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.

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

“…The fact that the improved cardiac function in the transplant model was also associated with changes in the expression of some genes (inflammatory, cell death effector and oxidant/antioxidant) but not others, requires further analysis. Nevertheless, the down-regulation of c-Jun is consistent with the results from many studies using PARP inhibitors or PARP silencing (Song et al, 2008;Huang et al, 2009;Mester et al, 2009;Kim et al, 2012;Radnai et al, 2012). Moreover, inhibition of neutrophil infiltration is consistent with previous findings showing similar effect of PARP inhibitors of other structural classes, as well as PARP1 deficiency in various models of ischaemia-reperfusion and inflammation Szabó, 1998;Zingarelli et al, 1998;Liaudet et al, 2001Liaudet et al, , 2002Mabley et al, 2001).…”

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

“…A potentially significant topic for sirtuin regulation is the observed impact of PARP-1 on both upstream modulators and signalling targets of sirtuins. PARP-1 appears to be critically involved in the modulation of Akt activity [91,186]; however, despite its importance for, inter alia, neurodegeneration [130], or ischemic damage [105] the mechanism of this interaction has not been explored further. PARP-1 also directly binds and PARylates FOXO1, leading to suppression of FOXO1-dependent genes [172].…”

Mice Deficient in Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) are More Susceptible to Retinal Ischemic Injury In Vivo

“…The mechanism underlying ischemic retinal degeneration and potential protective interventions are studied in a diversity of animal models (Dimitriu et al 2008;Moren et al 2009;Osborne et al 2004;Vidal-Sanz et al 2000). Similar to cerebral ischemia, the extent and degree of retinal ischemic damage largely depends on the model used and the animal strain and gender (Barnett and Osborne 1995;Davidson et al 2000;Mester et al 2009;Oliff et al 1997;Yamamoto et al 2006). Bilateral common carotid artery occlusion (BCCAO, also called 2-vessel occlusion), is a model of chronic cerebral hypoperfusion, leading also to ischemic retinal changes (Atlasz et al 2007a(Atlasz et al , b, 2010aFarkas et al 2007;Osborne et al 2004;Yamamoto et al 2006).…”