Abstract
PurposeTo investigate the protective effects of a novel cyclopeptide C*HSDGIC* (CHC) from the cyclization of Pituitary adenylate cyclase-activating polypeptide (PACAP) (1–5) in cellular and rodent models of retinal ganglion cell apoptosis.Methodology/Principal FindingsDouble-labeling immunohistochemistry was used to detect the expression of Thy-1 and PACAP receptor type 1 in a retinal ganglion cell line RGC-5. The apoptosis of RGC-5 cells was induced by 0.02 J/cm2 Ultraviolet B irradiation. MTT assay, flow cytometry, fluorescence microscopy were used to investigate the viability, the level of reactive oxygen species (ROS) and apoptosis of RGC-5 cells respectively. CHC attenuated apoptotic cell death induced by Ultraviolet B irradiation and inhibited the excessive generation of ROS. Moreover, CHC treatment resulted in decreased expression of Bax and concomitant increase of Bcl-2, as was revealed by western-blot analysis. The in vivo apoptosis of retinal ganglion cells was induced by injecting 50 mM N-methyl-D-aspartate (NMDA) (100 nmol in a 2 µL saline solution) intravitreally, and different dosages of CHC were administered. At day 7, rats in CHC+ NMDA-treated groups showed obvious aversion to light when compared to NMDA rats. Electroretinogram recordings revealed a marked decrease in the amplitudes of a-wave, b-wave, and photopic negative response due to NMDA damage. In retina receiving intravitreal NMDA and CHC co-treatment, these values were significantly increased. CHC treatment also resulted in less NMDA-induced cell loss and a decrease in the proportion of dUTP end-labeling-positive cells in ganglion cell line.ConclusionsC*HSDGIC*, a novel cyclopeptide from PACAP (1–5) attenuates apoptosis in RGC-5 cells and inhibits NMDA-induced retinal neuronal death. The beneficial effects may occur via the mitochondria pathway. PACAP derivatives like CHC may serve as a promising candidate for neuroprotection in glaucoma.
Highlights
Glaucoma is conventionally defined as a chronic optic neuropathy characterized by the progressive loss of retinal ganglion cells (RGCs) and optic nerve fibers [1]
Pituitary adenylate cyclase activating polypeptide (PACAP) derivatives like CHC may serve as a promising candidate for neuroprotection in glaucoma
Via the mediation of PACAP receptor type 1 (PAC1), PACAP has well-known neuroprotective effects in retinal neuronal cultures in vitro and against in vivo retinal degenerations including excitotoxic injury induced by glutamate and kainate, ischemic injury, degeneration caused by UV-A light, optic nerve transection and streptozotocin-induced diabetic retinopathy [7]
Summary
Glaucoma is conventionally defined as a chronic optic neuropathy characterized by the progressive loss of retinal ganglion cells (RGCs) and optic nerve fibers [1]. Given that glaucoma is essentially a neurodegenerative disorder, the development of neuroprotective therapeutic strategies that are based on intraocular pressure lowering is required [2]. Neuroprotectants such as neurotrophic factors represent an important candidate treatment for glaucoma neuropathy. As a PACAP preferring receptor, PAC1 which mediates the most effects of PACAP as a neurotransmitter, neuro-modulator, neurotrophic factor and neuro-protector has been demonstrated as the predominant receptor type of PACAP in RGCs, amacrine cells, inner nuclear layer and Muller cells [6]. Via the mediation of PAC1, PACAP has well-known neuroprotective effects in retinal neuronal cultures in vitro and against in vivo retinal degenerations including excitotoxic injury induced by glutamate and kainate, ischemic injury, degeneration caused by UV-A light, optic nerve transection and streptozotocin-induced diabetic retinopathy [7]
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