•A novel 18-amino acid peptide is identified and characterized.•The peptide is neuroprotective both in vitro and in vivo models.•The mechanism relies on activation of Akt pathway.Ischemic neuronal injury is associated with several life- and vision-threatening diseases. Neuroprotection is essential in the treatment of these diseases. Here, we identified and characterized a novel peptide, FK18, from basic fibroblast growth factor (bFGF). We further assessed the neuroprotective effects of this peptide and its potential mechanisms using the in vitro oxygen–glucose deprivation (OGD) model in SH-SY5Y cells and the in vivo retinal ischemia-reperfusion (I/R) injury model to mimic ischemic neuronal injury. Our results suggested that FK18 significantly increased the viability of and attenuated the apoptosis of SH-SY5Y cells. It also markedly alleviated I/R-induced retinal neuronal apoptosis, damage to retinal ganglion cells (RGCs), and morphological and functional damage to the retina. Moreover, FK18 increased Akt phosphorylation under both normoxic and OGD conditions, attenuated mitochondrial translocation of the proapoptotic protein Bad, up-regulated the expression of Bcl-2/Bax, and inhibited the release of cytochrome c from the mitochondria into the cytoplasm. These results suggested that FK18 is a novel neuroprotective agent that may serve as a prototype for neuroprotective drug development.

BackgroundThe accumulation of advanced glycated end products (AGEs) in retinal blood vessels is one of the major etiological factors contributing to diabetic retinopathy. Aminoguanidine (AG) is one of the most extensively used inhibitors of AGEs formation. The aim of this study was to investigate whether AG could protect the development of diabetic retinopathy through inhibition of AGEs.MethodsRat diabetes was induced by intraperitoneal injection with streptozotocin (STZ). AG was given to rats in drinking water. Retina was extracted 3 and 6 months following STZ and AG administration. Immunochemistry and transmission electron microscope were used to detect the expression of AGEs and retina morphology.ResultsExtensive staining of AGEs was detected in retinal blood vessels of 3- and 6-month diabetic rats, while no significant staining was found in the control non-diabetic retina or AG treated groups. Pericyte loss, endothelial cell proliferation, increased ratio of endothelial cells/pericytes, acellular capillaries and capillary occlusion were observed in the retina of 6-month diabetic rats. The increased electron density of retinal capillary basement membrane, mitochondrial swelling in pericytes and endothelial cells were also found in 6-month diabetic rats. The 3-month diabetic rats and the AG-treated rats did not have similar morphological changes compared to control group. The AGEs staining in AG-treated rats was still weakly positive.ConclusionsAGEs plays pivotal roles in diabetic retinopathy. AGE deposition occurs prior to retinal microvasculature changes. AG could prevent the onset and development of diabetic retinopathy through inhibition of AGEs.

Necroptosis is a recently discovered programmed necrosis. Evidence demonstrated the importance of necroptosis in neuronal cell death. Necrostatin-1 is a specific inhibitor of necroptosis. In this study, we investigated the role of necrostatin-1 on photoreceptor survival and functional protection after experimental retinal detachment (RD) in rats. Necrostatin-1/inactive analogue of necrostatin-1 was introduced into the subretinal space at RD induction and 6 hours afterward, respectively. We found that necrostatin-1 attenuated retinal histopathological damage and reduced plasma membrane breakdown (a morphological hallmark of necroptosis) in outer retinal layers. Transmission electron microscopy showed that necrostatin-1 directly protected neurons by inhibiting necroptotic, not apoptotic, cell death. Treatment with necrostatin-1 inhibited the induction of receptor-interacting protein kinase phosphorylation after RD (a biomarker of necroptosis). Finally, electroretinographic recording proved that necrostatin-1 contributed to objective functional improvement after RD. These findings indicate that necrostatin-1 is a promising therapeutic agent that protects photoreceptors from necroptosis and improves functional outcome.

Anti-vascular endothelial growth factor (VEGF) therapies are widely used for the treatment of neovascular fundus diseases such as diabetic retinopathy. However, these agents need to be injected intravitreally, because their strong hydrophilicity and high molecular weight prevent them from penetrating cell membranes and complex tissue barriers. Moreover, the repeated injections that are required can cause infection and tissue injury. In this study, we used in vivo-directed evolution phage display technology to identify a novel dodecapeptide, named CC12, with the ability to penetrate the ocular barrier in a noninvasive (via conjunctival sac instillation) or minimally invasive (via retrobulbar injection) manner. KV11, an antiangiogenesis peptide previously demonstrated to inhibit pathological neovascularization in the retina, was then used as a model antiangiogenesis cargo for CC12. We found that conjugation of KV11 peptide with CC12 peptide facilitated the delivery of KV11 to the retina, resulting in significant inhibition of retinal neovascularization development via topical application without tissue toxicity. Collectively, our data of multilevel evaluations demonstrate that CC12 may enable the noninvasive to minimally invasive intraocular delivery of antiangiogenic therapeutics.

•miR-93 is downregulated in the eyes of LPS-induced EIU rats.•miR-93 is downregulated in LPS-treated RAW 264.7 cells.•miR-93 inhibits LPS-induced inflammatory cytokine production.•miR-93 inhibits LPS-induced activation of NF-κB signaling through IRAK4.Endotoxin-induced uveitis (EIU) is an animal model of acute ocular inflammation for the study of human endogenous anterior uveitis. The mechanisms accounting for the development of ocular inflammation remain hazy. MicroRNAs (mi-RNAs) have been proposed as novel regulators of inflammation. It remains unclear whether a microRNA-mediated regulatory mechanism is involved in LPS-induced EIU. In this study, we report that miR-93 expression in the eyes of EIU rats and LPS-stimulated macrophages is significantly decreased. We also show that miR-93 inhibits NF-κB activation and pro-inflammatory cytokines by targeting IRAK4 expression. We further demonstrate that miR-93 inhibits IRAK4 expression by binding directly to the 3′-UTR of IRAK4. Our findings suggest that miR-93 is a negative regulator of the immune response in EIU.