glucagon-like-peptide-1 and Neurodegenerative-Diseases

Glucagon-like peptide-1 (GLP-1) is a human incretin hormone derived from the proglucagon molecule. GLP-1 receptor agonists are frequently used to treat type 2 diabetes mellitus and obesity. However, the hormone affects the liver, pancreas, brain, fat cells, heart, and gastrointestinal tract. The objective of this study was to perform a systematic review on the use of GLP-1 other than in treating diabetes. PubMed, Cochrane, and Embase were searched, and the PRISMA guidelines were followed. Nineteen clinical studies were selected. The results showed that GLP-1 agonists can benefit defined off-medication motor scores in Parkinson's Disease and improve emotional well-being. In Alzheimer's disease, GLP-1 analogs can improve the brain's glucose metabolism by improving glucose transport across the blood-brain barrier. In depression, the analogs can improve quality of life and depression scales. GLP-1 analogs can also have a role in treating chemical dependency, inhibiting dopaminergic release in the brain's reward centers, decreasing withdrawal effects and relapses. These medications can also improve lipotoxicity by reducing visceral adiposity and decreasing liver fat deposition, reducing insulin resistance and the development of non-alcoholic fatty liver diseases. The adverse effects are primarily gastrointestinal. Therefore, GLP-1 analogs can benefit other conditions besides traditional diabetes and obesity uses.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Management; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Neurodegenerative Diseases; Obesity; Peptide Fragments; Treatment Outcome

Recent clinical guidelines have emphasized the importance of screening for cognitive impairment in older adults with diabetes, however, there is still a lack of understanding about the drug therapy. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are widely used in the treatment of type 2 diabetes and potential applications may include the treatment of obesity as well as the adjunctive treatment of type 1 diabetes mellitus in combination with insulin. Growing evidence suggests that GLP-1 RA has the potential to treat neurodegenerative diseases, particularly in diabetes-related Alzheimer's disease (AD) and Parkinson's disease (PD). Here, we review the molecular mechanisms of the neuroprotective effects of GLP-1 RA in diabetes-related degenerative diseases, including AD and PD, and their potential effects.

Topics: Aged; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin; Neurodegenerative Diseases

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent neurodegenerative disorders. Despite their pathophysiological and clinical differences, they share several mechanistic similarities at cellular and sub-cellular levels. The current treatments of AD and PD are only symptomatic, since many clinically-tested drugs failed to prevent or halt their progression. There is now evidence that type 2 diabetes mellitus is among the main risk factors for AD and PD and that the insulin resistance in the brain plays a crucial role in their neuropathological processes. Therefore, insulin nasal administration was suggested for the treatment of AD and PD, both in diabetic and non-diabetic patients. However, the adverse effects of chronic insulin prompted the research of alternative strategies, such as the novel antidiabetic drugs based on the incretin hormones glucagon-like protein-1 (GLP-1) and glucose-dependent insulinotropic Peptide (GIP). The rapid inactivation of these incretins by dipeptidyl-peptidase IV (DPP-IV) suggested the development of DPP-IV-resistant GLP-1 receptor agonists (GLP-1Ras), the recent dual GLP-1/GIP receptor agonists and the DPP-IV inhibitors (DPP-IVis). This review will first describe the experimental, pathophysiological and clinical approach for AD and PD treatment with insulin. Afterwards, the main pharmacologic properties of GLP-1Ras and of DPP-IVis will be discussed, detailing their ability to cross the BBB and get access to the brain for GLP-1Ras, and the novel strategies for BBB crossing as regards DPP-IVis. Emphasis will be placed on the main findings obtained from AD and PD experimental models about the neuroprotective effects of these drugs. For AD, the improvement of learning and memory exerted by incretin-based drugs correlated with reduction of chronic inflammation, brain Aβ plaque, tau hyperphosphorylation, protection of mitochondria, enhancement of energy utilisation. For PD, both GLP-1Ras and of DPP-IVis reversed the nigrostriatal dopaminergic cell loss progression, restored dopamine synthesis, exerted anti-inflammatory activity and improved motor functions. Finally, the encouraging results of the first clinical trials on AD and PD patients and the adverse effects of GLP-1Ras and DPP-IVis will be discussed, highlighting how the above-mentioned neuroprotective effects have a great potential to be translated into clinical settings and that the incretin-based approach represents novel promising strategy for the

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Neurodegenerative Diseases; Neuroprotective Agents

The glucagon-like peptide-1 (GLP-1) is a pleiotropic hormone well known for its incretin effect in the glucose-dependent stimulation of insulin secretion. However, GLP-1 is also produced in the brain and displays a critical role in neuroprotection and inflammation by activating the GLP-1 receptor signaling pathways. Several studies in vivo and in vitro using preclinical models of neurodegenerative diseases show that GLP-1R activation has anti-inflammatory properties. This review explores the molecular mechanistic action of GLP-1 RAS in relation to inflammation in the brain. These findings update our knowledge of the potential benefits of GLP-1RAS actions in reducing the inflammatory response. These molecules emerge as a potential therapeutic tool in treating neurodegenerative diseases and neuroinflammatory pathologies.

Topics: Brain; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Inflammation; Neurodegenerative Diseases

Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation.

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Neurodegenerative Diseases; Neuroinflammatory Diseases; Parkinson Disease

GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.).. To summarize current knowledge about GLP-1 receptor agonist.

Topics: Animals; Blood Glucose; Body Weight; Cardiovascular System; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemia; Immunoglobulin Fc Fragments; Insulin; Liraglutide; Neurodegenerative Diseases; Peptides; Psoriasis; Recombinant Fusion Proteins

There is a large unmet medical need to find disease modifying therapies against neurodegenerative diseases. This review summarizes data indicating that insulin resistance occurs in neurodegeneration and strategies to normalize insulin sensitivity in neurons may provide neuroprotective actions. In particular, recent preclinical and clinical studies in Parkinson's disease and Alzheimer's disease have indicated that glucagon-like peptide 1 (GLP1) agonism and dipeptidyl peptidase-4 inhibition may exert neuroprotection. Mechanistic insights from these studies and future directions for drug development against neurodegeneration based on GLP1 agonism are discussed.

Topics: Animals; Cognition Disorders; Dipeptidyl-Peptidase IV Inhibitors; Drug Repositioning; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Neurodegenerative Diseases; Neuroprotective Agents

Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) exert pleiotropic effects on endocrine pancreas and nervous system. Expression of GIP and GIP receptor (GIPR) in neurons, their roles in neurogenesis, synaptic plasticity, neurotransmission, and neuromodulation uniquely position GIPR for therapeutic applications in neurodegenerative disorders. GIP analogs acting as GIPR agonists attenuate neurobehavioral and neuropathological sequelae of neurodegenerative disorders in preclinical models, e.g. Alzheimer's disease (AD), Parkinson's disease (PD), and cerebrovascular disorders. Modulation of GIPR signaling offers an unprecedented approach for disease modification by arresting neuronal viability decline, enabling neuronal regeneration, and reducing neuroinflammation. Growth-promoting effects of GIP signaling and broad-based neuroprotection highlight the therapeutic potential of GIPR agonists. Areas covered: This review focuses on the role of GIPR-mediated signaling in the central nervous system in neurophysiological and neuropathological conditions. In context of neurodegeneration, the article summarizes potential of targeting GIPR signaling for neurodegenerative conditions such as AD, PD, traumatic brain injury, and cerebrovascular disorders. Expert opinion: GIPR represents a validated therapeutic target for neurodegenerative disorders. GIPR agonists impart symptomatic improvements, slowed neurodegeneration, and enhanced neuronal regenerative capacity in preclinical models. Modulation of GIPR signaling is potentially a viable therapeutic approach for disease modification in neurodegenerative disorders.

Topics: Animals; Drug Development; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Neurodegenerative Diseases; Receptors, Gastrointestinal Hormone; Signal Transduction

Glucagon-like peptide-1 (GLP-1) is released in response to meals and exerts important roles in the maintenance of normal glucose homeostasis. GLP-1 is also important in the regulation of neurologic and cognitive functions. These actions are mediated via neurons in the nucleus of the solitary tract that project to multiple regions expressing GLP-1 receptors (GLP-1Rs). Treatment with GLP-1R agonists (GLP-1-RAs) reduces ischemia-induced hyperactivity, oxidative stress, neuronal damage and apoptosis, cerebral infarct volume, and neurologic damage, after cerebral ischemia, in experimental models. Ongoing human trials report a neuroprotective effect of GLP-1-RAs in Alzheimer's and Parkinson's disease. In this review, we discuss the role of GLP-1 and GLP-1-RAs in the nervous system with focus on GLP-1 actions on appetite regulation, glucose homeostasis, and neuroprotection.

Topics: Animals; Central Nervous System; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Neurodegenerative Diseases; Peripheral Nervous System

The link between diabetes mellitus and Alzheimer's disease (AD) has been known for the last few decades. Since insulin and insulin receptors are known to be present in the brain, the downstream signalling as well as the effect of hyperinsulinemia have been extensively studied in both AD and Parkinson's disease. Glucagon-like peptide-1 (GLP-1) is a hormone belonging to the incretin family, and its receptors (GLP-1Rs) can be found in pancreatic cells and in vascular endothelium. Interestingly, GLP-1Rs are found in the neuronal cell body and dendrites in the central nervous system (CNS), in particular in the hypothalamus, hippocampus, cerebral cortex and olfactory bulb. Several studies have shown the importance of both insulin and GLP-1 signalling on cognitive function, and many preclinical studies have been performed to evaluate the potential protective role of GLP-1 on the brain. Here we review the underlying mechanism of insulin and GLP-1 signalling in the CNS, as well as the preclinical data for the use of GLP-1 analogues such as liraglutide, exenatide and lixisenatide in neurodegenerative diseases.

Topics: Alzheimer Disease; Animals; Glucagon-Like Peptide 1; Humans; Insulin; Neurodegenerative Diseases; Neuroprotective Agents

The incretin hormone glucagon-like peptide 1 (GLP-1) has many effects in the body. It is best known for the 'incretin effect', facilitating insulin release from the pancreas under hyperglycaemic conditions. Building on this, GLP-1 mimetics have been developed as a treatment for type 2 diabetes. In the course of monitoring of patients, it has become apparent that GLP-1 mimetics have a range of other physiological effects in the body. In preclinical trials, a substantial body of evidence has been built that these mimetics have neuroprotective and anti-inflammatory effects. GLP-1 also has very similar growth-factor-like properties to insulin, which is presumably the underlying basis of the neuroprotective effects. In preclinical studies of Alzheimer's disease (AD), Parkinson's disease (PD), stroke and other neurodegenerative disorders, it has been shown that most GLP-1 mimetics cross the blood-brain barrier and show impressive neuroprotective effects in numerous studies. In animal models of AD, GLP-1 mimetics such as exendin-4, liraglutide and lixisenatide have shown protective effects in the CNS by reducing β-amyloid plaques, preventing loss of synapses and memory impairments, and reducing oxidative stress and the chronic inflammatory response in the brain. In animal models of PD, exendin-4 showed protection of dopaminergic neurons in the substantia nigra and prevention of dopamine loss in the basal ganglia while preserving motor control. These encouraging findings have spawned several clinical trials, some of which have shown encouraging initial results. Therefore, GLP-1 mimetics show great promise as a novel treatment for neurodegenerative conditions.

Topics: Animals; Glucagon-Like Peptide 1; Humans; Neurodegenerative Diseases; Neuroprotective Agents

There is increasing evidence to suggest that glucagon-like peptide 1 (GLP1) analogs are neuroprotective in animal models. In transgenic mice, both insulin and GLP1 analogs reduced inflammation, increased stem cell proliferation, reduced apoptosis, and increased dendritic growth. Furthermore, insulin desensitization was also observed in these animals, and reduced glucose uptake in the brain, as shown on FDG-PET imaging. In this review we discussed the role of PET and MRI in evaluating the effect of GLP1 analogs in disease progression in both Alzheimer's and Parkinson's disease. We have also discussed the potential novel PET markers that will allow us to understand the mechanism by which GLP1 exerts its effects.

Topics: Animals; Brain; Disease Models, Animal; Glucagon-Like Peptide 1; Humans; Mice; Mice, Transgenic; Neurodegenerative Diseases; Neuroimaging; Neuroprotective Agents; Radionuclide Imaging

Insulin and Insulin Growth Factor-1 (IGF-1) play a major role in body homeostasis and glucose regulation. They also have paracrine/autocrine functions in the brain. The Insulin/IGF-1 signaling pathway contributes to the control of neuronal excitability, nerve cell metabolism and cell survival. Glucagon like peptide-1 (GLP-1), known as an insulinotropic hormone has similar functions and growth like properties as insulin/IGF-1. Growing evidence suggests that dysfunction of these pathways contribute to the progressive loss of neurons in Alzheimer's disease (AD) and Parkinson's disease (PD), the two most frequent neurodegenerative disorders. These findings have led to numerous studies in preclinical models of neurodegenerative disorders targeting insulin/IGF-1 and GLP-1 signaling with currently available anti-diabetics. These studies have shown that administration of insulin, IGF-1 and GLP-1 agonists reverses signaling abnormalities and has positive effects on surrogate markers of neurodegeneration and behavioral outcomes. Several proof-of-concept studies are underway that attempt to translate the encouraging preclinical results to patients suffering from AD and PD. In the first part of this review, we discuss physiological functions of insulin/IGF-1 and GLP-1 signaling pathways including downstream targets and receptors distribution within the brain. In the second part, we undertake a comprehensive overview of preclinical studies targeting insulin/IGF-1 or GLP-1 signaling for treating AD and PD. We then detail the design of clinical trials that have used anti-diabetics for treating AD and PD patients. We close with future considerations that treat relevant issues for successful translation of these encouraging preclinical results into treatments for patients with AD and PD.

Topics: Animals; Brain; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Humans; Insulin; Insulin-Like Growth Factor I; Neurodegenerative Diseases

Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic incretin hormone with both pancreatic and extrapancreatic effects. Studies of GLP-1 reveal significant effects in regions of brain tissue that regulate appetite and satiety. GLP-1 mimetics are used for the treatment of type 2 diabetes mellitus. GLP-1 interacts with peripheral functions in which the autonomic nervous system plays an important role, and emerging pre-clinical findings indicate a potential neuroprotective role of the peptide, for example in models of stroke and in neurodegenerative disorders. A century ago, Leonor Michaelis and Maud Menten described the steady-state enzyme kinetics that still apply to the multiple receptors, transporters and enzymes that define the biochemical reactions of the brain, including the glucose-dependent impact of GLP-1 on blood-brain glucose transfer and metabolism. This MiniReview examines the potential of GLP-1 as a molecule of interest for the understanding of brain energy metabolism and with reference to the impact on brain metabolism related to appetite and satiety regulation, stroke and neurodegenerative disorders. These effects can be understood only by reference to the original formulation of the Michaelis-Menten equation as applied to a chain of kinetically controlled steps. Indeed, the effects of GLP-1 receptor activation on blood-brain glucose transfer and brain metabolism of glucose depend on the glucose concentration and relative affinities of the steps both in vitro and in vivo, as in the pancreas.

Topics: Animals; Biological Transport; Blood-Brain Barrier; Brain; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Neurodegenerative Diseases; Receptors, Glucagon; Stroke

Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies.

Topics: Adiponectin; Alzheimer Disease; Body Weight; Brain-Derived Neurotrophic Factor; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Leptin; Metabolic Diseases; Neurodegenerative Diseases

Like type-2 diabetes mellitus (T2DM), neurodegenerative disorders and stroke are an ever increasing, health, social and economic burden for developed Westernized countries. Age is an important risk factor in all of these; due to the rapidly increasing rise in the elderly population T2DM and neurodegenerative disorders, both represent a looming threat to healthcare systems. Whereas several efficacious drugs are currently available to ameliorate T2DM, effective treatments to counteract pathogenic processes of neurodegenerative disorders are lacking and represent a major scientific and pharmaceutical challenge. Epidemiological data indicate an association between T2DM and most major neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Likewise, there is an association between T2DM and stroke incidence. Studies have revealed that common pathophysiological features, including oxidative stress, insulin resistance, abnormal protein processing and cognitive decline, occur across these. Based on the presence of shared mechanisms and signalling pathways in these seemingly distinct diseases, one could hypothesize that an effective treatment for one disorder could prove beneficial in the others. Glucagon-like peptide-1 (GLP-1)-based anti-diabetic drugs have drawn particular attention as an effective new strategy to not only regulate blood glucose but also to reduce apoptotic cell death of pancreatic beta cells in T2DM. Evidence supports a neurotrophic and neuroprotective role of GLP-1 receptor (R) stimulation in an increasing array of cellular and animal neurodegeneration models as well as in neurogenesis. Herein, we review the physiological role of GLP-1 in the nervous system, focused towards the potential benefit of GLP-1R stimulation as an immediately translatable treatment strategy for acute and chronic neurological disorders.

Topics: Animals; Brain; Cerebrovascular Disorders; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Receptors, Glucagon

The current understanding of neurodegenerative processes in sporadic diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) or multiple sclerosis is very limited. Several risk factors have been identified that may shed light on the underlying mechanisms that initiate the neurodegeneration. Type 2 diabetes mellitus has been identified as a risk factor for AD and PD. In AD patients, desensitization of insulin receptors in the brain has been shown, even in non-diabetic patients. Insulin acts as a growth factor in the brain and supports neuronal repair, dendritic sprouting and synaptogenesis, and protection from oxidative stress. Importantly, several drugs have been developed to treat type 2 diabetes that re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes. 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 to insulin, and has been shown to reduce a range of degenerative processes. In pre-clinical studies, GLP-1 and longer-lasting protease-resistant analogues cross the blood-brain barrier, protect memory formation (AD) or motor activity (PD), protect synapses and synaptic functions, enhance neurogenesis, reduce apoptosis, protect neurons from oxidative stress, and reduce plaque formation and the chronic inflammation response in the brains of mouse models of AD, PD, amyotrophic lateral sclerosis, stroke and other degenerative diseases. GLP-1 signalling does not affect blood sugar levels in non-diabetic people and therapies that affect GLP-1 signalling have a good safety profile as shown by the chronic application of drugs currently on the market (liraglutide, Victoza(®); NovoNordisk, Copenhagen, Denmark, and exendin-4, Byetta(®); Amylin, San Diego, CA, USA). Based on the extensive evidence, several clinical trials are currently underway, testing liraglutide and exendin-4 in AD and PD patients. Therefore, GLP-1 analogues show great promise as a novel treatment for AD or other neurodegenerative conditions.

Topics: Animals; Clinical Trials, Phase II as Topic; Glucagon-Like Peptide 1; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Randomized Controlled Trials as Topic; Risk Factors

Multiple sclerosis (MS) is a disabling neurodegenerative disease that causes demyelination and axonal degeneration of the central nervous system. Current treatments are partially effective in managing MS relapses and have a negligible impact on treating MS cognitive deficits and cannot enhance neuronal remyelination, imposing a need for a new MS remedy. Semaglutide, a novel glucagon-like peptide-1 agonist, has recently displayed a neuroprotective effect on several neurodegenerative diseases, suggesting that it may have a protective effect in MS. Therefore, this study was conducted to investigate the influence of semaglutide on experimental autoimmune encephalomyelitis (EAE)-induced MS in mice. Here, EAE was induced in mice using spinal cord homogenate, which eventually altered the mice's cognitive and motor functions, similar to what is observed in MS. Interestingly, intraperitoneally administered semaglutide (25 nmol/kg/day) amended EAE-induced cognitive and motor deficits observed in novel object recognition, open field, rotarod, and grip strength tests. Moreover, histological examination revealed that semaglutide treatment attenuated hippocampal damage and corpus callosum demyelination caused by EAE. Additionally, biochemical testing revealed that semaglutide activates the PI3K/Akt axis, which eventually hampers GSK-3β activity. GSK-3β activity inhibition attenuates demyelination and triggers remyelination through CREB/BDNF; furthermore, it boosts Nrf2 and SOD levels, protecting the mice from EAE-induced oxidative stress. Additionally, GSK-3β inhibition minimizes neuroinflammation, as reflected by decreased NF-kβ and TNF-α levels. In conclusion, semaglutide has a neuroprotective effect in EAE-induced MS in mice, which is mediated by activating the ramified PI3K/Akt/GSK-3β pathway.

Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3 beta; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Neurodegenerative Diseases; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

Obesity is associated with multiple comorbidities, such as metabolic abnormalities and cognitive dysfunction. Moreover, accumulating evidence indicates that neurodegenerative disorders are associated with chronic neuroinflammation. GLP-1 receptor agonists (RAs) have been extensively studied as a treatment for type 2 diabetes. Emerging evidence has demonstrated a protective effect of GLP-1 RAs on neurodegenerative disease, which is independent of its glucose-lowering effects. In this study, we aimed to examine the effects of a long-acting GLP-1 RA, exenatide, on high-fat diet (HFD)-induced neuroinflammation and related brain function impairment. First, mice treated with exenatide exhibited significantly reduced HFD-increased body weight and blood glucose. In an open field test, exenatide treatment ameliorated the reduction in local motor activity and anxiety in HFD-fed mice. Moreover, HFD induced astrogliosis, microgliosis, and upregulation of IL-1β, IL-6 and TNF-α in hippocampus and cortex. Exenatide treatment reduced HFD-induced astrogliosis and IL-1β and TNF-α expressions. Moreover, exenatide increased phosphor-ERK and M2-type microglia marker arginase-1 expression in the hippocampus and cortex. In addition, we found that scavenger receptor-A4 protein expression was induced by HFD and was subsequently inhibited by exenatide. SR-A4 knockout reversed the locomotor activity impairment but not the anxiety behavior caused by HFD consumption. SR-A4 knockout also reduced HFD-induced neuroinflammation, as shown by the reduced expression of GFAP and IBA-1 compared with that in wild-type control mice. These results demonstrate that exenatide decreases HFD-increased neuroinflammation and promotes anti-inflammatory M2 differentiation. The inhibition of SR-A4 by exenatide exerts anti-inflammatory activity.

Topics: Animals; Anxiety; Diabetes Mellitus, Type 2; Diet, High-Fat; Down-Regulation; Exenatide; Gliosis; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Locomotion; Mice; Mice, Inbred C57BL; Microglia; Neurodegenerative Diseases; Neuroinflammatory Diseases; Obesity; Tumor Necrosis Factor-alpha

Parkinson's disease (PD) is the second most common neurodegenerative disease, and no treatment is available to stop its progression. Studies have shown that the colonic pathology of PD precedes that of the brain. The 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model and the human A53T α-synuclein (α-syn) transgenic PD mouse model show colonic pathology and intestinal dopaminergic neuronal damage, which is comparable to the intestinal pathology of PD. Cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), which are brain-gut peptides, have neurotrophic and anti-inflammatory properties. Two GLP-1R agonists have already shown robust effects in phase II trials in PD patients. However, whether they have beneficial effects on colonic pathology in PD remains unclear. In this study, MPTP-treated mice and human A53T α-syn transgenic mice were intraperitoneally injected with a CCK analogue or Liraglutide, a GLP-1 analogue, once a day for 5 weeks. Levels of colonic epithelial tight junction proteins including occludin and zonula occludens-1 (ZO-1), inflammatory biomarkers including inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α), brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH) and α-syn were analyzed. The results show that the CCK analogue and Liraglutide both restored the disruption of intestinal tight junction, reduced colonic inflammation, inhibited colonic dopaminergic neurons reduction and the accumulation of α-syn oligomers in the colon of both PD mice models. This study suggested that CCK or GLP-1 analogues could be beneficial to the improvement of leaky gut barrier, inflammation, dopaminergic neuron impairment and accumulation of α-syn in the colon of PD patients.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Synuclein; Animals; Cholecystokinin; Colon; Disease Models, Animal; Dopaminergic Neurons; Glucagon-Like Peptide 1; Humans; Inflammation; Liraglutide; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurodegenerative Diseases; Parkinson Disease; Tight Junctions

Glucagon-like peptide-1 (GLP-1) is best known for its insulinotropic action following food intake. Its metabolite, GLP-1 (9-36), was assumed biologically inactive because of low GLP-1 receptor (GLP-1R) affinity and non-insulinotropic properties; however, recent studies contradict this assumption. Increased use of FDA approved GLP-1 analogues for treating metabolic disorders and neurodegenerative diseases raises interest in GLP-1 (9-36)'s biological role. We use human SH-SY5Y neuroblastoma cells and a GLP-1R over-expressing variety (#9), in both undifferentiated and differentiated states, to evaluate the neurotrophic/neuroprotective effects of GLP-1 (9-36) against toxic glutamate exposure and other oxidative stress models (via the MTS, LDH or ROS assays). In addition, we examine GLP-1 (9-36)'s signaling pathways, including cyclic-adenosine monophosphate (cAMP), protein kinase-A (PKA), and 5' adenosine monophosphate-activated protein kinase (AMPK) via the use of ELISA, pharmacological inhibitors, or GLP-1R antagonist. Human HMC3 and mouse IMG microglial cell lines were used to study the anti-inflammatory effects of GLP-1 (9-36) against lipopolysaccharide (LPS) (via ELISA). Finally, we applied GLP-1 (9-36) to primary dissociation cultures challenged with α-synuclein or amyloid-β and assessed survival and morphology via immunochemistry. We demonstrate evidence of GLP-1R, cAMP, PKA, and AMPK-mediated neurotrophic and neuroprotective effects of GLP-1 (9-36). The metabolite significantly reduced IL-6 and TNF-α levels in HMC3 and IMG microglial cells, respectively. Lastly, we show mild but significant effects of GLP-1 (9-36) in primary neuron cultures challenged with α-synuclein or amyloid-β. These studies enhance understanding of GLP-1 (9-36)'s effects on the nervous system and its potential as a primary or complementary treatment in pathological contexts.

Topics: Animals; Anti-Inflammatory Agents; Cell Line, Transformed; Cell Line, Tumor; Cells, Cultured; Coculture Techniques; Dose-Response Relationship, Drug; Female; Glucagon-Like Peptide 1; Humans; Mice; Microglia; Neurodegenerative Diseases; Neuroprotective Agents; Pregnancy; Rats; Rats, Sprague-Dawley

Neuroinflammation is a key pathological component of neurodegenerative disease and is characterized by microglial activation and the secretion of proinflammatory mediators. We previously reported that a surge in prostaglandin D. In the current study, we discovered notable neuroinflammation (increased PGD. Our results suggest that neurological phenotypes in GPR120 KO mice are probably caused by dysfunction of intestinal GPR120. These observations raise the possibility that intestinal GLP-1 secretion, stimulated by intestinal GPR120, may remotely contributed to suppress PGD

Topics: Animals; Behavior, Animal; Fatty Acids, Unsaturated; Glucagon-Like Peptide 1; Hippocampus; Liraglutide; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Neurodegenerative Diseases; Neuroinflammatory Diseases; Prostaglandin D2; Receptors, G-Protein-Coupled; Suppression, Genetic

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by the accumulation of extracellular amyloid plaques and intraneuronal neurofibrillary tangles. These tangles mainly consist of hyperphosphorylated tau protein. As it induces tau hyperphosphorylation in vitro and in vivo, hypothermia is a useful tool for screening potential neuroprotective compounds that ameliorate tau pathology. In this study, we examined the effect of prolactin-releasing peptide (PrRP), its lipidized analog palm11-PrRP31 and glucagon-like-peptide-1 agonist liraglutide, substances with anorexigenic and antidiabetic properties, on tau phosphorylation and on the main kinases and phosphatases involved in AD development. Our study was conducted in a neuroblastoma cell line SH-SY5Y and rat primary neuronal cultures under normothermic and hypothermic conditions. Hypothermia induced a significant increase in tau phosphorylation at the pThr212 and pSer396/pSer404 epitopes. The palmitoylated analogs liraglutide and palm11-PrRP31 attenuated tau hyperphosphorylation, suggesting their potential use in the treatment of neurodegenerative diseases.

Topics: Animals; Cell Line; Glucagon-Like Peptide 1; Humans; Hypothermia, Induced; Liraglutide; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Phosphorylation; Prolactin-Releasing Hormone; Rats; tau Proteins

The insulinotropic hormone glucagon-like peptide-1 (7-36)-amide (GLP-1) has potent effects on glucose-dependent insulin secretion, insulin gene expression, and pancreatic islet cell formation and is presently in clinical trials as a therapy for type 2 diabetes mellitus. We report on the effects of GLP-1 and two of its long-acting analogs, exendin-4 and exendin-4 WOT, on neuronal proliferation and differentiation, and on the metabolism of two neuronal proteins in the rat pheochromocytoma (PC12) cell line, which has been shown to express the GLP-1 receptor. We observed that GLP-1 and exendin-4 induced neurite outgrowth in a manner similar to nerve growth factor (NGF), which was reversed by coincubation with the selective GLP-1 receptor antagonist exendin (9-39). Furthermore, exendin-4 could promote NGF-initiated differentiation and may rescue degenerating cells after NGF-mediated withdrawal. These effects were induced in the absence of cellular dysfunction and toxicity as quantitatively measured by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase assays, respectively. Our findings suggest that such peptides may be used in reversing or halting the neurodegenerative process observed in neurodegenerative diseases, such as the peripheral neuropathy associated with type 2 diabetes mellitus and Alzheimer's and Parkinson's diseases. Due to its novel twin action, GLP-1 and exendin-4 have therapeutic potential for the treatment of diabetic peripheral neuropathy and these central nervous system disorders.

Topics: Amino Acid Sequence; Animals; Antimetabolites; Apoptosis; Blotting, Western; Bromodeoxyuridine; Cell Differentiation; Cyclic AMP; DNA Replication; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Immunohistochemistry; L-Lactate Dehydrogenase; Molecular Sequence Data; Nerve Growth Factor; Neurodegenerative Diseases; PC12 Cells; Peptide Fragments; Peptides; Protein Precursors; Rats; Receptors, Glucagon; Stimulation, Chemical; Tetrazolium Salts; Thiazoles; Venoms