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Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors Reduce Reactive Gliosis and Improve Angiostatin Levels in Retina of Diabetic Rats

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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.

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Acknowledgments

The authors are thankful to Kuznetsov K.I. (PhD, research fellow) and Professor Veselovsky N.S. (Bogomoletz Institute of Physiology of NAS of Ukraine) for their cooperation, expert technical assistance, and fruitful discussion.

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Authors and Affiliations

  1. Department of Vitamin and Coenzyme Biochemistry, Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine, Kyiv, Ukraine

    Mykhailo M. Guzyk & Tamara M. Kuchmerovska

  2. Department of Enzyme Chemistry and Biochemistry, Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine, 9 Leontovicha Str., Kyiv, 01601, Ukraine

    Artem A. Tykhomyrov & Tatiana V. Grinenko

  3. Department of Biophysics and Biochemistry, Dnipropetrovsk National University, Dnipropetrovsk, Ukraine

    Victor S. Nedzvetsky & Irina V. Prischepa

  4. Department of Bioorganic & Biological Chemistry, O.O. Bogomolets National Medical University, Kyiv, Ukraine

    Lesya V. Yanitska

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  1. Mykhailo M. Guzyk
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Correspondence to Artem A. Tykhomyrov.

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All applicable international, national, and Institutional Animal Care and Use Committee at Palladin Institute of Biochemistry of NASU (Kyiv, Ukraine; No. 0112U002625) guidelines for the care and use of animals were followed.

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Guzyk, M.M., Tykhomyrov, A.A., Nedzvetsky, V.S. et al. Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors Reduce Reactive Gliosis and Improve Angiostatin Levels in Retina of Diabetic Rats. Neurochem Res 41, 2526–2537 (2016). https://doi.org/10.1007/s11064-016-1964-3

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