The effects of 1,5-isoquinolinediol (IQD) and nicotinamide (NAm), inhibitors of poly-(ADP-ribose) polymerase-1 (PARP-1), on inflammatory processes and activation of PARP-1 under conditions of the development of experimental diabetic neuropathy, DN (a complication of streptozotocin-induced type-1 diabetes) in rats were studied. The content of IL-4 in blood serum in the case of DN was 50% higher, while that of monocyte-chemotactic protein-1 was 90% higher than those in the control. The content of gamma-interferon also increased, while the content of the granulocyte-macrophage colony-stimulating factor did not change. Against the background of activation of PARP-1 and a decrease in the content of the substrate of this enzyme nicotinamide adenine dinucleotide (NAD) in the brain, fragmentation of PARP-1 was intensified; an increase in the ratio of the contents of a 89 kDa fragment/intact enzyme molecules proved this fact. The mentioned two structurally dissimilar PARP-1 inhibitors partly or entirely normalized the above parameters under DN conditions. These results demonstrate that PARP-1 is one of the main functional targets in realization of the effects of IQD and NAm. At the same time, the spectrum of action of these inhibitors is wider. In particular, they affect the level of proinflammatory cytokines. The ability of the investigated PARP-1 inhibitors to prevent cell death in the brain by suppressing activation and fragmentation of the above-mentioned enzyme shows that other types of action of these agents at the molecular level are possible; these may be the maintenance of the genome integrity in the brain structures under DN conditions and preventing the development of inflammatory processes. Thus, the examined inhibitors can be used in the future in the treatment of brain dysfunctions that are complications of type-1 diabetes mellitus.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
A. I. Vinik, M. L. Nevoret, C. Casellini, et al., “Diabetic neuropathy,” Endocrinol. Metab. Clin. North Am., 42, No. 4, 747-787 (2013).
S. Tesfaye, A. J. M. Boulton, P. J. Dyck, et al., “On behalf of the Toronto diabetic neuropathy expert group. Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments,” Diabetes Care, 33, No. 10, 2285-2293 (2010).
A. Hosseini and M. Abdollahi, “Diabetic neuropathy and oxidative stress: therapeutic perspectives,” Oxid. Med. Cell. Longev, Publ. online, April 24 (2013).
R. V. Stavniichuk and T. M. Kuchmerovs’ka, “Diabetic neuropathy. The role of 12/15 lipoxygenase and metabolism of arachidonic acid,” Endokrinologiya, 19, No. 2, 156-166 (2014).
M. M. Guzyk, K. O. Dyakun, L. V. Yanits’ka, and T. M. Kuchmerovs’ka, “Effects of inhibitors of poly(ADP-ribose)polymerase on some indices of oxidative stress in leucocytes of the rat blood at experimental diabetes mellitus,” Ukr. Biokhim. Zh., 85, No. 1, 62-70 (2013).
T. M. Kuchmerovs’ka, G. V. Donchenko, T. M. Tikhonenko, et al., “Effects of nicotinamide on the viability of islet cells in the pancreatic gland,” Ukr. Biokhim. Zh., 84, No. 2, 81-88 (2012).
P. Sytze Van Dam, M. A. Cotter, B. Bravenboer, et al., “Pathogenesis of diabetic neuropathy: Focus on neurovascular mechanisms,” Eur. J. Pharmacol., 719, Nos. 1/3, 180-186 (2013).
R. V. Stavniichuk, A. A. Obrosov, V. R. Drel, et al., “12/15-Lipoxygenase inhibition counteracts MAPK phosphorylation in mouse and cell culture models of diabetic peripheral neuropathy,” J. Diabetes Mellitus, 3, No. 3, doi: 10.4236/jdm.2013.33015, Aug (2013).
S. Chattopadhyay, M. Ramanathan, J. Das, and S. K. Bhattacharya, “Animal models in experimental diabetes mellitus,” Indian J. Exp. Biol., 35, No. 11, 1141-1145 (1997).
D. H. Williamson, P. Lund, and H. A. Krebs, “The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver,” Biochem. J., 103, No. 2, 514-527 (1967).
C. N. Pace, F. Vajdos, L. Fee, et al., “How to measure and predict the molar absorption coefficient of a protein,” Protein Sci.: Publ. Protein Soc., 4, No. 11, 2411-2423 (1995).
M. M. Bradford, “A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding,” Anal. Biochem., 72, 248-254 (1976).
Y. Tanigawa, M. Kawamura, and M. Shimoyama, “Effect of polyamines on ADP-ribosylation of nuclear proteins from rat liver,” Biochem. Biophys. Res. Commun., 76, No. 2, 406-412 (1976).
T. E. Shaiken and A. R. Opekun, “Dissecting the cell to nucleus, perinucleus and cytosol,” Sci. Rep., 4, 4923, doi: https://doi.org/10.1038/srep04923 (2014).
U. K. Laemmli, “Cleavage of structural proteins during the assembly of the head of bacteriophage t4,” Nature, 227, No. 5259, 680-685 (1970).
M. M. Andres and J. J. Luszczki, “Modified western blot technique in fast detection of heme oxygenase (ho-1/ho-2) in various tissues and organs of experimental animals,” Ann. Univ. Mariae Curie-Skłodowska. Sectio D: Medicina, 59, No. 2, 298-302 (2004).
C. A. Heid, J. Stevens, K. J. Livak, and P. M. Williams, “Real time quantitative PCR,” Genome Res., 6, No. 10, 986-994 (1996).
A. G. Minchenko, V. E. Armstead, I. L. Opentanova, and A. M. Lefer, “Endothelin-1, endothelin receptors and ecNos gene transcription in vital organs during traumatic shock in rats,” Endothelium: J. Endothel. Cell Res., 6, No. 4, 303-314 (1999).
A. S. Greenberg and M. L. McDaniel, “Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes,” Eur. J. Clin. Investat., 32, Suppl. 3, 24-34 (2002).
C. A. Dinarello, “Proinflammatory cytokines,” CHEST, 118, No. 2, 503-508 (2000).
S. M. Opal and V. A. DePalo, “Anti-inflammatory cytokines,” CHEST, 117, No. 4, 1162-1172 (2000).
K. Bhaskar, N. Maphis, G. Xu, et al., “Microglial derived tumor necrosis factor-α drives Alzheimer’s disease-related neuronal cell cycle events,” Neurobiol. Dis., 62, Febr. 273-285 (2014).
V. Sharma, V. Thakur, S. N. Singh, and R. Guleria, “Tumor necrosis factor and Alzheimer ’s disease: a cause and consequence relationship,” Bull. Clin. Psychopharmacol., 22, No. 1, 86-89 (2012).
T. Kuchmerovska, I. Shymanskyy, G. Donchenko, et al., “Poly(ADP-ribosyl)ation enhancement in brain cell nuclei is associated with diabetic neuropathy,” J. Diabetes Compilations, 18, No. 4, 198-204 (2004).
N. V. Maliuchenko, O. I. Kulaeva, E. Kotova, et al., “Molecular mechanisms of regulaion of transcription by PARP1,” Mol. Biol., 49, No. 1, 99-113 (2015).
N. H. Ugochukwu and C. L. Figgers, “Caloric restriction inhibits up-regulation of inflammatory cytokines and TNF-alpha, and activates IL-10 and haptoglobin in the plasma of streptozotocin-induced diabetic rats,” J. Nutr. Biochem., 18, No. 2, 120-126 (2007).
M. Cnop, N. Welsh, J.C. Jonas, et al., “Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes many differences, few similarities,” Diabetes, 54, No. 2, S97-S107 (2005).
P. Z. Costa and R. Soares, “Neovascularization in diabetes and its complications. unraveling the angiogenic paradox,” Life Sci., 92, No. 22, 1037-1045 (2013).
M. Rajesh, P. Mukhopadhyay, G. Godlewski, et al., “Poly(ADP-ribose)polymerase inhibition decreases angiogenesis,” Biochem. Biophys.Res. Commun., 350, No. 4, 1056-1062 (2006).
M. M. Guzyk, A. A. Tykhomyrov, V. S. Nedzvetsky, 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, No. 10, 2526-2537 (2016).
T. M. Kauppinen and R. A. Swanson, “The role of poly(ADP-ribose) polymerase-1 in CNS disease,” Neuroscience, 145, No. 4, 1267-1272 (2007).
I. Trikash, V. Gumenyuk, and T. Kuchmerovska, “Diabetes-induced impairments of the exocytosis process and effect of gabapentin: the link with cholesterol level in neuronal plasma membranes,” Neurochem. Res., 40, No. 4, 723-732 (2015).
D. V. Ferraris, “Evolution of poly(ADPribose) polymerase1 (PARP1) inhibitors. From concept to clinic,” J. Med. Chem., 53, No. 12, 4561-4584 (2010).
K. L. Bogan and C. Brenner, “Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition,” Annu. Rev. Nutr., 28, 115-130 (2008).
Z.-Z. Chong, S.-H. Lin, F. Li, and K. Maiese, “The sirtuin inhibitor nicotinamide enhances neuronal cell survival during acute anoxic injury through AKT, BAD, PARP, and mitochondrial associated “anti-apoptotic” pathways,” Curr. Neurovasc. Res., 2, No. 4, 271-285 (2005).
D. Surjana, G. M. Halliday, and D. L. Damian, “Role of nicotinamide in DNA damage, mutagenesis, and DNA repair,” J. Nucleic Acids, doi: https://doi.org/10.4061/2010/157591 (2010).
R. H. Houtkooper, C. Canto, R. J. Wanders, and J. Auwerx, “The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways,” Endocrinol. Rev., 31, No. 2, 194-223 (2010).
A. H. Guse, “Biochemistry, biology, and pharmacology of cyclic adenosine diphosphoribose (CADPR),” Curr. Med. Chem., 11, No. 7, 847-855 (2004).
E. Ferrero, N. Lo Buono, A. L. Horenstein, et al., “The ADP-ribosyl cyclases – the current evolutionary state of the ARCs,” Front. Biosci. (Landmark Edit.), 19, 986-1002 (2014).
R. Olszanecki, A. Gebska, J. Jawień, et al., “Inhibition of NOS-2 induction in LPS-stimulated J774.2 cells by 1, 5-isoquinolinediol, an inhibitor of PARP,” J. Physiol. Pharmacol., 57, No. 1, 109-117 (2006).
A. Jangra, A. K. Datusalia, and S. S. Sharma, “Reversal of neurobehavioral and neurochemical alterations in STZ-induced diabetic rats by FeTMPyP, a peroxynitrite decomposition catalyst and 1,5-isoquinolinediol, a poly(ADP-ribose) polymerase inhibitor,” Neurol. Res., 36, No. 7, 619-626 (2014).
L. Efremova, S. Schildknecht, M. Adam, et al., “Prevention of the degeneration of human dopaminergic neurons in an astrocyte co-culture system allowing endogenous drug metabolism,” Br. J. Pharmacol., 172, No. 16, 4119-4132 (2015).
V. Schreiber, F. Dantzer, J. C. Ame, and G. de Murcia, “Poly(ADP-ribose): novel functions for an old molecule,” Nat. Rev. Mol. Cell Biol., 7, July, 517-528 (2006).
R. Stavniichuk, V. R. Drel, H. Shevalye, et al., “Baicalein alleviates diabetic peripheral neuropathy through inhibition of oxidative-nitrosative stress and p38 MAPK activation,” Exp. Neurol., 230, No. 1, 106-113 (2011).
H. Nakajima, T. Kubo, H. Ihara, et al., “Nuclear-translocated glyceraldehyde-3-phosphate dehydrogenase promotes poly(ADP-ribose) polymerase-1 activation during oxidative/nitrosative stress in stroke,” J. Biol. Chem., 290, No. 23, 14493-14503 (2015).
S. A. Andrabi, T. M. Dawson, and V. L. Dawson, “Mitochondrial and nuclear cross talk in cell death: Parthanatos,” Ann. N. Y. Acad. Sci., 1147, 233-241 (2008).
S. Benafif and M. Hall, “An update on PARP inhibitors for the treatment of cancer,” Oncotargets Ther., 8, 519528 (2015).
N. J. Curtin and C. Szabo, “Therapeutic applications of PARP inhibitors: anticancer therapy and beyond,” Mol. Aspects Med., 34, No. 6, 1217-1256 (2012).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Guzyk, M.M., Dyakun, K., Yanytska, L.V. et al. Inhibitors of Poly(ADP-Ribose)Polymerase-1 as Agents Providing Correction of Brain Dysfunctions Induced by Experimental Diabetes. Neurophysiology 49, 183–193 (2017). https://doi.org/10.1007/s11062-017-9672-4
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11062-017-9672-4