Academic Journal
Protection of lipopolysaccharide-induced otic injury by a single dose administration of a novel dexamethasone formulation
| العنوان: | Protection of lipopolysaccharide-induced otic injury by a single dose administration of a novel dexamethasone formulation |
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| المؤلفون: | Murillo-Cuesta, Silvia, Lara, Ester, Bermúdez-Muñoz, Jose Mª, Torres-Campos, Elena, Rodriguez-de la Rosa, Lourdes, López-Larrubia, Pilar, Erickson, Signe R., Varela-Nieto, Isabel |
| المساهمون: | Centro de Investigación Biomédica en Red Enfermedades Raras (España), Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Comunidad de Madrid, Consejo Superior de Investigaciones Científicas (España), Varela-Nieto, Isabel |
| بيانات النشر: | BioMed Central |
| سنة النشر: | 2023 |
| المجموعة: | Digital.CSIC (Consejo Superior de Investigaciones Científicas / Spanish National Research Council) |
| مصطلحات موضوعية: | TLR, Strial vascular permeability, Corticosteroids, Bacterial infection, DEX-nanoformulation, Inflammation, Innate immune response, MRI |
| الوصف: | [Background] The blood-labyrinth barrier (BLB) separates the inner ear from the circulation and is critical for maintaining ionic homeostasis and limiting the entry of deleterious agents. BLB integrity is disrupted by bacterial lipopolysaccharide (LPS), which elicits a strong inflammatory response in the inner ear leading to irreversible otic damage. Prolonged administration of systemic corticosteroids is the available treatment, but it shows both limited efficacy and major adverse effects. SPT-2101 is a novel in situ-forming gel formulation of dexamethasone allowing slow and sustained drug release after single intratympanic administration. ; [Methods] We used a rat model of LPS-induced injury to define the functional, cellular and molecular mechanisms associated to BLB dysfunction and the protection by SPT-2101. Hearing was assessed by auditory brainstem response (ABR) recording, BLB permeability by gadolinium dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and Evans blue extravasation. Gross cochlear histology and cellular alterations were studied by hematoxylin-eosin staining and immunofluorescence. RT-qPCR, PCR array and western blotting were used to assess transcriptional and protein changes. ; [Results] LPS-challenged rats showed BLB breakdown and altered permeability as shown by the progressive increase in cochlear gadolinium uptake and Evans blue incorporation. LPS administration increased the cochlear expression of the LPS toll-like receptors Tlr2 and co-receptor Cd14, pro-inflammatory cytokines and receptors such as Il1b and ll1r1, and also the oxidative stress and inflammasome mediators NRF2 and NLRP3. LPS also increased IBA1-positive macrophage infiltration in the lateral wall and spiral ganglion. A single intratympanic injection of SPT-2101 protected BLB integrity and prevented otic injury. Comparable effects were obtained by repeated administration of systemic dexamethasone, but not by a single dose. SPT-2101 administration normalized molecular inflammatory mediators and suppressed ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2396-832X |
| Relation: | #PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115274RB-I00/ES/BASES GENETICAS Y MOLECULARES DE LA SORDERA NEUROSENSORIAL Y DEL DAÑO AUDITIVO: EXPLORACION DE NUEVAS DIANAS Y ESTRATEGIAS TERAPEUTICAS/; P2022/BMD-7236/MINA-CM; Publisher's version; Murillo-Cuesta, Silvia; Lara, Ester; Bermúdez-Muñoz, Jose Mª; Torres-Campos, Elena; Rodriguez-de la Rosa, Lourdes; Varela-Nieto, Isabel; 2023; LPS-induced cochlear inflammation and SPT-2101 treatment [Dataset]; DIGITAL.CSIC; https://doi.org/10.20350/digitalCSIC/15167; https://doi.org/10.1186/s41231-023-00156-6; Sí; Translational Medicine Communications 8: 23 (2023); http://hdl.handle.net/10261/337084 |
| DOI: | 10.1186/s41231-023-00156-6 |
| الاتاحة: | http://hdl.handle.net/10261/337084 https://doi.org/10.1186/s41231-023-00156-6 |
| Rights: | open |
| رقم الانضمام: | edsbas.402FC208 |
| قاعدة البيانات: | BASE |
| تدمد: | 2396832X |
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| DOI: | 10.1186/s41231-023-00156-6 |