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Biomed Pharmacother ; 133: 111041, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378949


Poly (ADP-ribose) polymerase 1 (PARP1)-dependent cell death in the retinal pigment epithelium (RPE) is implicated in dry age-related macular degeneration (AMD). Although PARP1 inhibitors are available for treating dry AMD, their delivery route is not ideal for patients. The aim of this study was to test the efficacy of a novel PARP1-inhibitory compound (PIC) in vitro and in vivo. This study presents PIC, a novel small molecule, with superior efficacy to PARP1 inhibitors in the market. PIC demonstrated a distinctive inhibitory profile against PARP isotypes than the FDA-approved PARP1 inhibitors. PIC inhibited PARP1 activation at an IC50 of 0.41 ± 0.15 nM in an enzyme-based assay in vitro and at IC50 and EC50 in ARPE-19 cells of 0.11 ± 0.02 nM and 0.22 ± 0.02 nM, respectively, upon H2O2 insult. PIC also moderated mitochondrial fission and depolarization and maintained cellular energy levels under oxidative stress in ARPE-19 cells. Furthermore, PIC demonstrated good corneal penetration in a rat model, presenting PIC as a promising candidate for eye drop therapeutics for dry AMD. When PIC was administered as an eye drop formulation, RPE morphology was preserved, maintaining the thickness of the outer nuclear layers under sodium iodate (SI) treatment in rats. In SI-treated rabbits, eye drop administration of PIC also retained the structural and functional integrity when analyzed using funduscopy and electroretinogram. Collectively, our data portray PIC as an attractive treatment measure for dry AMD.

Degeneração Macular/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Administração Oftálmica , Animais , Antioxidantes/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Humanos , Iodatos , Degeneração Macular/induzido quimicamente , Degeneração Macular/enzimologia , Degeneração Macular/patologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Absorção Ocular , Soluções Oftálmicas , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Coelhos , Ratos Sprague-Dawley , Epitélio Pigmentado da Retina/enzimologia , Epitélio Pigmentado da Retina/patologia
Platelets ; 15(1): 3-7, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14985170


Platelet activation is an important process in the pathogenesis of atherothrombosis. However, the serial changes of platelet activation in atherosclerotic ischemic stroke have not been determined. In this study, we measured serially platelet expression of CD63 and P-selectin and platelet aggregability to ADP and collagen. Measurements were made 24 and 72 h and 7 and 90 days after the ischemic event in 29 patients with atherosclerotic ischemic stroke. Platelet aggregability was significantly decreased after 72 h compared to that at 24 h of stroke onset. However, platelet CD63 and P-selectin expression remained high even 90 days after the events. These findings suggest that platelet hyperactivation in atherosclerotic ischemic stroke may be sustained for a considerable period.

Antígenos CD/sangue , Plaquetas/metabolismo , Isquemia Encefálica/sangue , Arteriosclerose Intracraniana/complicações , Selectina-P/sangue , Acidente Vascular Cerebral/sangue , Ticlopidina/análogos & derivados , Difosfato de Adenosina/farmacologia , Idoso , Anticoagulantes/farmacologia , Aspirina/farmacologia , Plaquetas/química , Plaquetas/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Clopidogrel , Colágeno/farmacologia , Feminino , Citometria de Fluxo , Heparina/farmacologia , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária , Inibidores da Agregação de Plaquetas/farmacologia , Contagem de Plaquetas , Complexo Glicoproteico GPIb-IX de Plaquetas/análise , Glicoproteínas da Membrana de Plaquetas , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Tetraspanina 30 , Ticlopidina/farmacologia , Fatores de Tempo