glucagon-like-peptide-1 and Nerve-Degeneration

For a long time, diabetic retinopathy (DR) has been one of the most severe complications of diabetes. The early treatment of DR is not clearly recognized. The additional benefit of hypoglycemic agents for DR has become a new research field. Glucagon-like peptide-1 receptor (GLP-1R) has been shown to be widely expressed in tissues including retina. Glucagon-like peptide-1 receptor agonists (GLP-1RA) have been generally used in the treatment of diabetic patients. Studies shows that GLP-1RA could inhibit nerve damage by decrease apoptosis of nerve cells and activation of glial cells. In addition, GLP-1RA plays a protective role for tight junction (TJ) and cells of blood retinal barrier (BRB). It also protects retina from BRB damage. In this review, we discuss the potential protective mechanisms of GLP-1RA for DR beyond the hypoglycemic effects.

Topics: Apoptosis; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Nerve Degeneration; Retina

Metabolic and neurodegenerative disorders have a growing prevalence in Western countries. Available epidemiologic and neurobiological evidences support the existence of a pathophysiological link between these conditions. Glucagon-like peptide 1 (GLP-1), whose activity is reduced in insulin resistance, has been implicated in central nervous system function, including cognition, synaptic plasticity, and neurogenesis. We review the experimental researches suggesting that GLP-1 dysfunction might be a mediating factor between Type 2 diabetes mellitus (T2DM) and neurodegeneration. Drug treatments enhancing GLP-1 activity hold out hope for treatment and prevention of Alzheimer's disease (AD) and cognitive decline.

Topics: Animals; Cognition Disorders; Diabetes Mellitus, Type 2; Endocrinology; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Nerve Degeneration; Therapies, Investigational

Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD). The underlying mechanism behind this unexpected link is most likely linked to the observed desensitization of insulin receptors in the brain. Insulin acts as a growth factor in the brain and supports neuronal repair, dendritic sprouting, and differentiation. Several drugs have been developed to treat type 2 diabetes which re-synthesize insulin receptors and may be of use to prevent neurodegenerative developments in AD. The incretin glucagon-like peptide-1 (GLP-1) is a hormone that facilitates insulin release under high blood sugar conditions. Interestingly, GLP-1 also has very similar growth factor like properties as insulin, and has been shown to protect neurons from toxic effects. In preclinical studies, GLP-1 and longer lasting analogues reduce apoptosis, protect neurons from oxidative stress, induce neurite outgrowth, protect synaptic plasticity and memory formation from the detrimental effects of β-amyloid, and reduce plaque formation and the inflammation response in the brains of mouse models of AD. An advantage of GLP-1 is that it does not affect blood sugar levels in nondiabetic people. Furthermore, recent research has shown that some GLP-1 analogues can cross the blood-brain barrier, including two that are on the market as a treatment for type 2 diabetes. Therefore, GLP-1 analogues show great promise as a novel treatment for AD or other neurodegenerative conditions.

Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Nerve Degeneration; Receptor, Insulin

Glucagon-like peptide-1 (7-36)--amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the gastrointestinal tract in response to food. It enhances pancreatic islet beta-cell proliferation, glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. GLP-1 receptors, are coupled to the cyclic AMP second messenger pathway, and are expressed throughout the brain of rodents and humans. We previously reported that GLP-1 and exendin-4, a naturally occurring, long-acting analogue of GLP-1 that binds the GLP-1 receptor (GLP-1R), possess neurotrophic properties. GLP-1R agonists protect neurons against amyloid-beta peptide (Abeta) and glutamate-induced apoptosis in cell culture studies and attenuate cholinergic neuron atrophy in the basal forebrain of the rat following an excitotoxic lesion. The biochemical cascades activated by neural GLP-1R stimulation are discussed in comparison to those activated by pancreatic receptors, and, additionally, are compared to signaling pathways associated with the classical neurotrophins. GLP-1R stimulation promotes pathways that favour cell survival over apoptosis. GLP-1 readily enters brain, and its diverse physiological actions, which include insulinotropic, cardiovascular as well as neurotrophic ones, may prove beneficial in a variety of diseases prevalent in aging, including Alzheimer's disease (AD). Its ability to lower brain levels of Abeta in mice would appear to be particularly pertinent in this regard. Furthermore, the ready availability of clinical material and the clinical history of its long term use in subjects with type 2 diabetes would support testing the value of GLP-1R agonists in AD trials.

Topics: Alzheimer Disease; Animals; Brain; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Nerve Degeneration; Peptide Fragments; Protein Precursors; Risk Factors; Signal Transduction

Glucagon-like peptide-1 (GLP-1) signaling in the brain plays an important role in the regulation of glucose metabolism, which is impaired in Alzheimer's disease (AD). Here, we detected the GLP-1 and GLP-1 receptor (GLP-1R) in AD human brain and APP/PS1/Tau transgenic (3xTg) mice brain, finding that they were both decreased in AD human and mice brain. Enhanced GLP-1 exerts its protective effects on AD, however, this is rapidly degraded into inactivated metabolites by dipeptidyl peptidase-4 (DPP-4), resulting in its extremely short half-time. DPP-4 inhibitors, thus, was applied to improve the level of GLP-1 and GLP-1R expression in the hippocampus and cortex of AD mice brains. It is also protected learning and memory and synaptic proteins, increased the O-Glycosylation and decreased abnormal phosphorylation of tau and neurofilaments (NFs), degraded intercellular β-amyloid (Aβ) accumulation and alleviated neurodegeneration related to GLP-1 signaling pathway.

Topics: Adamantane; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cerebral Cortex; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycosylation; Hippocampus; Humans; Intermediate Filaments; Learning; Memory Disorders; Mice; Mice, Transgenic; Nerve Degeneration; Phosphorylation; Signal Transduction; Sitagliptin Phosphate; tau Proteins

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been shown to be neuroprotective in previous studies in animal models of Alzheimer's or Parkinson's disease. Recently, novel dual-GLP-1/GIP receptor agonists that activate both receptors (DA) were developed to treat diabetes. We tested the protective effects of a novel potent DA against middle cerebral artery occlusion injury in rats and compared it with a potent GLP-1 analog, Val(8)-GLP-1(glu-PAL). Animals were evaluated for neurologic deficit score, infarct volume, and immunohistochemical analyses of the brain at several time points after ischemia. The Val(8)-GLP-1(glu-PAL)-treated and DA-treated groups showed significantly reduced scores of neurological dysfunction, cerebral infarction size, and percentage of TUNEL-positive apoptotic neurons. Furthermore, the expression of the apoptosis marker Bax, the inflammation marker iNOS, and the survival marker Bcl-2 was significantly increased. The DA-treated group was better protected against neurodegeneration than the Val(8)-GLP-1(glu-PAL) group, and the scores of neurological dysfunction, cerebral infarction size, and expression of Bcl-2 were higher, whereas the percentage of TUNEL-positive neurons and the levels of Bax and iNOS were lower in the DA group. DA treatment reduced the infarct volume and improved the functional deficit. It also suppressed the inflammatory response and cell apoptosis after reperfusion. In conclusion, the novel GIP and GLP-1 dual-receptor agonist is more neuroprotective than a GLP-1 receptor agonist in key biomarkers of neuronal degeneration.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Brain; Disease Models, Animal; Drug Evaluation, Preclinical; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Lipopeptides; Male; Motor Activity; Nerve Degeneration; Neurons; Neuroprotective Agents; Nitric Oxide Synthase Type II; Random Allocation; Rats, Sprague-Dawley; Receptors, Gastrointestinal Hormone

Type 2 diabetes is a risk factor in the development of Alzheimer's disease (AD). It has been shown that insulin signalling is desensitised in the brains of AD patients. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and long-lasting analogues such as liraglutide (Victoza(®)) are on the market as type 2 diabetes treatments. We have previously shown that liraglutide improved cognitive function, reduced amyloid plaque deposition, inflammation, overall APP and oligomer levels and enhanced LTP when injected peripherally for two months in 7 month old APPswe/PS1ΔE9 (APP/PS1) mice. This showed that liraglutide has preventive effects at the early stage of AD development. The current study investigated whether Liraglutide would have restorative effects in late-stage Alzheimer's disease in mice. Accordingly, 14-month-old APP/PS1 and littermate control mice were injected with Liraglutide (25 nmol/kg bw) ip. for 2 months. Spatial memory was improved by Liraglutide-treatment in APP/PS1 mice compared with APP/PS1 saline-treated mice. Overall plaque load was reduced by 33%, and inflammation reduced by 30%, while neuronal progenitor cell count in the dentate gyrus was increased by 50%. LTP was significantly enhanced in APP/PS1 liraglutide-treated mice compared with APP/PS1 saline mice, corroborated with increased synapse numbers in hippocampus and cortex. Total brain APP and beta-amyloid oligomer levels were reduced in Liraglutide-treated APP/PS1 mice while IDE levels were increased. These results demonstrate that Liraglutide not only has preventive properties, but also can reverse some of the key pathological hallmarks of AD. Liraglutide is now being tested in clinical trials in AD patients. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cell Count; Disease Models, Animal; Glucagon-Like Peptide 1; Inflammation; Liraglutide; Long-Term Potentiation; Male; Memory; Memory Disorders; Mice; Mice, Transgenic; Nerve Degeneration; Neuroprotective Agents; Plaque, Amyloid; Stem Cells; Synapses

Growing evidence suggests that type 2 diabetes mellitus (DM) is associated with age-dependent Alzheimer's disease (AD), the latter of which has even been considered as type 3 diabetes. Several physiopathological features including hyperglycemia, oxidative stress, and dysfunctional insulin signaling relate DM to AD. In this study, high glucose-, oxidative stress-induced neuronal injury and intracerebroventricular-streptozotocin (ICV-STZ) animals as the possible models for diabetes-related AD were employed to investigate the effects of exendin-4 (Ex-4), a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, on diabetes-associated Alzheimer-like changes as well as the molecular mechanisms involved. Our study demonstrated that GLP-1/Ex-4 could exert a protective effect against reduced viability of PC12 cells caused by high glucose and that this protective effect was mediated via the PI3-kinase pathway. In addition, GLP-1/Ex-4 ameliorated oxidative stress-induced injury in PC12 cells. In rat models, bilateral ICV-STZ administration was used to produce impaired insulin signaling in the brain. Fourteen days following ICV-STZ injection, rats treated with twice-daily Ex-4 had better learning and memory performance in the Morris water maze test compared with rats treated with saline. Additionally, histopathological evaluation confirmed the protective effects of Ex-4 treatment on hippocampal neurons against degeneration. Furthermore, we demonstrated that Ex-4 reversed ICV-STZ-induced tau hyperphosphorylation through downregulation of GSK-3β activity, a key kinase in both DM and AD. Our findings suggests that Ex-4 can protect neurons from diabetes-associated glucose metabolic dysregulation insults in vitro and from ICV-STZ insult in vivo, and that Ex-4 may prove of therapeutic value in the treatment of AD especially DM-related AD.

Topics: Alzheimer Disease; Animals; Blood Glucose; Cell Survival; Diabetes Mellitus, Experimental; Exenatide; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Hypoglycemic Agents; Insulin; Male; Nerve Degeneration; Oxidative Stress; Peptides; Rats; Rats, Wistar; Venoms

Type 2 diabetes is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting GLP-1 analogs, such as liraglutide, are on the market as diabetes therapeutics. GLP-1 has been shown to have neuroprotective properties in vitro and in vivo. Here we tested the effects of peripherally injected liraglutide in an Alzheimer mouse model, APP(swe)/PS1(ΔE9) (APP/PS1). Liraglutide was shown to cross the blood-brain barrier in an acute study. Liraglutide was injected for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old APP/PS1 and wild-type littermate controls. In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model. Overall β-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40-50%, while levels of soluble amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutide-treated APP/PS1 mice. Numbers of young neurons in the dentate gyrus were increased in APP/PS1 mice with treatment. Liraglutide treatment had little effect on littermate control mice, whose behavior was comparable to wild-type saline controls; however, synaptic plasticity was enhanced in the drug group. Our results show that liraglutide prevents key neurodegenerative developments found in Alzheimer's disease, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Blood-Brain Barrier; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Glucagon-Like Peptide 1; Hippocampus; Humans; Hypoglycemic Agents; Liraglutide; Long-Term Potentiation; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Degeneration; Presenilin-1; Recognition, Psychology; Synaptophysin

The aim of this study was to investigate the GLP-1 pathway effect on peripheral nerves using a DPP-IV inhibitor in streptozotocin (STZ)-induced diabetic rats.. Adult male Sprague Dawley rats were divided into four groups and two groups (n=6 in each) were given a DPP-IV inhibitor of 0.3mg/kg/day or 10mg/kg/day dissolved in water. Intraepidermal innervation was quantified as nerve fiber abundance per unit length of epidermis (IENF/mm) following an immunohistochemical procedure using the polyclonal antibody of anti-protein gene product 9.5 (PGP 9.5).. Daily administration of DPP-IV inhibitor to the experimental diabetes model at doses of 10mg/kg for 32 weeks protected nerve fiber loss compared with untreated rats as follows (IENF/mm): normal (9.89+/-0.34), diabetes mellitus (DM) (8.42+/-0.28), DM with 0.3mg/kg DPP-IV inhibitor (9.88+/-0.38), and DM with 10mg/kg DPP-IV inhibitor (10.36+/-0.32) (p<0.05). There was a significant reduction (% change) in the decrease of intraepidermal nerve fiber density (IENFD) in the DPP-IV inhibitor-treated groups during the experimental period: normal (10.1%), DM (25.8%), DM with 0.3mg/kg DPP-IV inhibitor (13.3%), and DM with 10mg/kg DPP-IV inhibitor (7.9%) (p<0.05).. Our study suggests that a DPP-IV inhibitor may prevent peripheral nerve degeneration in a diabetes-induced animal model and support the idea that GLP-1 may be useful in peripheral neuropathy.

Topics: Adamantane; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dipeptidyl-Peptidase IV Inhibitors; Eating; Electric Stimulation; Epidermis; Glucagon-Like Peptide 1; Humans; Insulin; Male; Nerve Degeneration; Nitriles; Peripheral Nerves; Pyrrolidines; Random Allocation; Rats; Rats, Sprague-Dawley; Ubiquitin Thiolesterase; Vildagliptin

Pyridoxine (vitamin B6) intoxicated rodents develop a peripheral neuropathy characterized by sensory nerve conduction deficits associated with disturbances of nerve fiber geometry and axonal atrophy. To investigate the possibility that glucagon-like peptide-1 (7-36)-amide (GLP-1) receptor agonism may influence axonal structure and function through neuroprotection neurotrophic support, effects of GLP-1 and its long acting analog, Exendin-4 (Ex4) treatment on pyridoxine-induced peripheral neuropathy were examined in rats using behavioral and morphometric techniques. GLP-1 is an endogenous insulinotropic peptide secreted from the gut in response to the presence of food. GLP-1 receptors (GLP-1R) are coupled to the cAMP second messenger pathway, and are expressed widely throughout neural tissues of humans and rodents. Recent studies have established that GLP-1 and Ex4, have multiple synergistic effects on glucose-dependent insulin secretion pathways of pancreatic beta-cells and on neural plasticity. Data reported here suggest that clinically relevant doses of GLP-1 and Ex4 may offer some protection against the sensory peripheral neuropathy induced by pyridoxine. Our findings suggest a potential role for these peptides in the treatment of neuropathies, including that associated with type II diabetes mellitus.

Topics: Amino Acid Sequence; Animals; Behavior, Animal; Blood Glucose; Body Weight; Exenatide; Ganglia, Spinal; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Male; Molecular Sequence Data; Muscle Tonus; Nerve Degeneration; Neurons, Afferent; Neuroprotective Agents; Peptides; Peripheral Nervous System Diseases; Postural Balance; Pyridoxine; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Sciatic Nerve; Venoms; Vitamins

Topics: Animals; Brain-Derived Neurotrophic Factor; Cyclic AMP; Glucagon; Glucagon-Like Peptide 1; Glucose; Glutamic Acid; Insulin; Insulin Secretion; Learning; Memory; Mice; Nerve Degeneration; Neuronal Plasticity; Pancreas; Peptide Fragments; Protein Precursors; Rats; Receptors, Neurotransmitter; Signal Transduction

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the L cells of the gastrointestinal tract in response to food. It has potent effects on glucose-dependent insulin secretion, insulin gene expression, and pancreatic islet cell formation. In type 2 diabetes, GLP-1, by continuous infusion, can normalize blood glucose and is presently being tested in clinical trials as a therapy for this disease. More recently, GLP-1 has been found to have central nervous system (CNS) effects and to stimulate neurite outgrowth in cultured cells. We now report that GLP-1, and its longer-acting analog exendin-4, can completely protect cultured rat hippocampal neurons against glutamate-induced apoptosis. Extrapolating these effects to a well defined rodent model of neurodegeneration, GLP-1 and exendin-4 greatly reduced ibotenic acid-induced depletion of choline acetyltransferase immunoreactivity in basal forebrain cholinergic neurons. These findings identify a novel neuroprotective/neurotrophic function of GLP-1 and suggest that such peptides may have potential for halting or reversing neurodegenerative processes in CNS disorders, such as Alzheimer's disease, and in neuropathies associated with type 2 diabetes mellitus.

Topics: Animals; Basal Ganglia; Cell Death; Cell Survival; Cells, Cultured; Choline O-Acetyltransferase; Cyclic AMP; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Exenatide; Glial Fibrillary Acidic Protein; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glutamic Acid; Hippocampus; Ibotenic Acid; Immunohistochemistry; Nerve Degeneration; Neurons; Parasympathetic Nervous System; Peptide Fragments; Peptides; Protein Precursors; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Receptors, Glucagon; Venoms