Novel neuroprotective strategies in ischemic retinal lesions

Abstract

Retinal ischemia can be effectively modeled by permanent bilateral common carotid artery occlusion, which leads to chronic hypoperfusion-induced degeneration in the entire rat retina. The complex pathways leading to retinal cell death offer a complex approach of neuroprotective strategies. In the present review we summarize recent findings with different neuroprotective candidate molecules. We describe the protective effects of intravitreal treatment with: (i) urocortin 2; (ii) a mitochondrial ATP-sensitive K(+) channel opener, diazoxide; (iii) a neurotrophic factor, pituitary adenylate cyclase activating polypeptide; and (iv) a novel poly(ADP-ribose) polymerase inhibitor (HO3089). The retinoprotective effects are demonstrated with morphological description and effects on apoptotic pathways using molecular biological techniques.

Keywords: BCCAO; PACAP; PARP-inhibitor; diazoxide; ischemia; rat retina; retinoprotection; urocortin 2.

Figure 1.

Microphotographs of different retinal sections. (A) Histological sections of control animals; (B) effects of bilateral common carotid artery occlusion (BCCAO). Extreme swelling of neuronal cell bodies and the fusion of the INL, IPL and GCL layers were observed. BCCAO caused severe overall retinal degeneration ameliorated by intravitreal injection of (C) urocortin 2, (D) diazoxide, (E) pituitary adenylate cyclase activating polypeptide and (F) the poly(ADP-ribose) polymerase inhibitor HO3089. Scale bar: 20 μm. Abbreviations: PL: photoreceptor layer; ONL: outer nuclear layer; OPL: outer plexiform layer; INL: inner nuclear layer; IPL: inner plexiform layer; GCL: ganglion cell layer.

Figure 2.

Quantification of the whole retina thickness (OLM-ILM), distinct retinal layers (A) and the cell number of GCL/100 μm in different conditions (B) by morphometrical analysis. Significant decreases were observed in BCCAO-induced retinal degeneration. The neuroprotective effects of urocortin 2; diazoxide; pituitary adenylate cyclase activating polypeptide and HO3089 treatments were quantified by the thickness of different retinal layers and also the cell number of GCL/100 μm. ^*p < 0.05 between untreated and BCCAO; ^#p < 0.05 BCCAO vs. BCCAO+different treatments. Results are presented as mean ± S.E.M. Statistical comparisons were made using the ANOVA test followed by Tukey-B`s post hoc analysis. Abbreviations: OLM: outer limiting membrane; ONL: outer nuclear layer; OPL: outer plexiform layer; INL: inner nuclear layer; IPL: inner plexiform layer; GCL: ganglion cell layer; ILM: inner limiting membrane.