PACAP Attenuates Optic Nerve Crush-Induced Retinal Ganglion Cell Apoptosis Via Activation of the CREB-Bcl-2 Pathway

Ye, Dan; Shi, Yuxun; Xu, Yue; Huang, Jingjing

doi:10.1007/s12031-019-01309-9

Cited by 36 publications

(23 citation statements)

References 49 publications

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“…Further evidence has been provided by more recent studies. Indeed, PACAP has been shown to inhibit apoptosis and promote survival of retinal ganglion cells in different models of retinal injury (Lakk et al, 2015; Ye et al, 2019). In addition, intravitreal or topical administrations of PACAP or a PAC1 agonist to ischemic retinas in vivo ameliorated ERG responses, prevented inflammation, and reduced the thinning of retinal layers and the loss of cells in the ganglion cell layer (Danyadi et al, 2014; Vaczy et al, 2016; Werling et al, 2017; Atlasz et al, 2018).…”

Section: Neuropeptidesmentioning

confidence: 99%

Relationships Between Neurodegeneration and Vascular Damage in Diabetic Retinopathy

2019

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Diabetic retinopathy (DR) is a common complication of diabetes and constitutes a major cause of vision impairment and blindness in the world. DR has long been described exclusively as a microvascular disease of the eye. However, in recent years, a growing interest has been focused on the contribution of neuroretinal degeneration to the pathogenesis of the disease, and there are observations suggesting that neuronal death in the early phases of DR may favor the development of microvascular abnormalities, followed by the full manifestation of the disease. However, the mediators that are involved in the crosslink between neurodegeneration and vascular changes have not yet been identified. According to our hypothesis, vascular endothelial growth factor (VEGF) could probably be the most important connecting link between the death of retinal neurons and the occurrence of microvascular lesions. Indeed, VEGF is known to play important neuroprotective actions; therefore, in the early phases of DR, it may be released in response to neuronal suffering, and it would act as a double-edged weapon inducing both neuroprotective and vasoactive effects. If this hypothesis is correct, then any retinal stress causing neuronal damage should be accompanied by VEGF upregulation and by vascular changes. Similarly, any compound with neuroprotective properties should also induce VEGF downregulation and amelioration of the vascular lesions. In this review, we searched for a correlation between neurodegeneration and vasculopathy in animal models of retinal diseases, examining the effects of different neuroprotective substances, ranging from nutraceuticals to antioxidants to neuropeptides and others and showing that reducing neuronal suffering also prevents overexpression of VEGF and vascular complications. Taken together, the reviewed evidence highlights the crucial role played by mediators such as VEGF in the relationship between retinal neuronal damage and vascular alterations and suggests that the use of neuroprotective substances could be an efficient strategy to prevent the onset or to retard the development of DR.

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Section: Neuropeptidesmentioning

confidence: 99%

Relationships Between Neurodegeneration and Vascular Damage in Diabetic Retinopathy

2019

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“…Several papers suggest that DR is not only a vascular damage, but neurodegeneration also plays a pivotal role in its pathogenesis (Zhang et al 2013;Simo and Hernandez 2015;Rossino et al 2019). Various neuropeptides and their receptors, including VIP and PACAP, were detected in the retina (Nakamachi et al 2012) and proved to be neuroprotective against different harmful stimuli, thus they can be considered as potential therapeutic agents in DR (Atlasz et al 2010a, b;Nakamachi et al 2012;Lakk et al 2015;Shioda et al 2016;Ye et al 2019). In vivo studies confirmed that intravitreal or topical administration of PACAP not only improves ERG responses, but attenuates inflammatory processes, protects neurons in the ganglion cell layer and diminishes the thinning of the rat retina (Danyadi et al 2014;Vaczy et al 2016;Werling et al 2017;Atlasz et al 2018).…”

Section: Discussionmentioning

confidence: 99%

PACAP is Protective Against Cellular Stress in Retinal Pigment Epithelial Cells

Fábián

Horváth

Opper

et al. 2021

Int J Pept Res Ther

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The integrity of the innermost, pigment epithelial layer of the retina is crucial for the photoreceptor survival and for maintaining the outer blood–retina barrier. In several ocular degenerations, such as diabetic retinopathy or macular edema, the stress caused by various harmful stimuli (hypoxia, oxidative stress, hyperosmosis) lead to severe molecular biological changes in this layer, promoting neovascularization of the retina. Pituitary adenylate cyclase activating polypeptide (PACAP) occurs throughout the whole body, including the eye. It has numerous functions in the retina, including the previously described anti-apoptotic and anti-angiogenic effects in retinal pigment epithelial cells. The aim of this present study was to investigate the influence of PACAP on different stress factors. In accordance with previous findings, PACAP significantly ameliorated the increased Hif1-α levels in hypoxic conditions. In H2O2-induced oxidative stress PACAP had an anti-apoptotic effect, it could decrease the expression of cytochrome-c and p53, while it upregulated the concentration of three antioxidants, namely SOD2, PON2 and thioredoxin. In conclusion, we provided new information on the molecular biological background of the retinoprotective effect of PACAP.

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“…The ONC model was established in SD rats as previously described. 13 , 14 In brief, rats were sedated by intraperitoneal injection with 10% chloral hydrate. A 4-mm length of optic nerve was exposed and crushed for 10 seconds at 2 mm behind the optic nerve head.…”

Section: Methodsmentioning

confidence: 99%

Down Syndrome Critical Region 1 Reduces Oxidative Stress–Induced Retinal Ganglion Cells Apoptosis via CREB–Bcl-2 Pathway

Shi

Huang

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose Irreversible retina ganglion cell (RGC) loss is a key process during glaucoma progression. Down syndrome critical region 1 (DSCR1) has been shown to have protective effects against neuronal death. In this study, we aimed to investigate the neuroprotective mechanisms of DSCR1 on RGCs. Methods DBA/2J mice and optic nerve crush (ONC) rat model were used for vivo assays. Oxidative stress model of primary RGCs was carried out with in vitro transduction. DSCR1 protein localization was assessed by immunofluorescence. Differential protein expression was validated by Western blot, and gene expression was detected by real-time PCR. TUNEL was used to identify cell apoptosis, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to analyze cell viability. Results Significant upregulation of DSCR1 was observed in DBA/2J mice, ONC rat model, and RGCs treated with H 2 O 2 , reaching peaks at the age of 6 months in DBA/2J mice, 5 days after ONC in rats, and 24 hours after H 2 O 2 treatment in RGCs, respectively. DSCR1 was shown to be expressed in the ganglion cell layer. In vitro, overexpressed DSCR1 significantly promoted phosphorylation of cyclic AMP response element binding protein (CREB), B-cell lymphoma 2 (Bcl-2) expression, and RGC survival rate while reducing cleaved caspase 3 expression in H 2 O 2 -treated RGCs. On the other hand, the opposite effects were shown after knockdown of DSCR1. In addition, silencing of CREB inhibited expression of DSCR1. Conclusions Our results suggested that DSCR1 might protect the RGCs against oxidative stress via the CREB–Bcl-2 pathway, which may provide a theoretical basis for future treatments of glaucoma.

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PACAP Attenuates Optic Nerve Crush-Induced Retinal Ganglion Cell Apoptosis Via Activation of the CREB-Bcl-2 Pathway

Cited by 36 publications

References 49 publications

Relationships Between Neurodegeneration and Vascular Damage in Diabetic Retinopathy

Relationships Between Neurodegeneration and Vascular Damage in Diabetic Retinopathy

PACAP is Protective Against Cellular Stress in Retinal Pigment Epithelial Cells

Down Syndrome Critical Region 1 Reduces Oxidative Stress–Induced Retinal Ganglion Cells Apoptosis via CREB–Bcl-2 Pathway

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