93a5672cf5622b1e3573f5637416fece ijms_a2018v19n11.pdf 02b47a3fef29557c1d5cce753349ee3570d2c88a ijms_a2018v19n11.pdf b08d347f4015e5ee803936da5fa9d0bc461620b0ddeea7705fd76614ecb3ec1b ijms_a2018v19n11.pdf Title: Topical Administration of Bosentan Prevents Retinal Neurodegeneration in Experimental Diabetes Subject: Experimental evidence suggests that endothelin 1 (ET-1) is involved in the development of retinal microvascular abnormalities induced by diabetes. The effects of ET-1 are mediated by endothelin A- and B-receptors (ETA and ETB). Endothelin B-receptors activation mediates retinal neurodegeneration but there are no data regarding the effectiveness of ETB receptor blockage in arresting retinal neurodegeneration induced by diabetes. The main aim of the present study was to assess the usefulness of topical administration of bosentan (a dual endothelin receptor antagonist) in preventing retinal neurodegeneration in diabetic (db/db) mice. For this purpose, db/db mice aged 10 weeks were treated with one drop of bosentan (5 mg/mL, n = 6) or vehicle (n = 6) administered twice daily for 14 days. Six non-diabetic (db/+) mice matched by age were included as the control group. Glial activation was evaluated by immunofluorescence using specific antibodies against glial fibrillary acidic protein (GFAP). Apoptosis was assessed by TUNEL method. A pharmacokinetic study was performed in rabbits. We found that topical administration of bosentan resulted in a significant decrease of reactive gliosis and apoptosis. The results of the pharmacokinetic study suggested that bosentan reached the retina through the trans-scleral route. We conclude that topical administration of bosentan was effective in preventing neurodegeneration in the diabetic retina and, therefore, could be a good candidate to be tested in clinical trials. Keywords: diabetic retinopathy; retinal neurodegeneration; endothelin-1; bosentan; db/db mouse Author: Patricia Bogdanov, Olga Simó-Servat, Joel Sampedro, Cristina Solà-Adell, Marta Garcia-Ramírez, Hugo Ramos, Marta Guerrero, Josep Maria Suñé-Negre, Josep Ramon Ticó, Bruno Montoro, Vicente Durán, Luís Arias, Cristina Hernández and Rafael Simó Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Tue Nov 13 09:31:01 2018 CET ModDate: Tue Nov 13 09:31:01 2018 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3567426 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- DPINWW+URWPalladioL-Ital Type 1 Custom yes yes no 129 0 ITTTUS+URWPalladioL-Bold Type 1 Custom yes yes no 130 0 JUXSQN+VnURWPalladioL-Bold Type 1 Custom yes yes no 131 0 CZYACF+URWPalladioL-Roma Type 1 Custom yes yes no 132 0 KORLVE+VnURWPalladioL Type 1 Custom yes yes no 133 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 138 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 139 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 158 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 159 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 160 0 BTSNHC+EURM10 Type 1 Builtin yes yes no 195 0 COGLGI+CMSY10 Type 1 Builtin yes yes no 220 0 FPWRKE+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 224 0 FPZBPV+PalatinoLinotype CID TrueType Identity-H yes yes yes 225 0 FPAJPQ+TimesNewRoman CID TrueType Identity-H yes yes yes 226 0 FPWRKE+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 227 0 FPWRKE+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 259 0 FPZBPV+PalatinoLinotype CID TrueType Identity-H yes yes yes 260 0 FPAJPQ+TimesNewRoman CID TrueType Identity-H yes yes yes 261 0 FPWRKE+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 262 0 FPWRKE+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 306 0 FPZBPV+PalatinoLinotype CID TrueType Identity-H yes yes yes 307 0 FPAJPQ+TimesNewRoman CID TrueType Identity-H yes yes yes 308 0 FPWRKE+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 309 0 FPWRKE+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 345 0 FPZBPV+PalatinoLinotype CID TrueType Identity-H yes yes yes 346 0 FPAJPQ+TimesNewRoman CID TrueType Identity-H yes yes yes 347 0 FPWRKE+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 348 0 DUJUUF+PazoMath-Italic Type 1 Builtin yes yes no 385 0 FPWRKE+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 391 0 FPZBPV+PalatinoLinotype CID TrueType Identity-H yes yes yes 392 0 FPAJPQ+TimesNewRoman CID TrueType Identity-H yes yes yes 393 0 FPWRKE+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 394 0 FPWRKE+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 429 0 FPZBPV+PalatinoLinotype CID TrueType Identity-H yes yes yes 430 0 FPAJPQ+TimesNewRoman CID TrueType Identity-H yes yes yes 431 0 FPWRKE+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 432 0 FPWRKE+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 480 0 FPZBPV+PalatinoLinotype CID TrueType Identity-H yes yes yes 481 0 FPAJPQ+TimesNewRoman CID TrueType Identity-H yes yes yes 482 0 FPWRKE+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 483 0 MPUDFL+PazoMath Type 1 Builtin yes yes no 519 0 java.lang.ClassCastException: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject cannot be cast to edu.harvard.hul.ois.jhove.module.pdf.PdfDictionary at edu.harvard.hul.ois.jhove.module.PdfModule.readDocCatalogDict(PdfModule.java:1284) at edu.harvard.hul.ois.jhove.module.PdfModule.parse(PdfModule.java:525) at edu.harvard.hul.ois.jhove.JhoveBase.processFile(JhoveBase.java:825) at edu.harvard.hul.ois.jhove.JhoveBase.process(JhoveBase.java:614) at edu.harvard.hul.ois.jhove.JhoveBase.dispatch(JhoveBase.java:465) at Jhove.main(Jhove.java:296) Jhove (Rel. 1.6, 2011-01-04) Date: 2019-02-14 17:33:30 CET RepresentationInformation: ijms_a2018v19n11.pdf ReportingModule: BYTESTREAM, Rel. 1.3 (2007-04-10) LastModified: 2019-01-15 12:22:31 CET Size: 3567426 Format: bytestream Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/octet-stream Checksum: 21488e39 Type: CRC32 Checksum: 93a5672cf5622b1e3573f5637416fece Type: MD5 Checksum: 02b47a3fef29557c1d5cce753349ee3570d2c88a Type: SHA-1