glucagon-like-peptide-1 and Cognition-Disorders

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

The incidence of both diabetes mellitus (DM) and dementia increases with aging and the incidence of dementia are higher in people with diabetes. Epidemiological and pathological data suggest that DM contributes to mild cognitive impairment (MCI) and dementia. DM seems to be an independent risk factor for MCI and Alzheimer's disease (AD) and is associated with more rapid cognitive decline. Recent evidence points out that insulin affects central nervous system functions, and can modulate cognitive functions. Impaired insulin signaling and insulin resistance in brain have been found to play an important role in the pathogenesis of AD. Human studies have shown that some oral antidiabetic medications can improve cognition in patients with MCI and AD. Intranasal insulin has also been shown to improve memory and cognitive abilities in MCI and AD patients. While it remains unclear whether management of diabetes will reduce the incidence of MCI and AD, emerging evidence suggests that diabetes therapies may improve cognitive function.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Animals; Clinical Trials as Topic; Cognition Disorders; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Metformin; Middle Aged; Risk Factors; Sulfonylurea Compounds; Thiazolidinediones

Incretins are a group of gastrointestinal hormones detected both peripherally and in the central nervous system (CNS). Recent studies have documented multiple effects of incretins on brain structure and function. Research into the neurological effects of incretins has primarily focused on animal models of neurodegenerative disorders (e.g., Alzheimer's Disease, Huntington's and Parkinson's diseases). Mood disorders (e.g. bipolar disorder (BD), major depressive disorder (MDD)) are associated with similar alterations in brain structure and function, as well as a range of cognitive deficits (e.g. memory, learning, executive function). Brain abnormalities and cognitive deficits are also found in populations with metabolic disorders (e.g., diabetes mellitus Type 2). In addition, individuals with mood disorders often have co-morbid metabolic conditions, thus treatment strategies which can effectively treat both cognitive deficits and metabolic abnormalities represent a possible integrated treatment avenue. In particular, glucagon-like peptide-1 (GLP-1) and its more stable, longer-lasting analogues have been demonstrated to exert neuroprotective and anti-apoptotic effects, reduce beta-amyloid (Aβ) plaque accumulation, modulate long-term potentiation and synaptic plasticity, and promote differentiation of neuronal progenitor cells. In animal models of behaviour, treatment with GLP-1 receptor agonists has been demonstrated to improve measures of cognitive function including learning and memory, as well as reduce depressive behaviour. Available GLP-1 treatments also have a favourable metabolic profile which includes weight loss and reduced risk for hypoglycemia. Systematic evaluation of the effects of GLP-1 treatment in psychiatric populations who evince cognitive deficits represents a promising treatment avenue.

Topics: Cognition Disorders; Glucagon-Like Peptide 1; Humans; Mood Disorders; Neuroprotective Agents

Level of adiposity is linked to manifest dementia and Alzheimer's disease in epidemiological studies. Overweight and obesity in mid- and late-life may increase risk for dementia, whereas decline in body weight or body mass index and underweight in years preceding and at the time of a dementia diagnosis may also relate to dementia. The role of adiposity during the period of cognitive decline is, as yet, not understood; however, some hypotheses relating adipose tissue to brain can be drawn. This review focuses on potential, varied mechanisms whereby adipose tissue may influence or interact with the brain and/or dementia risk during the dynamic period of life characterized by both body weight and cognitive decline. These mechanisms relate to: a) adipose tissue location and cell types, b) body composition, c) endocrine adipose, and d) the interplay among adipose, brain structure and function, and genes. This review will illustrate that adipose tissue is a quintessential, multifunctional tissue of the human body.

Topics: Adiponectin; Adipose Tissue; Adiposity; Body Composition; Body Mass Index; Body Weight; Brain; Cognition Disorders; Cytokines; Dementia; Glucagon-Like Peptide 1; Humans; Leptin

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

Diabetes and psychotic disorders are occasionally comorbid. Possible pathophysiologies linking these disorders include inflammation and oxidative stress. Glucagon like peptide-1 (GLP-1) agonists modulate glucose metabolism and may exert neuroprotective effects via central GLP-1 receptors.. To explore the effects of GLP-1 agonist, liraglutide, on ketamine-induced hyper-locomotion and cognitive dysfunction and the associated inflammation and oxidative stress in normoglycemic and diabetic rats.. Rats were divided into: Chow fed (non-diabetic) and high fat diet fed/STZ (diabetic) groups: I. non-diabetic/control, non-diabetic/liraglutide, non-diabetic/ketamine, non-diabetic/ketamine/liraglutide groups. II. diabetic/control, diabetic/liraglutide, diabetic/ketamine and diabetic/ketamine/liraglutide groups. Hyperlocomotion and cognitive dysfunction were assessed using open field and water maze tests. Biochemical parameters were measured in serum and hippocampus.. Ketamine induced hyperlocomotion and cognitive dysfunction, with hippocampal histopathological changes. Increase in tumour necrosis factor (TNF)-alpha and oxidative stress and reduction in brain-derived neurotrophic factor (BDNF) were noted. These changes were augmented in diabetic compared to non-diabetic rats. Liraglutide significantly improved hyperlocomotion, and cognitive dysfunction and hippocampal histopathological changes in non-diabetic and diabetic rats. Improvement in glucose homeostasis, reduction in TNF alpha and malondialdehyde, and increase in glutathione and BDNF were observed in serum and hippocampus.. Beneficial effects of liraglutide on ketamine-induced hyperlocomotion and cognitive dysfunction are associated with reduction in TNF alpha and oxidative stress. Since effects of liraglutide occurred in diabetic and non-diabetic rats, glycemic and non-glycemic effects (via central GLP-1 receptors) might be involved. Targeting oxidative stress and inflammation by GLP-1 agonists, may be a promising approach in psychotic patients with diabetes.

Topics: Animals; Behavior, Animal; Blood Glucose; Brain-Derived Neurotrophic Factor; Cognition Disorders; Diabetes Mellitus, Experimental; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose; Hippocampus; Hypoglycemic Agents; Inflammation; Insulin; Ketamine; Learning; Liraglutide; Male; Maze Learning; Movement; Oxidative Stress; Psychotic Disorders; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Topics: Amyloid; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Biomarkers; Brain-Derived Neurotrophic Factor; Cognition Disorders; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3 beta; Hippocampus; Insulin-Like Growth Factor I; Kindling, Neurologic; Male; Matrix Metalloproteinase 9; Neural Inhibition; Neurons; Neurotransmitter Agents; Pentylenetetrazole; Rats, Wistar; Receptor for Advanced Glycation End Products; Seizures; Signal Transduction; Sitagliptin Phosphate; Spatial Memory; tau Proteins

Topics: Alzheimer Disease; Animals; Blood Glucose; Body Weight; Cognition Disorders; Disease Models, Animal; Female; Gene Expression; Glucagon-Like Peptide 1; Hippocampus; Long-Term Potentiation; Male; Memory; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Nootropic Agents; Receptors, Gastrointestinal Hormone; Receptors, Glucagon

Glucagon-like peptide-1 (GLP-1) is an incretin hormone shown to be active in the treatment of type-2 diabetes (T2D) and has also been shown as efficacious in Alzheimer's disease (AD). Dipeptidyl peptidase-4 (DPP-4), an enzyme that is expressed in numerous cells, rapidly inactivates endogenous GLP-1. Therefore, DPP-4 inhibition is employed as a therapeutic avenue to increase GLP-1 levels in the management of T2D. The effectiveness of DPP-4 inhibitors in the treatment of AD has been reported in various animal models of AD. With this background, the present study was designed to examine the effectiveness of linagliptin, a DPP-4 inhibitor in the 3xTg-AD mouse model of Alzheimer's disease. Nine-month-old 3xTg-AD mice were administered linagliptin orally (5, 10, and 20 mg/kg) for 8 weeks. At the end of the linagliptin treatment, mice were evaluated for cognitive ability on the Morris Water Maze and Y-maze. Following cognitive evaluation, mice were sacrificed to determine the effect of the linagliptin on brain incretin levels, amyloid burden, tau phosphorylation, and neuroinflammation. We confirm that linagliptin treatment for 8 weeks mitigates the cognitive deficits present in 3xTg-AD mice. Moreover, linagliptin also improves brain incretin levels and attenuates amyloid beta, tau phosphorylation as well as neuroinflammation. In conclusion, linagliptin possesses neuroprotective properties that may be attributed to the improvement of incretin levels in the brain.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood Glucose; Cognition Disorders; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Linagliptin; Maze Learning; Mice; Mice, Transgenic; tau Proteins

Blast traumatic brain injury (B-TBI) affects military and civilian personnel. Presently, there are no approved drugs for blast brain injury.. Exendin-4 (Ex-4), administered subcutaneously, was evaluated as a pretreatment (48 hours) and postinjury treatment (2 hours) on neurodegeneration, behaviors, and gene expressions in a murine open field model of blast injury.. B-TBI induced neurodegeneration, changes in cognition, and genes expressions linked to dementia disorders. Ex-4, administered preinjury or postinjury, ameliorated B-TBI-induced neurodegeneration at 72 hours, memory deficits from days 7-14, and attenuated genes regulated by blast at day 14 postinjury.. The present data suggest shared pathologic processes between concussive and B-TBI, with end points amenable to beneficial therapeutic manipulation by Ex-4. B-TBI-induced dementia-related gene pathways and cognitive deficits in mice somewhat parallel epidemiologic studies of Barnes et al. who identified a greater risk in US military veterans who experienced diverse TBIs, for dementia in later life.

Topics: Animals; Blast Injuries; Brain Concussion; Cognition; Cognition Disorders; Exenatide; Gene Expression; Glucagon-Like Peptide 1; Injections, Subcutaneous; Male; Mice; Mice, Inbred ICR; Neuroprotective Agents; Peptides; Venoms

Sitagliptin, a new antidiabetic drug that inhibits dipeptidyl peptidase (DPP)-4 enzyme activity, has been reported to possess neuroprotective property. We tested the protective effects of sitagliptin against chronic cerebral hypoperfusion (CHP) in mice after bilateral carotid artery stenosis (BCAS).. Thirty C57BL/6 mice were divided into three groups: sham control (n = 10), CHP (n = 10) and CHP-sitagliptin (orally 600 mg/kg/day) (n = 10). Working memory was assessed with novel-object recognition test. MRI was performed at day 0 and day 90 after BCAS procedure prior to sacrifice.. Immunohistochemical (IHC) staining showed significantly enhanced white matter lesions, microglia activation and astrocytosis of white matter in CHP group than in sham control, but the changes were significantly suppressed after sitagliptin treatment (all P < 0.01). The mRNA expressions of inflammatory [tumour necrosis factor-alpha (TNF-α), monocyte chemoattractant protein (MCP-1) and matrix metalloproteinase (MMP)-2] and apoptotic (Bax) biomarkers showed an identical pattern, whereas the anti-inflammatory (interleukin, IL-10) and antiapoptotic (Bcl-2) biomarkers showed an opposite pattern compared with that of IHC among all groups (all P < 0.01). The protein expressions of oxidative stress (NOX-I, NOX-II, nitrotyrosin, oxidized protein), inflammatory [nuclear factor-kappa B (NF-κB), TNF-α and MMP-2], apoptotic [mitochondrial Bax, cleaved poly(ADP-ribose) polymerase (PARP)] and DNA-damage (γ-H2AX) markers showed an identical pattern, while expression pattern of antiapoptotic marker (Bcl-2) was opposite to that of IHC (all P < 0.01). Glycogen-like peptide-1 receptor protein expression progressively increased from sham control to CHP-sitagliptin (P < 0.01). The short-term working-memory loss and MRI/diffusion tensor imaging (DTI) showed a pattern identical to that of IHC in all groups (all P < 0.01).. Sitagliptin protected against cognitive impairment and brain damage in a murine CHP model.

Topics: Animals; Apoptosis; Brain; Brain Ischemia; Cognition Disorders; Drug Evaluation, Preclinical; Glucagon-Like Peptide 1; Hypoglycemic Agents; Inflammation; Interleukin-10; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Random Allocation; Sitagliptin Phosphate; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD), the most common form of dementia, is characterized by the loss of normal functions of brain cells and neuronal death, ultimately leading to memory loss. Recent accumulating evidences have demonstrated the therapeutic potential of anti-diabetic agents, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, for the treatment of Alzheimer's disease (AD), providing opportunities to explore and test the DPP-4 inhibitors for treating this fatal disease. Prior studies determining the efficacy of Pterocarpus marsupium (PM, Fabaceae) and Eugenia jambolana (EJ, Myrtaceae) extracts for ameliorating type 2 diabetes have demonstrated the DPP-4 inhibitory properties indicating the possibility of using of these extracts even for the treating AD. Therefore, in the present study, the neuroprotective roles of PM and EJ for ameliorating the streptozotocin (STZ) induced AD have been tested in rat model. Experimentally, PM and EJ extracts, at a dose range of 200 and 400mg/kg, were administered orally to STZ induced AD Wistar rats and cognitive evaluation tests were performed using radial arm maze and hole-board apparatus. Following 30 days of treatment with the extracts, a dose- and time-dependent attenuation of AD pathology, as evidenced by decreasing amyloid beta 42, total tau, phosphorylated tau and neuro-inflammation with an increase in glucagon-like peptide-1 (GLP-1) levels was observed. Therefore, PM and EJ extracts contain cognitive enhancers as well as neuroprotective agents against STZ induced AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognition Disorders; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Hippocampus; Male; Maze Learning; Neuroprotective Agents; Peptide Fragments; Phosphorylation; Phytotherapy; Plant Preparations; Plaque, Amyloid; Pterocarpus; Rats, Wistar; Streptozocin; Syzygium; tau Proteins; Time Factors

Adults who develop type 2 diabetes (T2D) at later stages are at a higher risk of developing Alzheimer's disease (AD). Pharmacological agents such as dipeptidyl peptidase-4 (DPP-4) inhibitors that increase the levels of glucagon-like peptide-1 (GLP-1) and ameliorate T2D have also become promising candidates as disease-modifying agents in the treatment of AD. The present study investigates the efficacy of vildagliptin, a DPP-4 inhibitor in a streptozotocin (STZ)-induced rat model of AD.. Three months following the induction of AD by intracerebral injection of STZ, animals were orally administered with vildagliptin (2.5, 5 and 10 mg/kg) for 30 days. Dose-dependent and time-course effects of vildagliptin on memory retention were investigated during the course of treatment. Following treatment, the animals were sacrificed, and brain tissues were used to evaluate the effects of vildagliptin on hippocampal and cortical GLP-1 levels, amyloid beta (Aβ) burden, tau phosphorylation and inflammatory markers.. The results reveal a time-dependent improvement in memory retention and a dose-dependent attenuation of Aβ, tau phosphorylation and inflammatory markers and increased GLP-1 levels.. These robust therapeutic effects of vildagliptin demonstrate a unique mechanism for Aβ and tau clearance and reverse the cognitive deficits and pathology observed in AD.

Topics: Adamantane; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognition Disorders; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Hippocampus; Hypoglycemic Agents; Interleukin-1beta; Male; Maze Learning; Nitriles; Pyrrolidines; Rats; Rats, Wistar; Streptozocin; tau Proteins; Tumor Necrosis Factor-alpha; Vildagliptin