| Título: | Diadenosine tetraphosphate induces tight junction disassembly thus increasing corneal epithelial permeability |
| Autores: | Loma Lozano, Patricia ; Guzmán Aránguez, Ana Isabel ; Pérez de Lara, María Jesús ; Pintor, Jesús |
| Tipo de documento: | texto impreso |
| Editorial: | The British Pharmacological Society / Wiley-Blackwell, 2015-02 |
| Dimensiones: | application/pdf |
| Nota general: | info:eu-repo/semantics/restrictedAccess |
| Idiomas: | |
| Palabras clave: | Estado = Publicado , Materia = Ciencias Biomédicas: Medicina: Oftalmología , Materia = Ciencias Biomédicas: Óptica y optometría: Anatomía ocular , Materia = Ciencias Biomédicas: Farmacia: Química farmaceútica , Tipo = Artículo |
| Resumen: |
BACKGROUND AND PURPOSE: Here, we have studied the effects of the dinucleotide P1, P4-Di (adenosine-5?) tetraphosphate (Ap4A) on corneal barrier function conferred by the tight junction (TJ) proteins and its possible involvement in ocular drug delivery and therapeutic efficiency. EXPERIMENTAL APPROACH: Experiments in vitro were performed using human corneal epithelial cells (HCLEs) treated with Ap4A (100 ?M) for 5 min. Western blot analysis and transepithelial electrical resistance (TEER) were performed to study the TJ protein levels and barrier function respectively. Intracellular pathways involved were determined using an ERK inhibitor and P2Y2 receptor siRNAs. In in vivo assays with New Zealand rabbits, TJ integrity was examined by zonula occludens-1 (ZO-1) staining. The hypotensive compound 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) was used to assess improved delivery, measuring its levels by HPLC and measuring intraocular pressure using 5-MCA-NAT, P2Y receptor antagonists and P2Y2 siRNAs. KEY RESULTS: Two hours after Ap4A pretreatment, TJ protein levels in HCLE cells were reduced around 40% compared with control. TEER values were significantly reduced at 2 and 4 h (68 and 52% respectively). TJ reduction and ERK activation were blocked by the ERK inhibitor U012 and P2Y2 siRNAs. In vivo, topical application of Ap4A disrupted ZO-1 membrane distribution. 5-MCA-NAT levels in the aqueous humour were higher when Ap4A was previously instilled and its hypotensive effect was also increased. This action was reversed by P2Y receptor antagonists and P2Y2 siRNA. CONCLUSIONS AND IMPLICATIONS: Ap4A increased corneal epithelial barrier permeability. Its application could improve ocular drug delivery and consequently therapeutic efficiency. |
| En línea: | https://eprints.ucm.es/40884/1/diadenosie-britishJourPharmac-2014.pdf |
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