GLP-1: Molecular mechanisms and outcomes of a complex signaling system

Smith, Nicholas K.; Hackett, Troy A.; Galli, Aurelio; Flynn, Charles R.

doi:10.1016/j.neuint.2019.04.010

Cited by 78 publications

(67 citation statements)

References 226 publications

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“…GLP-1 has also been recognized as a neuropeptide. Indeed, GLP-1 and its receptor GLP-1R are expressed in the brain, where they influence multiple neural circuits modulating feeding behavior and reward (Smith et al, 2019). Both GLP-1 and GLP-1R are expressed in mammalian retinas (Zhang et al, 2009; Zhang Y. et al, 2011; Hernandez et al, 2016a; Cai et al, 2017; Hebsgaard 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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“…Proteolytic cleavage and amidation of the precursor protein GLP-1(1–37) generate two GLP-1 active forms with the same biological activity namely GLP-1 (7–37) and the amidated GLP-1 (7–36). GLP-1 is degraded by a dipeptidyl-peptidase IV (DPP IV), a serine aminopeptidase expressed in the different organ, such as liver, pancreas, gut, and brain (Hopsu-Havu and Glenner, 1966; Smith et al, 2019). GLP-1 stimulates insulin secretion from the pancreatic beta-cells under hyperglycemic conditions and reduces glucagon secretion from the alfa-cells recovering insulin sensitivity and enhancing glycemic homeostasis (Meloni et al, 2013; Katsurada and Yada, 2016).…”

Section: Introductionmentioning

confidence: 99%

Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases

et al. 2019

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Diabetes mellitus is one of the major risk factors for cognitive dysfunction. The pathogenesis of brain impairment caused by chronic hyperglycemia is complex and includes mitochondrial dysfunction, neuroinflammation, neurotransmitters’ alteration, and vascular disease, which lead to cognitive impairment, neurodegeneration, loss of synaptic plasticity, brain aging, and dementia. Glucagon-like peptide-1 (GLP-1), a gut released hormone, is attracting attention as a possible link between metabolic and brain impairment. Several studies have shown the influence of GPL-1 on neuronal functions such as thermogenesis, blood pressure control, neurogenesis, neurodegeneration, retinal repair, and energy homeostasis. Moreover, modulation of GLP-1 activity can influence amyloid β peptide aggregation in Alzheimer’s disease (AD) and dopamine (DA) levels in Parkinson’s disease (PD). GLP-1 receptor agonists (GLP-1RAs) showed beneficial actions on brain ischemia in animal models, such as the reduction of cerebral infarct area and the improvement of neurological deficit, acting mainly through inhibition of oxidative stress, inflammation, and apoptosis. They might also exert a beneficial effect on the cognitive impairment induced by diabetes or obesity improving learning and memory by modulating synaptic plasticity. Moreover, GLP-1RAs reduced hippocampal neurodegeneration. Besides this, there are growing evidences on neuroprotective effects of these agonists in animal models of neurodegenerative diseases, regardless of diabetes. In PD animal models, GPL-1RAs were able to protect motor activity and dopaminergic neurons whereas in AD models, they seemed to improve nearly all neuropathological features and cognitive functions. Although further clinical studies of GPL-1RAs in humans are needed, they seem to be a promising therapy for diabetes-associated cognitive decline.

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“…It stimulates glucose-dependent insulin secretion and inhibits the secretion of glucagon [48]. GLP-1 and its receptor GLP-1R are expressed in the brain, where GLP-1 may affect multiple neural circuits and modulate feeding behavior and reward [49]. Both GLP-1 and GLP-1R have been detected in human, rat, and mouse retinas at both the mRNA and the protein level [50,51,52,53,54].…”

Section: Glucagon-like Peptide-1mentioning

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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GLP-1: Molecular mechanisms and outcomes of a complex signaling system

Cited by 78 publications

References 226 publications

Relationships Between Neurodegeneration and Vascular Damage in Diabetic Retinopathy

Relationships Between Neurodegeneration and Vascular Damage in Diabetic Retinopathy

Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases

Neuroprotective Peptides in Retinal Disease

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