glucagon-like-peptide-1 and Cognitive-Dysfunction

Increasing evidence shows a close relationship between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Recently, glucagon-like peptide-1 (GLP-1), a gut incretin hormone, has become a well-established treatment for T2DM and is likely to be involved in treating cognitive impairment. In this mini review, the similarities between AD and T2DM are summarised with the main focus on GLP-1-based therapeutics in AD.

Topics: Alzheimer Disease; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans

The linkage of neurodegenerative diseases with insulin resistance (IR) and type 2 diabetes mellitus (T2DM), including oxidative stress, mitochondrial dysfunction, excessive inflammatory responses and abnormal protein processing, and the correlation between cerebrovascular diseases and hyperglycemia has opened a new window for novel therapeutics for these cognitive disorders. Various antidiabetic agents have been studied for their potential treatment of cognitive disorders, among which the dipeptidyl peptidase-4 (DPP-4) inhibitors have been investigated more recently. So far, DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models, and cognitive benefits in diabetic patients with or without cognitive impairments. This review aims to summarize the potential mechanisms, advantages and limitations, and currently available evidence for developing DPP-4 inhibitors as a treatment of cognitive disorders.

Topics: Animals; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin Resistance

Traditional theories of neuroeconomics focus on reinforcement learning and reward value. We propose here a novel reframing of reinforcement learning and motivation that includes a hippocampal-dependent regulatory mechanism which balances cue-induced behavioral excitation with behavioral inhibition. This mechanism enables interoceptive cues produced by respective food or drug satiety to antagonize the ability of excitatory food- and drug-related environmental cues to retrieve the memories of food and drug reinforcers, thereby suppressing the power of those cues to evoke appetitive behavior. When the operation of this mechanism is impaired, ability of satiety signals to inhibit appetitive behavior is weakened because the relative balance between inhibition and simple excitation is shifted toward increased retrieval of food and drug memories by environmental cues. In the present paper, we (1) describe the associative processes that constitute this mechanism of hippocampal-dependent behavior inhibition; (2) describe how a prevailing obesity-promoting diet and drugs of abuse produce hippocampal pathophysiologies that can selectively impair this inhibitory function; and (3) propose how glucagon-like peptide 1 (GLP-1), an incretin hormone that is recognized as an important satiety signal, may work to protect the hippocampal-dependent inhibition. Our perspective may add to neuroscientific and neuroeconomic analyses of both overeating and drug abuse by outlining the role of hippocampal-dependent memory processes in the control of both food and drug seeking behaviors. In addition, this view suggests that consideration should be given to diet- and drug induced hippocampal pathophysiologies, as potential novel targets for the treatment of dysregulated energy and drug intake.

Topics: Animals; Appetite; Body Weight; Cognition; Cognitive Dysfunction; Cues; Diet, Western; Eating; Feeding Behavior; Female; Glucagon-Like Peptide 1; Hippocampus; Humans; Inhibition, Psychological; Interoception; Liraglutide; Male; Memory; Motivation; Obesity; Reinforcement, Psychology; Reward; Satiation; Substance-Related Disorders

Type 2 diabetes mellitus (T2DM) is a global disease that poses a significant threat to public health. The incidence of both diabetes and dementia has increased simultaneously. Researchers have found that a large proportion of dementia patients have T2DM. In recent years, increasing evidence has demonstrated a link between cognitive decline and T2DM. Although the exact pathogenesis of cognitive impairment in T2DM is still unknown, current studies suggest that hyperglycemia, cerebrovascular disease, brain insulin resistance, and changes in γ-aminobutyric acid (GABAergic) neurons may mediate the association between T2DM and cognitive impairment. These potential mechanisms may become targets for the treatment of cognitive disorders in patients with T2DM. Glucagon-like peptide-1 (GLP-1), a widely used anti-diabetic drug, has been shown to not only effectively lower blood glucose but also improve neurological function. Previous research has confirmed that GLP-1 and its analogues are effective in the treatment of cognitive impairment in patients with T2DM. This review describes current evidence on the mechanisms underlying the association between T2DM and cognitive impairment. In particular, this review focuses on recent advances in GLP-1 and its analogues for the treatment of T2DM-related cognitive impairment.

Topics: Cognitive Dysfunction; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins

Strong preclinical evidence suggests that exenatide, a glucagon-like peptide-1 (GLP- 1) receptor agonist used for treating type 2 diabetes, is neuroprotective and disease-modifying in Alzheimer's Disease (AD).. We performed an 18-month double-blind randomized placebo-controlled Phase II clinical trial to assess the safety and tolerability of exenatide and explore treatment responses for clinical, cognitive, and biomarker outcomes in early AD.. Eighteen participants with high probability AD based on cerebrospinal fluid (CSF) biomarkers completed the entire study prior to its early termination by the sponsor; partial outcomes were available for twentyone.. Exenatide was safe and well-tolerated, showing an expectedly higher incidence of nausea and decreased appetite compared to placebo and decreasing glucose and GLP-1 during Oral Glucose Tolerance Tests. Exenatide treatment produced no differences or trends compared to placebo for clinical and cognitive measures, MRI cortical thickness and volume, or biomarkers in CSF, plasma, and plasma neuronal extracellular vesicles (EV) except for a reduction of Aβ42 in EVs.. The positive finding of lower EV Aβ42 supports emerging evidence that plasma neuronal EVs provide an effective platform for demonstrating biomarker responses in clinical trials in AD. The study was underpowered due to early termination and therefore we cannot draw any firm conclusions. However, the analysis of secondary outcomes shows no trends in support of the hypothesis that exenatide is diseasemodifying in clinical AD, and lowering EV Aβ42 in and of itself may not improve cognitive outcomes in AD.

Topics: Aged; Alzheimer Disease; Biomarkers; Brain; Cognitive Dysfunction; Double-Blind Method; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Male; Neuroprotective Agents; Neuropsychological Tests; Pilot Projects

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cognition; Cognitive Dysfunction; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glucagon-Like Peptide 1; Glucose; Hippocampus; Mice; Mice, Transgenic

DPP-4 inhibitors have been shown to reverse amyloid deposition in Alzheimer's disease (AD) patients with cognitive impairment. Ocimum sanctum L. leaves reported the presence of important phytoconstituents which are reported to have DPP-4 inhibitory activity. To investigate the effects of petroleum ether extract of Ocimum sanctum L. (PEOS) in Intracerebroventricular streptozotocin (ICV-STZ) induced AD rats. ICV-STZ (3 mg/kg) was injected bilaterally into male Wistar rats, while sham animals received the artificial CSF. The ICV-STZ-induced rats were administered with three doses of PEOS (100, 200, and 400 mg/kg, p.o.) for thirty days. All experimental rats were subjected to behaviour parameters (radial arm maze task and novel object recognition test), neurochemical parameters such as GLP-1, Aβ42, and TNF-α levels, and histopathological examination (Congo red staining) of the left brain hemisphere. PEOS significantly reversed the spatial learning and memory deficit exhibited by ICV-STZ-induced rats. Furthermore, PEOS also shows promising results in retreating Aβ deposition, TNF α, and increasing GLP-1 levels. The histopathological study also showed a significant dose-dependent reduction in amyloid plaque formation and dense granule in PEOS -treated rats as compared to the ICV-STZ induced rats (Negative control). The results show that extract of Ocimum sanctum L. attenuated ICV-STZ-induced learning and memory deficits in rats and has the potential to be employed in the therapy of AD.

Topics: Alzheimer Disease; Animals; Cognitive Dysfunction; Congo Red; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glucagon-Like Peptide 1; Inflammation; Male; Maze Learning; Memory Disorders; Ocimum sanctum; Plant Extracts; Rats; Rats, Wistar; Streptozocin; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs.. To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD.. A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers.. DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels.. DA4-JC is a promising drug for the treatment of AD.

Topics: Alzheimer Disease; Animals; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Disease Models, Animal; Disks Large Homolog 4 Protein; Female; Glucagon-Like Peptide 1; Hippocampus; Humans; Long-Term Potentiation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Synapses

Background and aims Advanced glycation end products (AGEs) and receptor of advanced glycation end products (RAGE), are associated with cognition decline. We aim to investigate the effect of liraglutide on cognitive function in diabetic mice. Results Diabetic mice showed decreased cognitive function. Moreover, lower glucagon like peptide-1 (GLP-1) levels in plasma were detected in db/db mice. Additionally, up-regulated RAGE and down-regulated glucagon like peptide-1 (GLP-1R) levels were observed in db/db mice. However, decreased GLP-1R and increased RAGE were reversed by liraglutide. We also found decreased cellular activity in cells with AGEs. Moreover, AGEs up-regulated RAGE in PC12 and HT22 cells. However, liraglutide improved the cell activity damaged by AGEs. Although we did not discover the direct-interaction between RAGE and GLP-1R, elevated RAGE levels induced by AGEs were restored by liraglutide. Conclusion We demonstrated that the cognitive function of diabetic mice was improved by liraglutide via the down-regulation of RAGE. Methods db/db mice and db/m mice were used in this study. Liraglutide was used to remedy diabetic mice. Neurons and RAGE in hippocampus were shown by immunofluorescence. And then, PC12 cells or HT22 cells with AGEs were treated with liraglutide. GLP-1R and RAGE were measured by western blotting.

Topics: Animals; Cell Survival; Cognition; Cognitive Dysfunction; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycation End Products, Advanced; Hippocampus; Hypoglycemic Agents; Liraglutide; Mice; Mice, Obese; Neurons; PC12 Cells; Rats; Receptor for Advanced Glycation End Products

Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonists exhibit neurotrophic and neuroprotective effects. The aim of this study was to explore whether the GLP-1R agonist exendin-4 can alter surgery-induced behavioral deficits and exert neuroprotective effects via the activation of the hippocampal GLP-1/GLP-1R pathway. 120 male Sprague-Dawley rats (aged 18-20 months old) were randomly divided into four groups: control group, exendin-4 group, surgery group, and surgery + exendin-4 group. The animals received either exendin-4 (5 µg/kg/day) or saline intra-peritoneally for 14 days, and then were subjected to partial hepatectomy 24 h after the last injection. Behavioral changes were evaluated with Morris Water Maze and Open field testing on postoperative days 7 and 14. The levels of IL-1β, NF-κB, Iba-1, Synaptophysin, GLP-1/GLP-1R, GSK-3β, p-GSK-3β (Ser9), p-Tau (Ser396), and p-Tau (Ser202/199) in the hippocampus were measured at the same time point. Surgical trauma induced an exacerbated spatial learning and memory impairment, increased the levels of depressive performance, and enhanced hippocampal NF-κB and IL-1β expression in the aged rats on postoperative day 7. A corresponding decline in GLP-1R was also found following surgical challenge on postoperative day 7. Exendin-4 treatment partly reversed surgery-induced postoperative behavioral impairment, downregulated the levels of NF-κB and IL-1β, ameliorated tau hyperphosphorylation and enhanced the activity of p-GSK-3β (Ser9). Together, the downregulation of GLP-1R exacerbated surgery-induced behavior deficits. Exendin-4 treatment attenuated these effects by inhibiting neuroinflammation and tau hyperphosphorylation. These findings suggest that pretreatment with exendin-4 is a potential adjuvant for preventing surgery-induced behavioral deficits.

Topics: Animals; Behavior, Animal; Cognitive Dysfunction; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycogen Synthase Kinase 3 beta; Hepatectomy; Hippocampus; Male; Neuroprotective Agents; NF-kappa B; Postoperative Cognitive Complications; Rats; Rats, Sprague-Dawley; Signal Transduction

Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with insulin resistance and glucose hypometabolism in the brain. Oral administration of galactose, a nutrient that provides an alternative source of energy, prevents and ameliorates early cognitive impairment in a streptozotocin-induced model (STZ-icv) of the sporadic AD (sAD). Here we explored the influence of 2-month oral galactose treatment (200 mg/kg/day) in the familial AD (fAD) by using 5- (5M) and 10- (10M) month-old transgenic Tg2576 mice mimicking the presymptomatic and the mild stage of fAD, and compared it to that observed in 7-month old STZ-icv rats mimicking mild-to-moderate sAD. Cognitive and behavioral performance was tested by Morris Water Maze, Open Field and Elevated Plus Maze tests, and metabolic status by intraperitoneal glucose tolerance test and fluorodeoxyglucose Positron-Emission Tomography scan. The level of insulin, glucagon-like peptide-1 (GLP-1) and soluble amyloid β1-42 (sAβ1-42) was measured by ELISA and the protein expression of insulin receptor (IR), glycogen synthase kinase-3β (GSK-3β), and pre-/post-synaptic markers by Western blot analysis. Although galactose normalized alterations in cerebral glucose metabolism in all Tg2576 mice (5M+2M; 10M+2M) and STZ-icv rats, it did not improve cognitive impairment in either model. Improvement of reduced grooming behavior and normalization in reduced plasma insulin levels were seen only in 5M+2M Tg2576 mice while in 10M+2M Tg2576 mice oral galactose induced metabolic exacerbation at the level of plasma insulin, GLP-1 homeostasis and glucose intolerance, and additionally increased hippocampal sAβ1-42 level, decreased IR expression and increased GSK-3β activity. The results indicate that therapeutic potential of oral galactose seems to depend on the stage and the type/model of AD and to differ in the absence and the presence of AD-like pathology.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cognitive Dysfunction; Fluorodeoxyglucose F18; Functional Neuroimaging; Galactose; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycogen Synthase Kinase 3 beta; Hippocampus; Insulin; Male; Maze Learning; Mice; Mice, Transgenic; Peptide Fragments; Positron-Emission Tomography; Rats; Receptor, Insulin; Streptozocin

The role of mitochondrial dysfunction has been well-documented in Alzheimer's disease (AD). Glucagon-like peptide 1 (GLP-1) receptor agonists are being utilized as neuroprotectants in the treatment of various neurological disorders, including AD. We conducted this study to explore the effects of exenatide (a GLP-1 receptor agonist) on β-amyloid plaque (Aβ)-induced cognitive impairment and mitochondrial dysfunction in 5xFAD transgenic mice. Spatial memory test showed that exenatide administration (100 μg/kg twice per day) prevented cognitive decline after 16 weeks of treatment. Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cognitive Dysfunction; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hippocampus; Male; Memory; Mice; Mice, Inbred Strains; Mice, Transgenic; Mitochondria; Neuroprotective Agents; Plaque, Amyloid; Synapses

Diabetes mellitus can cause cognitive impairments, a state between normal aging and dementia. Effective clinical interventions are urgently needed to prevent or treat this complication. Liraglutide as a glucagon-like peptide 1 analog has been shown to exert memory-enhancing and neuroprotective effects on neurodegenerative diseases. This study aims to investigate the neuroprotective effects of liraglutide in streptozotocin (STZ)-induced diabetic mice with cognitive deficits.. Male C57BL/6J mice were intraperitoneal injected with STZ (65 mg/kg body weight daily for 5 days) to induce type 1 diabetes model. Then the mice were treated with liraglutide (250 mg/kg/day, for 6 weeks) or saline. Weekly changes of body weight and fasting blood glucose were measured. Cognitive performance was evaluated by Morris water maze test. The ultrastructure of hippocampus was observed by transmission electron microscope. The superoxide dismutase activities and malondialdehyde levels in the hippocampus were detected by biochemistry assay. Apoptosis-related proteins and phosphoinositide 3-kinase (PI3K)/protein kinase-B (Akt) signaling were detected by Western blotting.. We found that STZ-induced diabetic mice exhibited impaired learning and memory, ultrastructure damage of hippocampal neurons and synapses, exacerbated oxidative stress and neuronal apoptosis, as compared to the control mice. These effects were attenuated by the treatment with liraglutide. Furthermore, liraglutide reversed diabetes-induced alterations in PI3K/Akt signaling pathway that plays an essential role in modulating neuronal survival, apoptosis and plasticity.. These data suggest that the neuroprotective effects of liraglutide on diabetes-induced cognitive impairments are associated with the improvements of hippocampal synapses and inhibition of neuronal apoptosis.

Topics: Animals; Apoptosis; Blood Glucose; Cognition; Cognitive Dysfunction; Diabetes Complications; Diabetes Mellitus, Experimental; Disease Models, Animal; Glucagon-Like Peptide 1; Hippocampus; Hypoglycemic Agents; Liraglutide; Male; Memory; Mice; Mice, Inbred C57BL; Neurons; Neuroprotection; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Streptozocin; Synapses

Alzheimer's disease (AD) is a multifactorial condition in which, along with amyloid-β (Aβ) and tau-related pathology, the synergistic activity of co-morbidity factors promote the onset and progression of the disease. Epidemiological evidence indicates that glucose intolerance, deficits in insulin secretion, or type-2 diabetes mellitus (T2DM) participate in increasing cognitive impairment or dementia risk. Insulin plays a pivotal role in the process as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a synthetic GLP-1 analog employed in T2DM. However, exenatide has also been shown to affect the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models. In this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. We investigated the effects of exenatide treatment in 3xTg-AD mice challenged with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, Aβ and tau pathology, and cognitive performances. Results of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD without affecting systemic metabolism or promoting changes in cognitive performances.

Topics: Alzheimer Disease; Animals; Brain; Brain-Derived Neurotrophic Factor; Cognitive Dysfunction; Disease Models, Animal; Exenatide; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Mice; Neuroimmunomodulation; Neuronal Plasticity; Neuroprotective Agents; Signal Transduction

Modulation of insulin-dependent signaling is emerging as a valuable therapeutic tool to target neurodegeneration. In the brain, the activation of insulin receptors promotes cell growth, neuronal repair, and protection. Altered brain insulin signaling participates in the cognitive decline seen in Alzheimer's disease patients and the aging brain. Glucagon-like peptide-1 (GLP-1) regulates insulin secretion and, along with GLP-1 analogues, enhances neurotrophic signaling and counteracts cognitive deficits in preclinical models of neurodegeneration. Moreover, recent evidence indicates that GLP-1 modulates the activity of the brain-derived neurotrophic factor (BDNF). In this study, in adult wild-type mice, here employed as a model of mid-life brain aging, we evaluated the effects of a 2-month treatment with exenatide, a GLP-1 analogue. We found that exenatide promotes the enhancement of long-term memory performances. Biochemical and imaging analyses show that the drug promotes the activation of the BDNF-TrkB neurotrophic axis and inhibits apoptosis by decreasing p75NTR-mediated signaling. The study provides preclinical evidence for the use of exenatide to delay age-dependent cognitive decline.

Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Cells, Cultured; Cognition; Cognitive Aging; Cognitive Dysfunction; Exenatide; Female; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Male; Membrane Glycoproteins; Memory, Long-Term; Mice, Inbred Strains; Nootropic Agents; Peptides; Protein-Tyrosine Kinases; Receptor, Insulin; Signal Transduction; Venoms

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. The early primary symptom of AD is the decline of memory ability, which gradually develops into complete dementia. Type 2 diabetes mellitus (T2DM) is an important risk factor of AD; and mimetics of the incretin hormone GLP-1 developed to treat diabetes are being tested as a novel therapeutic strategy for AD. In the present study, we reported for the first time the neuroprotective effects of a novel GLP-1/GIP dual agonist DA5-CH that activates the incretin hormone GLP-1 and GIP receptors in the APP/PS1 transgenic AD mouse model. We found that: (1) DA5-CH administration effectively improved working-memory and long-term spatial memory of 9-month-old AD mice in Y-maze and Morris water maze tests; (2) DA5-CH also reduced hippocampal amyloid senile plaques and phosphorylated tau protein levels; (3) DA5-CH basically reversed the deficits in hippocampal late-phase long-term potentiation; (4) DA5-CH up-regulated the levels of p-PI3K and p-AKT growth factor kinases and prevented excessive activation of p-GSK3β in the hippocampus of APP/PS1 mice. Therefore, the neuroprotection of DA5-CH in alleviating cognitive impairments and pathological damages might be associated with the improvement of hippocampal synaptic plasticity and activation of the PI3K/AKT signaling pathway. We propose that DA5-CH may be beneficial for the treatment of AD patients, especially those with T2DM or hyperglycemia.

Topics: Alzheimer Disease; Animals; Cognition; Cognitive Dysfunction; Disease Models, Animal; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Male; Maze Learning; Memory, Short-Term; Mice; Mice, Transgenic; Peptides; Phosphorylation; Signal Transduction; tau Proteins

To observe the protective effects of potassium channel opener nicorandil against cognitive dysfunction in mice with streptozotocin (STZ)-induced diabetes.. C57BL/6J mouse models of type 1 diabetes mellitus (T1DM) were established by intraperitoneal injection of STZ and received daily treatment with intragastric administration of nicorandil or saline (model group) for 4 consecutive weeks, with normal C57BL/6J mice serving as control. Fasting blood glucose level was recorded every week and Morris water maze was used to evaluate the cognitive behavior of the mice in the 4th week. At the end of the experiment, the mice were sacrificed to observe the ultrastructural changes in the hippocampus and pancreas under transmission electron microscopy; the contents of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the hippocampus and SOD activity and MDA level in the brain tissue were determined.. Compared with the control group, the model group showed significantly increased fasting blood glucose (P<0.001), significantly prolonged escape latency (P<0.05) and increased swimming distance (P<0.01) with ultrastructural damage of pancreatic β cells and in the hippocampus; GIP and GLP-1 contents in the hippocampus (P<0.01) and SOD activity in the brain were significantly decreased (P<0.05) and MDA content was significantly increased in the model group (P<0.05). Compared with the model group, nicorandil treatment did not cause significant changes in fasting blood glucose, but significantly reduced the swimming distance (P<0.05); nicorandil did not improve the ultrastructural changes in pancreatic β cells but obviously improved the ultrastructures of hippocampal neurons and synapses. Nicorandil also significantly increased the contents of GIP and GLP-1 in the hippocampus (P<0.05), enhanced SOD activity (P<0.05) and decreased MDA level (P<0.01) in the brain tissue.. Nicorandil improves cognitive dysfunction in mice with STZ-induced diabetes by increasing GIP and GLP-1 contents in the hippocampus and promoting antioxidation to relieve hippocampal injury.

Topics: Animals; Blood Glucose; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Hippocampus; Insulin-Secreting Cells; Malondialdehyde; Mice; Mice, Inbred C57BL; Nicorandil; Streptozocin; Superoxide Dismutase

To reveal potential association between glucagon-like peptide 1 (GLP-1) concentration in serum and mild cognitive function impairment (MCI) in type 2 diabetes mellitus (T2DM) patients.. A total of 106 T2DM patients and 47 normal controls were recruited in this study. Montreal Cognitive Assessment (MoCA) was performed in all subjects. Among the 106 patients, 52 presented with MCI. Fasting blood glucose (FBG), total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C), triglyceride (TG), uric acid (UA) and GLP-1 levels were also assessed in all subjects.. Patients with MCI had higher serum concentrations of FBG and TC and lower concentrations of GLP-1 and HDL-C than controls. Bivariate correlation analysis showed that MCI in T2DM patients closely correlated with FBG, HDL-C, and GLP-1 levels. Moreover, ordinal regression analysis showed that GLP-1 concentration in serum was protective for MCI in T2DM patients (OR = 0.025; 95%CI: 0.005-3.934).. Our results indicated that low concentration of GLP-1 may play a role in the pathogenesis of MCI in T2DM patients.

Topics: Adult; Biomarkers; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Risk Factors

In a recent study, we demonstrated the potential of a cell-penetrating peptide (CPP) penetratin to deliver the peptide drug insulin to the brain via nasal administration, and its pharmacological effect on the mild cognitive dysfunction in senescence-accelerated mouse (SAMP8). However, the therapeutic potential of intranasal insulin administration was attenuated when applied to the aged SAMP8 with severe cognitive dysfunction. The present study, therefore, aimed to overcome the difficulty in treating severe cognitive dysfunction using insulin by investigating potential alternatives, glucagon-like peptide-1 (GLP-1) receptor agonists such as exendin-4. Examination using normal ddY mice demonstrated that the distribution of exendin-4 throughout the brain was dramatically increased by intranasal coadministration with the L-form of penetratin. The activation of hippocampal insulin signaling after the simultaneous nose-to-brain delivery of exendin-4 and an adequate level of insulin were confirmed by analyzing the phosphorylation of Akt. Furthermore, spatial learning ability, evaluated in the Morris water maze test after daily administration of exendin-4 with L-penetratin and supplemental insulin for 4 weeks, suggested therapeutic efficacy against severe cognitive dysfunction. The present study suggests that nose-to-brain delivery of exendin-4 with supplemental insulin, mediated by CPP coadministration, shows promise for the treatment of progressive cognitive dysfunction in SAMP8.

Topics: Administration, Intranasal; Amyloid beta-Peptides; Animals; Brain; Cell-Penetrating Peptides; Cognitive Dysfunction; Drug Carriers; Exenatide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Male; Memory Disorders; Mice; Signal Transduction

BACKGROUND Glucagon-like peptide-1 (GLP-1) has been reported to exert some beneficial effects on the central nervous system (CNS). However, the effect of GLP-1 on cognitive impairment associated with type 2 diabetes is not well known. This study investigated the effect of GLP-1 on ameliorating memory deficits in type 2 diabetic rats. MATERIAL AND METHODS Type 2 diabetic rats were induced by a high-sugar, high-fat diet, followed by streptozotocin (STZ) injection and then tested in the Morris Water Maze (MWM) 1 week after the induction of diabetes. The mRNA expression of Arc, APP, BACE1, and PS1 were determined by real-time quantitative PCR, and the Arc protein was analyzed by immunoblotting and immunohistochemistry. RESULTS Type 2 diabetic rats exhibited a significant decline in learning and memory in the MWM tests, but GLP-1 treatment was able to protect this decline and significantly improved learning ability and memory. The mRNA expression assays showed that GLP-1 treatment markedly reduced Arc, APP, BACE1, and PS1 expressions, which were elevated in the diabetic rats. Immunoblotting and immunohistochemistry results also confirmed that Arc protein increased in the hippocampus of diabetic rats, but was reduced after GLP-1 treatment. CONCLUSIONS Our findings suggest that GLP-1 treatment improves learning and memory deficits in type 2 diabetic rats, and this effect is likely through the reduction of Arc expression in the hippocampus.

Topics: Animals; Blood Glucose; Cognitive Dysfunction; Cytoskeletal Proteins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Glucagon-Like Peptide 1; Hippocampus; Male; Maze Learning; Memory Disorders; Nerve Tissue Proteins; Rats; Rats, Sprague-Dawley