93a5672cf5622b1e3573f5637416fece pmc_30428543.pdf 02b47a3fef29557c1d5cce753349ee3570d2c88a pmc_30428543.pdf b08d347f4015e5ee803936da5fa9d0bc461620b0ddeea7705fd76614ecb3ec1b pmc_30428543.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 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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 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-01-19 05:38:07 CET RepresentationInformation: pmc_30428543.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2020-08-03 03:46:57 CEST Size: 3567426 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false 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えふねちの〠げづぴどのちび〠 Item: Title: ぁのどねちぬび〠 Item: Title: ぉねねふのはとどびぴはっとづねどびぴひべ〠てはひ〠ぅのつはぴとづぬどの〠〨ぅご〭〱〩〠ぁのつ〠ぅのつはぴとづぬどの〠げづっづばぴはひび〠〨ぅごぁ〭げ〠ちのつ〠ぅごあ〭げ〩〠 Item: Title: ぎづふひはつづでづのづひちぴどはの〠きづちびふひづねづのぴび〠 Children: Item: Title: きづちびふひづねづのぴび〠はて〠ぇぬどちぬ〠ぁっぴどぶちぴどはの〠 Item: Title: ぉねねふのはとどびぴはっとづねどっちぬ〠ぁのちぬべびどび〠てはひ〠ぁばはばぴはびどび〠ぁびびづびびねづのぴ〠 Item: Title: くぴとづひ〠ぉねねふのはとどびぴはっとづねどっちぬ〠ぁのちぬべびどび〠 Item: Title: ぐとちひねちっはにどのづぴどっ〠ぁのちぬべびづび〠 Item: Title: ぉの〠ざどぴひは〠こぴふつどづび〠どの〠えふねちの〠げづぴどのちぬ〠ぅのつはぴとづぬどちぬ〠ぃづぬぬび〠 Children: Item: Title: きづちびふひづねづのぴ〠はて〠えげぅぃ〠ぐづひねづちぢどぬどぴべ〠 Item: Title: げぎぁ〠ぅへぴひちっぴどはの〠ちのつ〠けふちのぴどぴちぴどぶづ〠げづちぬ〭ごどねづ〠ぐぃげ〠 Item: Title: こぴちぴどびぴどっちぬ〠ぁのちぬべびどび〠 Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: DPINWW+URWPalladioL-Ital FontSubset: true FirstChar: 40 LastChar: 121 FontDescriptor: FontName: DPINWW+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: DUJUUF+PazoMath-Italic FontSubset: true FirstChar: 97 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