exenatide and Cognitive-Dysfunction

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

Large numbers of people with type 2 diabetes are obese. However, changes in cognition and related brain function in obese people with diabetes have not been characterized. Here, we investigated cognition, olfactory function, and odor-induced brain alterations in these patients and therapeutic effects of glucagon-like peptide 1 receptor agonists (GLP-1Ras) on their psychological behavior and olfactory networks.. Cognitive, olfactory, and odor-induced brain activation assessments were administered to 35 obese and 35 nonobese people with type 2 diabetes and 35 control subjects matched for age, sex, and education. Among them, 20 obese individuals with diabetes with inadequate glycemic control and metformin monotherapy received GLP-1Ra treatment for 3 months and were reassessed for metabolic, cognitive, olfactory, and neuroimaging changes.. Obese subjects with diabetes demonstrated lower general cognition and olfactory threshold scores, decreased left hippocampal activation, and disrupted seed-based functional connectivity with right insula compared with nonobese subjects with diabetes. Negative associations were found between adiposity and episodic memory and between fasting insulin and processing speed test time in diabetes. Mediation analyses showed that olfactory function and left hippocampus activation mediated these correlations. With 3-month GLP-1Ra treatment, obese subjects with diabetes exhibited improved Montreal Cognitive Assessment (MoCA) score, olfactory test total score, and enhanced odor-induced right parahippocampus activation.. Obese subjects with type 2 diabetes showed impaired cognition and dysfunctional olfaction and brain networks, the latter of which mediated adiposity in cognitive impairment of diabetes. GLP-1Ras ameliorated cognitive and olfactory abnormalities in obese subjects with diabetes, providing new perspectives for early diagnosis and therapeutic approaches for cognitive decrements in these patients.

Topics: Adiposity; Adult; Aged; Blood Glucose; Brain; Cognition; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Exenatide; Female; Functional Neuroimaging; Glucagon-Like Peptide-1 Receptor; Humans; Insulin; Liraglutide; Magnetic Resonance Imaging; Male; Metformin; Middle Aged; Obesity; Olfaction Disorders; Olfactory Perception; Smell

Schizophrenia is associated with profound cognitive and psychosocial impairments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for diabetes and obesity treatment, and animal studies have indicated cognitive-enhancing effects. In this investigator-initiated, double-blind, randomized, placebo-controlled trial, we tested non-metabolic effects of exenatide once-weekly (Bydureon™) in obese, antipsychotic-treated patients with schizohrenia spectrum disorder.. Before and after 3 months of exenatide (N = 20) or placebo (N = 20) treatment, patients were assessed with the following: Brief Assessment of Cognition in Schizophrenia (BACS), Rey-Osterreith complex figure test (REY), Short-Form Health Survey (SF-36), Personal and Social Performance Scale (PSP) and the Positive and Negative Syndrome Scale (PANSS). We used BACS composite score as the main outcome measure.. Repeated measures analysis of variance on BACS composite score showed significant effect of 'Time' (P < 0.001), no effect of 'Group' (P = 0.64) and no 'Time*Group' interaction (P = 0.77). For REY, SF-36, PSP and PANSS, only significant 'Time' effects were found.. The non-significant results of this first clinical trial exploring non-metabolic effects of a long-acting GLP-1RA in patients with schizophrenia could reflect a general problem of translating cognitive-enhancing effects of GLP-1RAs from animals to humans or be explained by factors specifically related to schizophrenia spectrum patients with obesity such as antipsychotic treatment.

Topics: Adult; Aged; Antipsychotic Agents; Cognitive Dysfunction; Comorbidity; Delayed-Action Preparations; Double-Blind Method; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Male; Middle Aged; Obesity; Peptides; Schizophrenia; Treatment Failure; Venoms; Young Adult

Type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD). Exendin-4 (Ex-4), a widely used glucagon-like peptide-1 receptor agonist drug in the treatment of T2D, has been demonstrated the therapeutic effects on diabetic encephalopathy (DE). Especially, the Ex-4 ameliorates the tau hyperphosphorylation and cognitive impairment in DE. And these crucial alterations are also important bridge between T2D and AD. However, its unique mechanism is unclear.. The db/db mice, high-fat-diet (HFD) / streptozotocin (STZ)-induced diabetic (HF-diabetic) mice, and high-glucose-damaged (HGD) HT-22 hippocampal cells were enrolled to examine the effects of Ex-4 on AD-like changes in T2D. The Novel object recognition test (NORT) and Morris water maze test (MWMT) were conducted to evaluate the cognitive impairment. The Dickkopf-1 (DKK1) was employed to weaken the activation of the Wnt/β-catenin pathway to explore the mechanism of Ex-4 in protecting the brain functions. The JASPAR was based to predict the interaction between NeuroD1 and the promoter region of Ins2. Moreover, the chromatin immunoprecipitation coupled with quantitative polymerase chain reaction (ChIP-qPCR) and luciferase reporter assays were performed.. Ex-4 alleviated the tau hyperphosphorylation, increased the brain-derived insulin, and improved the PI3K/AKT/GSK3-β signalling in db/db mice, HF-diabetic mice, and HGD HT-22 hippocampal neuronal cells. The NORT and MWMT indicated that Ex-4 alleviated the learning and memory deficits in HF-diabetic mice. The inhibitor Dickkopf-1 (DKK1) of the Wnt/β-catenin pathway significantly blocked the protective effects of Ex-4. Regarding further molecular mechanisms, NeuroD1 was affected by Ex-4 in vivo and in vitro, and the knockdown or overexpression of NeuroD1 suggested its crucial role in promoting the brain insulin by Ex-4. Meanwhile, the ChIP‒qPCR and luciferase reporter assays confirmed the combination between NeuroD1 and the promoter region of the insulin-encoding gene Ins2. And this interaction could be promoted by Ex-4.. Our study proposes that Ex-4 alleviates tau hyperphosphorylation and cognitive dysfunction by increasing Ins2-derived brain insulin through the Wnt/β-catenin/NeuroD1 signaling in T2D. And its also show new lights on part of the progress and mechanism on treatment targets for the DE in T2D.

Topics: Alzheimer Disease; Animals; beta Catenin; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Exenatide; Glycogen Synthase Kinase 3; Insulin; Mice; Phosphatidylinositol 3-Kinases

Exenatide could reduce blood glucose and alleviate cognitive dysfunction induced by diabetes mellitus (DM). In the present study, a diabetic model was established in Sprague‑Dawley rats to further explore the mechanism of exenatide on diabetes‑induced cognitive impairment. Notably, the model rats performed poorly in the Morris water maze test and had more apoptotic neurons compared with the control rats. By contrast, exenatide attenuated cognitive impairment and inhibited neuronal apoptosis in the DM rat model. To explore the neuroprotective mechanisms of exenatide, western blotting was performed to detect the expression levels of markers of endoplasmic reticulum stress, including cytochrome c (Cyt‑c), Caspase‑3, JNK and c‑JUN, in hippocampal tissue. Reverse transcription‑quantitative PCR was also performed to measure the mRNA expression levels of Cyt‑c and Caspase‑3. After 16 weeks of treatment, exenatide treatment downregulated Cyt‑c, Caspase‑3, phosphorylated (p)‑JNK and p‑c‑JUN expression in the hippocampal tissue of diabetic rats. Moreover, Cyt‑c, Caspase‑3, JNK and JUN expression levels were detected following treatment with a specific inhibitor of JNK (SP600125). The results revealed that SP600125 had similar inhibitory effects on the JNK pathway and ERS‑related protein expression (Cyt‑t, Caspase‑3, p‑JNK and p‑c‑JUN). These results suggested that exenatide improved cognitive dysfunction in DM rats and that the underlying mechanism may be associated with inhibiting apoptosis by suppressing the activation of JNK/c‑JUN.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Caspase 3; Cognitive Dysfunction; Cytochromes c; Diabetes Mellitus, Experimental; Exenatide; Genes, jun; Hippocampus; Insulin; Learning; Male; MAP Kinase Signaling System; Memory; Neurons; Neuroprotective Agents; Rats, Sprague-Dawley

The activation of the glucagon-like peptide-1 receptor (GLP-1R) has been purported to have antidepressant-like and cognitive-enhancing effects. Many people suffering from major depressive disorder (MDD) also experience deficits in cognition. While currently approved antidepressant pharmacotherapies can alleviate the mood symptoms in some patients, they do not treat the cognitive ones.. We tested whether systemic administration of a GLP-1R agonist would alter location discrimination, a cognitive task that is diminished in humans with MDD.. Male and female laboratory mice (6-8 weeks old, N = 6-14/sex) were trained in a touchscreen operant task of location discrimination. Upon reaching baseline criterion, mice were administered vehicle or a GLP-1R agonist, Exendin-4, systemically prior to testing in probe trials of varying difficulty.. Following GLP-1R activation, males showed modest yet non-significant performance in the location discrimination task. Females, however, showed enhanced performance during the most difficult probe tests following Exendin-4 administration.. GLP-1R activation appears to enhance overall performance in the location discrimination task and does so in a sex- and difficulty-dependent manner. These preliminary yet impactful data indicate that GLP-1R agonists may be useful as an adjunctive pharmacotherapy to treat cognitive deficits associated with MDD and/or multiple neurological disorders.

Topics: Animals; Cognition; Cognitive Dysfunction; Depressive Disorder, Major; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Male; Mice; Sex Factors

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 a progressive neurodegenerative disorder characterized by memory loss, disorientation and gradual deterioration of intellectual ability. In the pharmacotherapy of AD, the mitochondrial protective activity of Exendin-4 in experimental studies is yet to be established though its effectiveness is demonstrated in these patients. Therefore, the mitochondria protective activity of Exendin-4 (5 μg/kg, i.p.) was investigated in hippocampus and pre-frontal cortex (PFC) of AD-like animals. The amyloid beta (Aβ) was injected through bilateral intracerebroventricular route into lateral ventricles to induce AD-like manifestations in the male rats. Exendin-4 significantly attenuated Aβ-induced memory-deficits in the Morris water maze and Y-maze test protocols. Exendin-4 significantly decreased Aβ-induced increase in the level of Aβ in both brain regions. Exendin-4 significantly increased Aβ-induced decrease in acetylcholine level and activity of cholineacetyl transferase in all brain regions. Moreover, Exendin-4 significantly decreased Aβ-induced increase in the activity of acetylcholinestrase in both the brain regions. E4 significantly increased Aβ-induced decrease in mitochondrial function, integrity, respiratory control rate and ADP/O in all brain regions. Further, Exendin-4 significantly decreased Aβ-induced increase in the mitochondrial complex enzyme-I, IV and V activities in all brain regions. Furthermore, Exendin-4 significantly increased Aβ-induced decrease in the level of phosphorylated Akt and the ratio of phosphorylated Akt to Akt in both brain regions. However, LY294002 diminished the therapeutic effects of Exendin-4 on behavioral, biochemical and molecular observations in AD-like animals. Pearson's analysis showed that the attributes of mitochondrial dysfunction (MMP and RCR) exhibited significant correlation to the loss in memory formation, level of Aβ and cholinergic dysfunction in these animals. Thus, it can be speculated that Exendin-4 may mitigate AD-like manifestations including mitochondrial toxicity perhaps through PI3K/Akt-mediated pathway in the experimental animals. Hence, Exendin-4 could be a potential therapeutic alternative candidate in the management of AD.

Topics: Amyloid beta-Peptides; Animals; Brain; Cognitive Dysfunction; Exenatide; Injections, Intraventricular; Male; Maze Learning; Mitochondria; Peptide Fragments; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Signal Transduction

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

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

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

Mild blast traumatic brain injury (B-TBI) induced lasting cognitive impairments in novel object recognition and less severe deficits in Y-maze behaviors. B-TBI significantly reduced the levels of synaptophysin (SYP) protein staining in cortical (CTX) and hippocampal (HIPP) tissues. Treatment with exendin-4 (Ex-4) delivered by subcutaneous micro-osmotic pumps 48 hours prior to or 2 hours immediately after B-TBI prevented the induction of both cognitive deficits and B-TBI induced changes in SYP staining. The effects of a series of biaxial stretch injuries (BSI) on a neuronal derived cell line, HT22 cells, were assessed in an in vitro model of TBI. Biaxial stretch damage induced shrunken neurites and cell death. Treatment of HT22 cultures with Ex-4 (25 to 100 nM), prior to injury, attenuated the cytotoxic effects of BSI and preserved neurite length similar to sham treated cells. These data imply that treatment with Ex-4 may represent a viable option for the management of secondary events triggered by blast-induced, mild traumatic brain injury that is commonly observed in militarized zones.

Topics: Animals; Blast Injuries; Brain Injuries, Traumatic; Cell Line; Cognitive Dysfunction; Disease Models, Animal; Exenatide; Hippocampus; Male; Mice; Synaptophysin