Neuropeptide Y treatment induces retinal vasoconstriction and causes functional and histological retinal damage in a porcine ischaemia model

Christiansen, Anders Tolstrup; Sørensen, Nina Buus; Haanes, Kristian Agmund; Blixt, Frank W; Cour, Morten la; Warfvinge, Karin; Klemp, Kristian; Woldbye, David P.D.; Kiilgaard, Jens Folke

doi:10.1111/aos.13806

Cited by 7 publications

(5 citation statements)

References 56 publications

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“…In contrast, recent publications suggest NPY does not exert a protective effect in the retina and that NPY shows no association at gene level (SNP in NPY2R gene) in patients with diabetes . These reports utilize notably different models, addressing different questions but taken together, may suggest that NPY signalling is context‐dependent, with the potential to exert both beneficial neuroprotective and negative effects.…”

Section: Discussionmentioning

confidence: 89%

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Treatment of diabetic retinopathy through neuropeptide Y‐mediated enhancement of neurovascular microenvironment

Copland

Theodoropoulou

et al. 2020

J Cellular Molecular Medi

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Diabetic retinopathy (DR) is one of the most severe clinical manifestations of diabetes mellitus and a major cause of blindness. DR is principally a microvascular disease, although the pathogenesis also involves metabolic reactive intermediates which induce neuronal and glial activation resulting in disruption of the neurovascular unit and regulation of the microvasculature. However, the impact of neural/ glial activation in DR remains controversial, notwithstanding our understanding as to when neural/glial activation occurs in the course of disease. The objective of this study was to determine a potential protective role of neuropeptide Y (NPY) using an established model of DR permissive to N-methyl-D-aspartate (NMDA)-induced excitotoxic apoptosis of retinal ganglion cells (RGC) and vascular endothelial growth factor (VEGF)-induced vascular leakage. In vitro evaluation using primary retinal endothelial cells demonstrates that NPY promotes vascular integrity, demonstrated by maintained tight junction protein expression and reduced permeability in response to VEGF treatment. Furthermore, ex vivo assessment of retinal tissue explants shows that NPY can protect RGC from excitotoxic-induced apoptosis. In vivo clinical imaging and ex vivo tissue analysis in the diabetic model permitted assessment of NPY treatment in relation to neural and endothelial changes. The neuroprotective effects of NPY were confirmed by attenuating NMDA-induced retinal neural apoptosis and able to maintain inner retinal vascular integrity. These findings could have important clinical implications and offer novel therapeutic approaches for the treatment in the early stages of DR. K E Y W O R D S diabetic retinopathy, neurovascular unit, NPY, retinal ganglion cells, vascular permeability, ZO-1 | 3959 OU et al. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Ou K, Copland DA, Theodoropoulou S, et al. Treatment of diabetic retinopathy through neuropeptide Y-mediated enhancement of neurovascular microenvironment.

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Section: Discussionmentioning

confidence: 89%

“… Although no direct evidence in retinal endothelium, NPY can induce migration and proliferation of endothelial cells via its receptors and regulate their function . Conversely, a recent study demonstrates that NPY treatment in a model of acute retinal ischaemia reduced retinal function and tissue damage …”

Section: Introductionmentioning

confidence: 99%

Treatment of diabetic retinopathy through neuropeptide Y‐mediated enhancement of neurovascular microenvironment

Copland

Theodoropoulou

et al. 2020

J Cellular Molecular Medi

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“…Furthermore, Christiansen and colleagues tested the effects of intravitreal NPY treatment in a porcine model of acute retinal ischemia and found that it only enhanced ischemic damage ( Christiansen et al, 2018b ). These observations are markedly important as they contradict earlier results where NPY treatment has been found to convey neuroprotective effects or at least significant change in retinal health could not be observed following treatment (results from cell cultures by Alvaro et al, 2008 ; earlier experimental work reviewed by Santos-Carvalho et al, 2014 ; and a study conducted on rat retinas by Martins et al, 2015 ).…”

Section: Metabolic Retinal Diseases: Pathology and Neuropeptidesmentioning

confidence: 99%

“…These observations are markedly important as they contradict earlier results where NPY treatment has been found to convey neuroprotective effects or at least significant change in retinal health could not be observed following treatment (results from cell cultures by Alvaro et al, 2008 ; earlier experimental work reviewed by Santos-Carvalho et al, 2014 ; and a study conducted on rat retinas by Martins et al, 2015 ). Christiansen and colleagues argue that the damaging effect could have been masked in the ex vivo models used in earlier studies as NPY has been demonstrated to cause vasoconstriction in the retinal arteries ( Prieto et al, 1995 ; Christiansen et al, 2018b ). Regardless, NPY was shown to play no role in pathological retinal neovascularization in the OIR mouse model ( Schmid et al, 2012 ).…”

Section: Metabolic Retinal Diseases: Pathology and Neuropeptidesmentioning

confidence: 99%

Relevance of Peptide Homeostasis in Metabolic Retinal Degenerative Disorders: Curative Potential in Genetically Modified Mice

et al. 2022

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The mammalian retina contains approximately 30 neuropeptides that are synthetized by different neuronal cell populations, glia, and the pigmented epithelium. The presence of these neuropeptides leaves a mark on normal retinal molecular processes and physiology, and they are also crucial in fighting various pathologies (e.g., diabetic retinopathy, ischemia, age-related pathologies, glaucoma) because of their protective abilities. Retinal pathologies of different origin (metabolic, genetic) are extensively investigated by genetically manipulated in vivo mouse models that help us gain a better understanding of the molecular background of these pathomechanisms. These models offer opportunities to manipulate gene expression in different cell types to help reveal their roles in the preservation of retinal health or identify malfunction during diseases. In order to assess the current status of transgenic technologies available, we have conducted a literature survey focused on retinal disorders of metabolic origin, zooming in on the role of retinal neuropeptides in diabetic retinopathy and ischemia. First, we identified those neuropeptides that are most relevant to retinal pathologies in humans and the two clinically most relevant models, mice and rats. Then we continued our analysis with metabolic disorders, examining neuropeptide-related pathways leading to systemic or cellular damage and rescue. Last but not least, we reviewed the available literature on genetically modified mouse strains to understand how the manipulation of a single element of any given pathway (e.g., signal molecules, receptors, intracellular signaling pathways) could lead either to the worsening of disease conditions or, more frequently, to substantial improvements in retinal health. Most attention was given to studies which reported successful intervention against specific disorders. For these experiments, a detailed evaluation will be given and the possible role of converging intracellular pathways will be discussed. Using these converging intracellular pathways, curative effects of peptides could potentially be utilized in fighting metabolic retinal disorders.

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“…In particular, intravitreal injection of NPY after ischemia induction in pigs caused a significant reduction of retinal function, as evaluated by standard and global-flash multifocal ERG. This reduction was accompanied by histological damage, as for instance the reduction of ganglion cells, likely via NPY Y 1 and Y 2 , but not Y 5 receptors [94].…”

Section: Neuropeptide Ymentioning

confidence: 99%

Neuroprotective Peptides in Retinal Disease

Cervia

Catalani

Casini

2019

JCM

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In the pathogenesis of many disorders, neuronal death plays a key role. It is now assumed that neurodegeneration is caused by multiple and somewhat converging/overlapping death mechanisms, and that neurons are sensitive to unique death styles. In this respect, major advances in the knowledge of different types, mechanisms, and roles of neurodegeneration are crucial to restore the neuronal functions involved in neuroprotection. Several novel concepts have emerged recently, suggesting that the modulation of the neuropeptide system may provide an entirely new set of pharmacological approaches. Neuropeptides and their receptors are expressed widely in mammalian retinas, where they exert neuromodulatory functions including the processing of visual information. In multiple models of retinal diseases, different peptidergic substances play neuroprotective actions. Herein, we describe the novel advances on the protective roles of neuropeptides in the retina. In particular, we focus on the mechanisms by which peptides affect neuronal death/survival and the vascular lesions commonly associated with retinal neurodegenerative pathologies. The goal is to highlight the therapeutic potential of neuropeptide systems as neuroprotectants in retinal diseases.

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Neuropeptide Y treatment induces retinal vasoconstriction and causes functional and histological retinal damage in a porcine ischaemia model

Cited by 7 publications

References 56 publications

Treatment of diabetic retinopathy through neuropeptide Y‐mediated enhancement of neurovascular microenvironment

Treatment of diabetic retinopathy through neuropeptide Y‐mediated enhancement of neurovascular microenvironment

Relevance of Peptide Homeostasis in Metabolic Retinal Degenerative Disorders: Curative Potential in Genetically Modified Mice

Neuroprotective Peptides in Retinal Disease

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