title: Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors Reduce Reactive Gliosis and Improve Angiostatin Levels in Retina of Diabetic Rats.
abstract: Diabetic retinopathy (DR) is a multifactorial disease characterized by reactive gliosis and disbalance of angiogenesis regulators, contributing to endothelial dysfunction and microvascular complications. This study was organized to elucidate whether poly(ADP-ribose) polymerase-1 (PARP-1) inhibition could attenuate diabetes-induced damage to macroglia and correct angiogenic disbalance in diabetic rat retina. After 8 weeks of streptozotocin (STZ)-induced diabetes, Wistar male rats were treated with PARP-1 inhibitors, nicotinamide (NAm) or 3-aminobenzamide (3-AB) (100 and 30 mg/kg/daily i.p., respectively), for 14 days. After the 10-weeks experiment period, retinas were undergone an immunohistochemical staining for glial fibrillary acidic protein (GFAP), while western blots were performed to evaluate effects of PAPR-1 inhibitors on the levels of PARP-1, poly(ADP-ribosyl)ated proteins (PARs), GFAP, and angiostatin isoforms. Diabetes induced significant up-regulation and activation of retinal PARP-1, reactive gliosis development, and GFAP overexpression compared to non-diabetic control. Moreover, extensive fragmentation of both PARP-1 and GFAP (hallmarks of apoptosis and macroglia reactivation, respectively) in diabetic retina was also observed. Levels of angiostatin isoforms were dramatically decreased in diabetic retina, sustaining aberrant pro-angiogenic condition. Both NAm and 3-AB markedly attenuated damage to macroglia, evidenced by down-regulation of PARP-1, PARs and total GFAP compared to diabetic non-treated group. PARP-1-inhibitory therapy prevented formation of PARP-1 and GFAP cleavage-derived products. In retinas of anti-PARP-treated diabetic animals, partial restoration of angiostatin's levels was shown. Therefore, PARP-1 inhibitors counteract diabetes-induced injuries and manifest retinoprotective effects, including attenuation of reactive gliosis and improvement of angiogenic status, thus, such agents could be considered as promising candidates for DR management.
authors.affiliation: Department of Vitamin and Coenzyme Biochemistry, Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Mykhailo M
authors.initials: MM
authors.lastname: Guzyk
authors.affiliation: Department of Enzyme Chemistry and Biochemistry, Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine, 9 Leontovicha Str., Kyiv, 01601, Ukraine. artem_tykhomyrov@ukr.net.
authors.forename: Artem A
authors.initials: AA
authors.lastname: Tykhomyrov
authors.affiliation: Department of Biophysics and Biochemistry, Dnipropetrovsk National University, Dnipropetrovsk, Ukraine.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Nedzvetsky
authors.affiliation: Department of Biophysics and Biochemistry, Dnipropetrovsk National University, Dnipropetrovsk, Ukraine.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Prischepa
authors.affiliation: Department of Enzyme Chemistry and Biochemistry, Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine, 9 Leontovicha Str., Kyiv, 01601, Ukraine.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Grinenko
authors.affiliation: Department of Bioorganic & Biological Chemistry, O.O. Bogomolets National Medical University, Kyiv, Ukraine.
authors.forename: Lesya V
authors.initials: LV
authors.lastname: Yanitska
authors.affiliation: Department of Vitamin and Coenzyme Biochemistry, Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Tamara M
authors.initials: TM
authors.lastname: Kuchmerovska
mesh_terms: D043168:Angiostatins / Q000378:metabolism*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005911:Gliosis / Q000378:metabolism*; D008297:Male; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D017208:Rats, Wistar; D012160:Retina / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D043168:Angiostatins; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: Angiostatins; Diabetic retinopathy; Glial fibrillary acidic protein (GFAP); Poly(ADP-ribose) polymerase-1 (PARP-1); Reactive gliosis