title: Protection against chronic hypoperfusion-induced retinal neurodegeneration by PARP inhibition via activation of PI-3-kinase Akt pathway and suppression of JNK and p38 MAP kinases.
abstract: Poly(ADP-ribose) polymerase (PARP) activation is considered as a major regulator of cell death in various pathophysiological conditions, however, no direct information is available about its role in chronic hypoperfusion-induced neuronal death. Here, we provide evidence for the protective effect of PARP inhibition on degenerative retinal damage induced by bilateral common carotid artery occlusion (BCCAO), an adequate chronic hypoperfusion murine model. We found that BCCAO in adult male Wistar rats led to severe degeneration of all retinal layers that was attenuated by a carboxaminobenzimidazol-derivative PARP inhibitor (HO3089) administered unilaterally into the vitreous body immediately following carotid occlusion and then 4 times in a 2-week-period. Normal morphological structure of the retina was preserved and the thickness of the retinal layers was increased in HO3089-treated eyes compared to the BCCAO eyes. For Western blot studies, HO3089 was administered immediately after BCCAO and retinas were removed 4 h later. According to Western blot analysis utilizing phosphorylation-specific primary antibodies, besides activating poly-ADP-ribose (PAR) synthesis, BCCAO induced phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). HO3089 inhibited PAR synthesis, and decreased the phosphorylation of these proapoptotic MAPKs. In addition, HO3089 treatment induced phosphorylation, that is activation, of the protective Akt/glycogen synthase kinase (GSK)-3beta and extracellular signal-regulated kinase (ERK1/2) signaling pathways. These data indicate that PARP activation has a major role in mediating chronic hypoperfusion-induced neuronal death, and inhibition of the enzyme prevents the pathological changes both in the morphology and the kinase signaling cascades involved. These results identify PARP inhibition as a possible molecular target in the clinical management of chronic hypoperfusion-induced neurodegenerative diseases including ocular ischemic syndrome.
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Mester
authors.forename: Aliz
authors.initials: A
authors.lastname: Szabo
authors.forename: Tamas
authors.initials: T
authors.lastname: Atlasz
authors.forename: Krisztina
authors.initials: K
authors.lastname: Szabadfi
authors.forename: Dora
authors.initials: D
authors.lastname: Reglodi
authors.forename: Peter
authors.initials: P
authors.lastname: Kiss
authors.forename: Boglarka
authors.initials: B
authors.lastname: Racz
authors.forename: Andrea
authors.initials: A
authors.lastname: Tamas
authors.forename: Ferenc
authors.initials: F
authors.lastname: Gallyas
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.forename: Eniko
authors.initials: E
authors.lastname: Hocsak
authors.forename: Robert
authors.initials: R
authors.lastname: Gabriel
authors.forename: Krisztina
authors.initials: K
authors.lastname: Kovacs
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000633:toxicity; D002340:Carotid Artery Diseases / Q000150:complications; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D012162:Retinal Degeneration / Q000209:etiology* / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; C508983:HO 3089; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4