animales Recién Nacidos , Bilirrubina/toxicidad , Nervio Coclear/efectos de los fármacos , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Femenino , Cobayas , Masculino , Microscopía Electrónica de Transmisión , Ganglio Espiral de la Cóclea/efectos de los fármacosRESUMEN
It is hypothesized that in sine-wave replicas of natural speech, lexical tone recognition would be severely impaired due to the loss of F0 information, but the linguistic information at the sentence level could be retrieved even with limited tone information. Forty-one native Mandarin-Chinese-speaking listeners participated in the experiments. Results showed that sine-wave tone-recognition performance was on average only 32.7% correct. However, sine-wave sentence-recognition performance was very accurate, approximately 92% correct on average. Therefore the functional load of lexical tones on sentence recognition is limited, and the high-level recognition of sine-wave sentences is likely attributed to the perceptual organization that is influenced by top-down processes.
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Lenguaje , Reconocimiento en Psicología/fisiología , Acústica del Lenguaje , Percepción del Habla/fisiología , Adulto , China , Señales (Psicología) , Femenino , Humanos , Masculino , Fonética , Espectrografía del Sonido , Adulto JovenRESUMEN
BACKGROUND: This study aimed to evaluate the efficacy and safety of primary maxillomandibular advancement (MMA) with concomitant adjunctive revised uvulopalatopharyngoplasty with uvula preservation (H-UPPP) in selected patients with severe obstructive sleep apnea-hypopnea syndrome (OSASH). METHODS: Eleven consecutive male patients with velo-orohypopharyngeal and hypopharyngeal narrowing underwent MMA with concomitant H-UPPP for severe OSAHS. All patients underwent a physical examination, Epworth Sleepiness Scale evaluation, cephalometry, nocturnal polysomnogram, and velopharyngeal insufficiency questionnaire survey before and at 6 to 12 months after surgery. RESULTS: On the basis of the success criteria, defined as an apnea-hypopnea index less than 20 and a decrease greater than 50%, the success rate was 91%. The apnea-hypopnea index decreased from 67.44 (13.30) to 9.41 (7.20) events per hour (P < 0.001) and the lowest oxygen saturation increased from 63.0% (10.70%) to 88.55% (4.59%) (P < 0.001) after surgery. All patients showed a significant decrease in mandibular plane to hyoid bone and increase in PAS after surgery. One patient reported regurgitation of liquids when drinking hastily after surgery. Two patients reported regurgitation as occasional occurrences. Half a year later, 2 patients reported complete resolution of the symptoms. One patient still complained of rare regurgitation of liquids when drinking quickly. Five patients had paresthesia of the lower lip; in 4 patients, the paresthesia had resolved by 12 months after surgery. One patient still complained of paresthesia of the lower lip after 2 years of follow-up. No major complication (eg, upper airway obstruction) occurred. CONCLUSIONS: Primary MMA with concomitant adjunctive H-UPPP is effective in selected patients with severe OSAHS without major complications.
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Procedimientos Quirúrgicos Ortognáticos/métodos , Apnea Obstructiva del Sueño/cirugía , Adulto , Cefalometría , Humanos , Masculino , Avance Mandibular , Maxilar/cirugía , Osteotomía Maxilar , Paladar Blando/cirugía , Faringe/cirugía , Índice de Severidad de la Enfermedad , Apnea Obstructiva del Sueño/fisiopatología , Resultado del Tratamiento , Úvula/cirugíaRESUMEN
Objectives: A huge population, especially the elderly, suffers from otogenic vertigo. However, the multi-modal vestibular network changes, secondary to periphery vestibular dysfunction, have not been fully elucidated. We aim to identify potential microstate electroencephalography (EEG) signatures for otogenic vertigo in this study. Materials and Methods: Patients with recurrent otogenic vertigo and age-matched healthy adults were recruited. We performed 256-channel EEG recording of all participants at resting state. Neuropsychological questionnaires and vestibular function tests were taken as a measurement of patients' symptoms and severity. We clustered microstates into four classes (A, B, C, and D) and identified their dynamic and syntax alterations of them. These features were further fed into a support vector machine (SVM) classifier to identify microstate signatures for vertigo. Results: We compared 40 patients to 45 healthy adults, finding an increase in the duration of Microstate A, and both the occurrence and time coverage of Microstate D. The coverage and occurrence of Microstate C decreased significantly, and the probabilities of non-random transitions between Microstate A and D, as well as Microstate B and C, also changed. To distinguish the patients, the SVM classifier, which is built based on these features, got a balanced accuracy of 0.79 with a sensitivity of 0.78 and a specificity of 0.8. Conclusion: There are several temporal dynamic alterations of EEG microstates in patients with otogenic vertigo, especially in Microstate D, reflecting the underlying process of visual-vestibular reorganization and attention redistribution. This neurophysiological signature of microstates could be used to identify patients with vertigo in the future.
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Neuroinflammation is a key pathological factor in numerous neurological disorders. Cumulating evidence has indicated critical roles of NAD+/NADH metabolism in multiple major diseases, while the role of malate-aspartate shuttle (MAS) - a major NADH shuttle - in inflammation has remained unclear. In this study we investigated the roles of MAS in LPS-induced neuroinflammation both in vivo and in vitro. Immunofluorescence staining, Western blot assay and Real-time PCR assays were conducted to determine the activation of Iba-1, the protein levels of iNOS and COX2 and the mRNA levels of IL-1ß, IL-6, and TNF-α in vivo, showing that both pre-treatment and post-treatment of aminooxyacetic acid (AOAA) - an MAS inhibitor - profoundly decreased the LPS-induced neuroinflammation in mice. BV2 microglia was also used as a cellular model to investigate the mechanisms of this finding, in which such assays as Western blot assay and nitrite assay. Our study further indicated that AOAA produced its effects on LPS-induced microglial activation by its effects on MAS: Pyruvate treatment reversed the effects of AOAA on the cytosolic NAD+/NADH ratio, which also restored the LPS-induced activation of the AOAA-treated microglia. Moreover, the lactate dehydrogenase (LDH) inhibitor GSK2837808A blocked the effects of pyruvate on the AOAA-produced decreases in both the cytosolic NAD+/NADH ratio and LPS-induced microglial activation. Our study has further suggested that AOAA produced inhibition of LPS-induced microglial activation at least partially by decreasing STAT3 phosphorylation. Collectively, our findings have indicated AOAA as a new and effective drug for inhibiting LPS-induced neuroinflammation. Our study has also indicated that MAS is a novel mediator of LPS-induced neuroinflammation due to its capacity to modulate LPS-induced STAT3 phosphorylation, which has further highlighted a critical role of NAD+/NADH metabolism in inflammation.
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Although embryonic stem cells or induced pluripotent stem cells are able to differentiate into inner ear hair cells (HCs), they have drawbacks limiting their clinical application, including a potential risk of tumourigenicity. Direct reprogramming of fibroblasts to inner ear HCs could offer an alternative solution to this problem. Here, we present a stepwise guidance protocol to induce mouse embryonic fibroblasts to differentiate into inner ear HC-like cells (HCLs) via mesenchymal-to-epithelial transition and then acquisition of otic sensory epithelial cell traits by overexpression of three key transcription factors. These induced HCLs express multiple HC-specific proteins, display protrusions reminiscent of ciliary bundle structures, respond to voltage stimulation, form functional mechanotransduction channels, and exhibit a transcriptional profile of HC signature. Together, our work provides a new method to produce functional HCLs in vitro, which may have important implications for studies of HC development, drug discovery, and cell replacement therapy for hearing loss.
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OBJECTIVE: To examine the effect of multisensory exercise on balance disorders. METHODS: PubMed, Scopus and Web of Science were searched to identify eligible studies published before January 1, 2020. Eligible studies included randomized control trials (RCTs), non-randomized studies, case-control studies, and cohort studies. The methodological quality of the included studies was evaluated using JBI Critical Appraisal Checklists for RCTs and for Quasi-Experimental Studies by two researchers independently. A narrative synthesis of intervention characteristics and health-related outcomes was performed. RESULTS: A total of 11 non-randomized studies and 9 RCTs were eligible, including 667 participants. The results supported our assumption that multisensory exercise improved balance in people with balance disorders. All of the 20 studies were believed to be of high or moderate quality. CONCLUSION: Our study confirmed that multisensory exercise was effective in improving balance in people with balance disorders. Multisensory exercises could lower the risk of fall and enhance confidence level to improve the quality of life. Further research is needed to investigate the optimal strategy of multisensory exercises and explore the underlying neural and molecular mechanisms of balance improvement brought by multisensory exercises.
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Terapia por Ejercicio , Ejercicio Físico/fisiología , Equilibrio Postural/fisiología , Humanos , Calidad de VidaRESUMEN
Neonatal hyperbilirubinemia is a common clinical condition that can lead to brain encephalopathy, particularly when concurrent with acidosis due to infection, ischemia, and hypoxia. The prevailing view is that acidosis increases the permeability of the blood-brain barrier to bilirubin and exacerbates its neurotoxicity. In this study, we found that the concentration of the cell death marker, lactate dehydrogenase (LDH) in cerebrospinal fluid (CSF), is elevated in infants with both hyperbilirubinemia and acidosis and showed stronger correlation with the severity of acidosis rather than increased bilirubin concentration. In mouse neonatal neurons, bilirubin exhibits limited toxicity but robustly potentiates the activity of acid-sensing ion channels (ASICs), resulting in increases in intracellular Ca2+ concentration, spike firings, and cell death. Furthermore, neonatal conditioning with concurrent hyperbilirubinemia and hypoxia-induced acidosis promoted long-term impairments in learning and memory and complex sensorimotor functions in vivo, which are largely attenuated in ASIC1a null mice. These findings suggest that targeting acidosis and ASICs may attenuate neonatal hyperbilirubinemia complications.
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Bilirrubina , Hiperbilirrubinemia Neonatal , Canales Iónicos Sensibles al Ácido , Animales , Hiperbilirrubinemia Neonatal/complicaciones , Recién Nacido , Ratones , Ratones Noqueados , NeuronasRESUMEN
We designed a prospective study to evaluate changes in tinnitus after vestibular schwannoma (VS) surgery. Subjects included 41 patients who were diagnosed with a VS and underwent translabyrinthine microsurgery (TLM) between January 2015 and May 2016. All patients underwent related examinations and were asked to answer the Tinnitus Handicap Inventory (THI) scale and a visual analog scale (VAS) of tinnitus severity both pre- and postoperatively. Of the 41 patients, 31 (75.6%) suffered from tinnitus before surgery. Microsurgery was associated with an overall decrease in tinnitus (p < 0.001). There was a significant improvement in THI and VAS scores after surgery (p = 0.001 and p = 0.005, respectively). The decrease in THI scores in the low-frequency group was significantly larger than that of the mid- and high-frequency groups after surgery (p = 0.034 and p = 0.001, respectively). The loudness of tinnitus decreased significantly after surgery (p = 0.031). Tinnitus in patients with VS improved after TLM. Patients with mid-/high-frequency tinnitus and louder tinnitus preoperatively seemed to have a worse prognosis than those with low-frequency and quieter tinnitus.
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Microcirugia/efectos adversos , Neuroma Acústico/complicaciones , Neuroma Acústico/cirugía , Acúfeno/diagnóstico , Acúfeno/etiología , Adulto , Anciano , Audiometría/métodos , Susceptibilidad a Enfermedades , Femenino , Humanos , Masculino , Microcirugia/métodos , Persona de Mediana Edad , Neuroma Acústico/diagnóstico , Índice de Severidad de la Enfermedad , Evaluación de Síntomas , Resultado del Tratamiento , Carga TumoralRESUMEN
Previous studies have reported the effects of obstructive sleep apnea (OSA) and cardiometabolic disorders on cardiovascular disease (CVD), but associations between cardiometabolic biomarkers and two cardinal features of OSA (chronic intermittent hypoxia and sleep fragmentation) and their interactions on CVD in OSA populations remain unclear. A total of 1727 subjects were included in this observational study. Data on overnight polysomnography parameters, biochemical biomarkers, and anthropometric measurements were collected. Metabolic syndrome (MS), including blood pressure, waist circumference (WC), fasting glucose, triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), was diagnosed based on modified criteria of the Adult Treatment Panel III. WC, mean arterial pressure, TG and low-density lipoprotein cholesterol (LDL-C) were independently associated with apnea-hypopnea index (AHI) after adjustment for confounding factors (ß = 0.578, P = 0.000; ß = 0.157, P = 0.001; ß = 1.003, P = 0.019; and ß = 4.067, P = 0.0005, respectively). Furthermore, the interaction analysis revealed joint effects between hypertension, obesity, hyperglycemia, and LDL-C dyslipidemia and AHI on CVD. The relative excess risks of CVD due to the interactions with OSA were 2.06, 1.02, 0.48, and 1.42, respectively (all P < 0.05). In contrast, we found no independent effect of the microarousal index (MAI) on CVD. However, LDL-C level and some MS components (WC, TG) were associated with MAI. Our findings indicate that hypoxemia and cardiometabolic disorders in OSA may potentiate their unfavorable effects on CVD. Sleep fragmentation may indirectly predispose patients with OSA to an increased risk of CVD. Thus, cardiometabolic disorders and OSA synergistically influence cardiometabolic risk patterns.
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Enfermedades Cardiovasculares/epidemiología , Síndrome Metabólico/epidemiología , Apnea Obstructiva del Sueño/diagnóstico , Adulto , Presión Sanguínea , Femenino , Glucosa/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Polisomnografía , Circunferencia de la CinturaRESUMEN
Neonatal jaundice is prevalent among newborns and can lead to severe neurological deficits, particularly sensorimotor dysfunction. Previous studies have shown that bilirubin (BIL) enhances the intrinsic excitability of central neurons and this can potentially contribute to their overexcitation, Ca2+ overload, and neurotoxicity. However, the cellular mechanisms underlying elevated neuronal excitability remain unknown. By performing patch-clamp recordings from neonatal neurons in the rat medial vestibular nucleus (MVN), a crucial relay station for locomotor and balance control, we found that BIL (3 µM) drastically increases the spontaneous firing rates by upregulating the current-mediated voltage-gated sodium channels (VGSCs), while shifting their voltage-dependent activation toward more hyperpolarized potentials. Immunofluorescence labeling and western immunoblotting with an anti-NaV1.1 antibody, revealed that BIL elevates the expression of VGSCs by promoting their recruitment to the membrane. Furthermore, we found that this VGSC-trafficking process is Ca2+ dependent because preloading MVN neurons with the Ca2+ buffer BAPTA-AM, or exocytosis inhibitor TAT-NSF700, prevents the effects of BIL, indicating the upregulated activity and density of functional VGSCs as the core mechanism accountable for the BIL-induced overexcitation of neonatal neurons. Most importantly, rectification of such overexcitation with a low dose of VGSC blocker lidocaine significantly attenuates BIL-induced cell death. We suggest that this enhancement of VGSC currents directly contributes to the vulnerability of neonatal brain to hyperbilirubinemia, implicating the activity and trafficking of NaV1.1 channels as a potential target for neuroprotection in cases of severe jaundice.
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Potenciales de Acción/efectos de los fármacos , Bilirrubina/toxicidad , Calcio/metabolismo , Neuronas/efectos de los fármacos , Canales de Sodio Activados por Voltaje/metabolismo , Animales , Muerte Celular , Exocitosis/efectos de los fármacos , Canal de Sodio Activado por Voltaje NAV1.1/metabolismo , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología , Núcleos Vestibulares/citología , Núcleos Vestibulares/efectos de los fármacos , Núcleos Vestibulares/metabolismoRESUMEN
Gap detection has been used as an evaluation tool for temporal processing in subjects with sensorineural hearing loss (SNHL). However, the results from other reports are varied making it difficult to clearly define the impact of SNHL on the temporal processing ability of the auditory system. Specifically, we do not know if and how a high-frequency hearing loss impacts, presumably through off-channel interaction, the temporal processing in low-frequency channels where hearing sensitivity is virtually normal. In this experiment, gap-evoked responses in a low-frequency band (0.5-8 kHz) were recorded in the inferior colliculus (IC) and auditory cortex (AC) of guinea pigs through implanted electrodes, before and after a slopping high-frequency hearing loss, which was induced by over-stimulation using a 12-kHz-tone. The results showed that the gap thresholds in the low-frequency region increased gradually and became significantly higher 8 weeks after the induced high-frequency hearing loss. In addition, the response latency was slightly increased in the IC but this was not true for the AC. These results strongly indicate that a high-frequency hearing loss exerted an off-channel impact on temporal processing in the low-frequency region of the auditory system.
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Corteza Auditiva/anatomía & histología , Pérdida Auditiva de Alta Frecuencia/diagnóstico , Pérdida Auditiva Provocada por Ruido/diagnóstico , Colículos Inferiores/anatomía & histología , Ruido , Estimulación Acústica , Acústica , Animales , Umbral Auditivo , Cóclea/patología , Modelos Animales de Enfermedad , Electrodos , Cobayas , Microscopía Electrónica de Rastreo , Órgano Espiral/ultraestructuraRESUMEN
In developing sensory systems, elaborate morphological connectivity between peripheral cells and first-order central neurons emerges via genetic programming before the onset of sensory activities. However, how the first-order central neurons acquire the capacity to interface with peripheral cells remains elusive. By making patch-clamp recordings from mouse brainstem slices, we found that a subset of neurons in the cochlear nuclei, the first central station to receive peripheral acoustic impulses, exhibits spontaneous firings (SFs) as early as at birth, and the fraction of such neurons increases during the prehearing period. SFs are reduced but not eliminated by a cocktail of blockers for excitatory and inhibitory synaptic inputs, implicating the involvement of intrinsic pacemaker channels. Furthermore, we demonstrate that these intrinsic firings (IFs) are largely driven by hyperpolarization- and cyclic nucleotide-gated channel (HCN) mediated currents (Ih), as evidenced by their attenuation in the presence of HCN blockers or in neurons from HCN1 knockout mice. Interestingly, genetic deletion of HCN1 cannot be fully compensated by other pacemaker conductances and precludes age-dependent up regulation in the fraction of spontaneous active neurons and their firing rate. Surprisingly, neurons with SFs show accelerated development in excitability, spike waveform and firing pattern as well as synaptic pruning towards mature phenotypes compared to those without SFs. Our results imply that SFs of the first-order central neurons may reciprocally promote their wiring and firing with peripheral inputs, potentially enabling the correlated activity and crosstalk between the developing brain and external environment.
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BACKGROUND: Standard management has been recommended for obstructive sleep apnea (OSA) by several guidelines, but patient choice in the practical setting is unclear. METHODS: A survey nested in two prospective cohort studies of OSA (enrollment: 2001-2010) in China. The last interview was conducted between July 2014 and May 2015, using a comprehensive 10-point questionnaire administered in a face-to-face or telephone interview, and assessed (I) whether the participant had received any OSA treatment; (II) why he or she had decided for or against treatment; (III) what treatment was received; (IV) whether the participant used continuous positive airway pressure (CPAP) or OA daily; and (V) the perceived efficacy of therapy. RESULTS: A total of 4,097 subjects with a mean age of 45 years [37-55] responded to this survey, with a response rate of 79.4% (4,097/5,160); 2,779 subjects (67.8%) did not receive any treatment: 1,485 (53.4%) believed that their condition was not serious, despite severe OSA in 53.7% of the patients. A multivariate regression showed that the decision to receive treatment was associated with: age between 45-59 years [odds ratio (OR) 0.805, 95% CI: 0.691-0.936; P<0.001], female gender (OR 0.492, 95% CI: 0.383-0.631; P<0.001), severe OSA (OR 1.92, 95% CI: 1.01-3.64; P<0.001), hypertension (OR 1.414, 95% CI: 1.209-1.654; P<0.001) and diabetes (OR 1.760, 95% CI: 1.043-2.972; P=0.034). In subjects receiving treatment (n=1,318), 50.9% reported negative perceptions about the treatments. CONCLUSIONS: Nearly two thirds of Chinese patients choose not to receive treatment after OSA diagnosis, and nearly half are negative about their treatments for OSA. This requires clinical attention, and warrants further study in different geographic settings.