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Histological assessment of hippocampal CA1 pyramidal neuron numbers. Brains were sampled in the horizontal plane using systematic uniform random sampling to ensure representation of the entire hippocampus. The major subfields of the mouse hippocampus are indicated in panel A (2x magnification). Panel B shows the border between CA1 and CA2. The CA1 region (Giemsa stained) was delineated on average in 8 sections per animal using a 10x objective based on cell morphology (B). CA1 pyramidal neurons are smaller and more densely organized than CA2 neurons (C; white arrows = CA1 pyramidal neuron, black arrows = CA2 pyramidal neuron; 40x magnification).
Source publication
Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor agonists, currently used in the management of type 2 diabetes, exhibit neurotrophic and neuroprotective effects in amyloid-β (Aβ) toxicity models of Alzheimer's disease (AD). We investigated the potential pro-cognitive and neuroprotective effects of the once-daily GLP-1 receptor...
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1 Introduction
The combination of GLP‐1 receptor agonists and insulin is effective in type 2 diabetes (T2D) treatment. However, its longitudinal efficacy and safety in elderly patients have not been established. We evaluated whether liraglutide (Lira) added to insulin therapy safely improved glycaemic control in T2D patients aged >65 years.
2 Meth...
To evaluate whether liraglutide or roflumilast significantly affects body weight when compared to metformin in obese women with PCOS.
A 12-week prospective randomized open-label study was conducted with 45 obese women with PCOS diagnosed by the ASRM-ESHRE Rotterdam criteria. They were randomized to metformin (MET) 1000 mg BID or liraglutide (LIRA)...
Aims
To evaluate the long‐term cost‐effectiveness of IDegLira (fixed‐ratio combination insulin degludec/liraglutide) versus comparator regimens for type 2 diabetes in Spain based on real‐world evidence.
Materials and Methods
Clinical data were taken from the European Xultophy Treatment Retrospective Audit (EXTRA) real‐world evidence study in which...
Objectives: To study the possible anti-seizure and neuroprotective effect of glucagon like peptide 1 (GLP1) analogue (liraglutide) in a pentylenetetrazole (PTZ) induced kindled rat model and its underlying mechanisms. Methods: Thirty Sprague Dawley rats were allocated into 3 equal groups; i) Normal group: normal rats received normal saline, ii) PTZ...
Citations
... Hippocampal neuronal loss, especially in the CA1 region, is closely associated with diabetic cognitive dysfunction (Hansen et al. 2015). To further confirm the neuroprotective effects of Art on T2DM mice, neuronal cell injury and loss were assessed by H&E staining. ...
... The pathological injury and loss of neurons in the hippocampus, especially in the CA1 region, play a critical role in diabetes-associated cognitive impairment (da Costa et al. 2013;Hansen et al. 2015;Sima and Li 2005). Due to the protective effects of Art on hippocampal neurons, this agent in ameliorating diabetic cognitive deficits has gradually received attention (Poorgholam et al. 2023). ...
Background
Neuronal ferroptosis plays a critical role in the pathogenesis of cognitive deficits. The present study explored whether artemisinin protected type 2 diabetes mellitus (T2DM) mice from cognitive impairments by attenuating neuronal ferroptosis in the hippocampal CA1 region.
Methods
STZ-induced T2DM mice were treated with artemisinin (40 mg/kg, i.p.), or cotreated with artemisinin and Nrf2 inhibitor MEL385 or ferroptosis inducer erastin for 4 weeks. Cognitive performance was determined by the Morris water maze and Y maze tests. Hippocampal ROS, MDA, GSH, and Fe ²⁺ contents were detected by assay kits. Nrf2, p-Nrf2, HO-1, and GPX4 proteins in hippocampal CA1 were assessed by Western blotting. Hippocampal neuron injury and mitochondrial morphology were observed using H&E staining and a transmission electron microscope, respectively.
Results
Artemisinin reversed diabetic cognitive impairments, decreased the concentrations of ROS, MDA and Fe ²⁺ , and increased the levels of p-Nr2, HO-1, GPX4 and GSH. Moreover, artemisinin alleviated neuronal loss and ferroptosis in the hippocampal CA1 region. However, these neuroprotective effects of artemisinin were abolished by Nrf2 inhibitor ML385 and ferroptosis inducer erastin.
Conclusion
Artemisinin effectively ameliorates neuropathological changes and learning and memory decline in T2DM mice; the underlying mechanism involves the activation of Nrf2 to inhibit neuronal ferroptosis in the hippocampus.
Graphical Abstract
... The administration of GLP-1R agonists into the hippocampus prevents learning and memory impairment caused by the administration of amyloid β [75]. GLP-1R agonists, when administered to mice, reduce the progression of Alzheimer's disease (AD) [76,77]. In asthma, a glucose transport across the BBB is reduced, and a 6-month administration of liraglutide in asthma patients largely neutralized this process [78]. ...
Modern approaches to the treatment of type 2 diabetes mellitus (T2DM) are aimed not only at glycemic control, but also at reducing cardiovascular risks. The increasing prevalence of the disease and the need for effective treatment options highlight the importance of glucagon-like peptide-1 (GLP-1) receptor agonists in the pharmacotherapy structure.
The aim of the work was to review the literature regarding the physiology of GLP-1 and the therapeutic potential and development trends of its agonists.
Materials and methods. The search for the review materials was carried out using the abstract databases of PubMed, Google Scholar and e-Library. The search was carried out for publications from 2000 to 2023, using the following keywords: “GLP-1”; “GLP-1R agonists”; “GIP”; “exenatide”; “liraglutide”; “dulaglutide”; “semaglutide”; “lixisenatide”; “albiglutide”; “taspoglutide” taking into account various spellings.
Results. The interaction of almost all food components with enteroendocrine cells of the intestine leads to the secretion of incretins (primarily GLP-1) into the blood, triggering a complex of physiological reactions aimed primarily at the rapid utilization of incoming glucose (regulation of insulin and glucagon secretion), as well as the central regulation of dietary behavior (slowing gastric emptying and the formation of a feeling of satiety). A wide distribution of the GLP-1 receptor in various tissues and organs, its connection with intracellular signaling cascades aimed at launching energy-consuming remodeling (recovery) processes in endothelial cells, heart, neurons, beta cells, etc., is the basis for a wide range of pleiotropic effects of GLP-1 unrelated to its hypoglycemic effect. The discovery of synthetic GLP-1 receptor agonists with a long period of action has made it possible not only to therapeutically influence various parts of carbohydrate metabolism disorders, but also to increase the functional reserves of the target diabetes organs, reducing the risk of developing complications of the disease. Incretin-like drugs are well tolerated, with nausea being the most common side effect. The factors limiting a wider use of the drugs include their high cost and the preferred form of a subcutaneous solution. The current research is focused on the development of long-acting, oral, dual and triple agonists, fixed-dose combinations, and small molecule drugs.
Conclusion. GLP-1 receptor agonists are a class of effective and safe drugs for the treatment of diabetes and obesity, which is rapidly developing in the most advanced areas of pharmacy. A further development of this group and the solution of the identified problems will open up new opportunities for the treatment of diabetes and its complications.
... There was also rescued cognition in APP/PS1xdb/db mice, as was demonstrated by the new object demonstration test (p < 0.001) and the Morris water maze (p < 0.001) [100]. A number of other animal studies have been conducted, clearly delineating the positive effect of LRGT on AD pathology [101][102][103]. ELAD, Evaluation of Liraglutide in the treatment of Alzheimer's Disease, was a phase IIb double blinded, randomized, placebo-controlled trial conducted in multiple centers in the UK, where 204 adults with mild to moderate AD received subcutaneous injections of either LRGT or placebo once daily for 12 months [104]. ...
Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are chronic, progressive disorders affecting the elderly, which fosters global healthcare concern with the growing aging population. Both T2DM and AD have been linked with increasing age, advanced glycosylation end products, obesity, and insulin resistance. Insulin resistance in the periphery is significant in the development of T2DM and it has been posited that insulin resistance in the brain plays a key role in AD pathogenesis, earning AD the name “type 3 diabetes”. These clinical and epidemiological links between AD and T2DM have become increasingly pronounced throughout the years, and serve as a means to investigate the effects of antidiabetic therapies in AD, such as metformin, intranasal insulin, incretins, DPP4 inhibitors, PPAR-γ agonists, SGLT2 inhibitors. The majority of these drugs have shown benefit in preclinical trials, and have shown some promising results in clinical trials, with the improvement of cognitive faculties in participants with mild cognitive impairment and AD. In this review, we have summarize the benefits, risks, and conflicting data that currently exist for diabetic drugs being repurposed for the treatment of AD.
... Liraglutide also improved memory retention in the SAMP8 mouse, a mouse model of accelerated aging and sporadic AD. This model demonstrated a liraglutide-dependent increase in the number of CA1 pyramidal neurons in the hippocampus region implicated in human memory loss [65]. In an in vitro model of beta-amyloid toxicity in neurons, treatment with semaglutide reversed the negative effects of beta-amyloid on cell viability by increasing the expression of an anti-apoptotic effector, Bcl-2, and decreasing the expression of pro-apoptotic effector, Bax. ...
Glucagon-like peptide-1 receptor agonists (GLP1RA) have been transformative for patients and clinicians in treating type-2 diabetes and obesity. Drugs of this class, the bioavailability of which is continuously improving, enable weight loss and control blood glucose with minimal unwanted side effects. Since adopting GLP1RA for treating metabolic diseases, animal and clinical studies have revealed their beneficial effects on several other pathologies, including cardiovascular diseases, neurodegeneration, kidney disease, and cancer. A notable commonality between these diseases is their association with older age. Clinical trials and preclinical data suggest that GLP1RA may improve outcomes in these aging-related diseases. Some of the benefits of GLP1RA may be indirect due to their effects on obesity and glucose metabolism. However, there is building evidence that GLP1RA may also act directly on multiple organs implicated in aging-related pathology. This review aims to compile the studies reporting the effects of GLP1RA on aging-related diseases and discuss potential underlying mechanisms.
... (1) Protection against metabolic and oxidative trauma in Parkinson's disease and stroke [33] (2) Protection of neurons against the lack of oxygen and glucose with antiapoptotic mechanism [34] (3) Prevention against cell death in traumatic brain damage and correction of cognitive deficits [35] (4) Restoring of behavioral disorders occurring upon traumatic brain damage [36] (5) Prevention of hippocampal gene expression changes induced by traumatic brain damage or such changes in Alzheimer's disease (AD) [37,38] (6) Prevention of blood-brain barrier impairment occurring upon traumatic brain damage and also of cortical neuronal damage [36] (7) Correction of neurological function disorders due to tauopathy [39] (8) Correction of memory related to the increase of the neuron count in hippocampal CA1 region in AD. [40] Moreover, numerous studies in the literature have reported the neuroprotective effects of GLP-1 agonists. ...
Objective
The aim of this study is to present the expressions of Calreticulin (CALR) and Glucagon-like peptide-1 (GLP-1) in high-grade gliomas and to further show the relation between the levels of these molecules and Ki-67 index, presence of Isocitrate dehydrogenase (IDH)-1 mutation, and tumor grade.
Patients and Methods
A total of 43 patients who underwent surgical resection due to high-grade gliomas (HGG) (grades III and IV) were included. The control group comprised 27 people who showed no gross pathology in the brain during the autopsy procedures. Adequately sized tumor samples were removed from each patient during surgery, and cerebral tissues were removed from the control subjects during the autopsy procedures. Each sample was stored at −80°C as rapidly as possible until the enzyme assay.
Results
Patients with high-grade gliomas showed significantly higher levels of CALR and significantly lower levels of GLP-1 when compared to control subjects ( P = 0.001). CALR levels were significantly higher, GLP-1 levels were significantly lower in grade IV gliomas than those in grade III gliomas ( P = 0.001). Gliomas with negative IDH-1 mutations had significantly higher CALR expressions and gliomas with positive IDH-1 mutations showed significantly higher GLP-1 expressions ( P = 0.01). A positive correlation between Ki-67 and CALR and a negative correlation between Ki-67 and GLP-1 expressions were observed in grade IV gliomas ( P = 0.001).
Conclusions
Our results showed that higher CALR and lower GLP-1 expressions are found in HGGs compared to normal cerebral tissues.
... It also reduces chronic inflammation and increases long-term potentiation (LTP) in Alzheimer's mice model (McClean et al. 2010(McClean et al. , 2011(McClean et al. , 2015. In addition, treatment with Liraglutide significantly increases memory retention and total hippocampal CA1 pyramidal neuron numbers (Hansen et al. 2015). In the hyperhomocysteinemia rat model, Liraglutide reduced tau hyperphosphorylation and Aβ overproduction, which may alleviate AD-like cognitive impairment . ...
Alzheimer’s disease (AD) and Type 2 diabetes mellitus (T2DM) are two of the most common age-related diseases. There is accumulating evidence of an overlap in the pathophysiological mechanisms of these two diseases. Studies have demonstrated insulin pathway alternation may interact with amyloid-β protein deposition and tau protein phosphorylation, two essential factors in AD. So attention to the use of anti-diabetic drugs in AD treatment has increased in recent years. In vitro, in vivo, and clinical studies have evaluated possible neuroprotective effects of anti-diabetic different medicines in AD, with some promising results. Here we review the evidence on the therapeutic potential of insulin, metformin, Glucagon-like peptide-1 receptor agonist (GLP1R), thiazolidinediones (TZDs), Dipeptidyl Peptidase IV (DPP IV) Inhibitors, Sulfonylureas, Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors, Alpha-glucosidase inhibitors, and Amylin analog against AD. Given that many questions remain unanswered, further studies are required to confirm the positive effects of anti-diabetic drugs in AD treatment. So to date, no particular anti-diabetic drugs can be recommended to treat AD.
... 100 In addition, liraglutide improved memory function in a model of senescence-accelerated mouse-prone 8 (SAMP8) mice, which naturally occurrs in mice that displays a phenotype of accelerated ageing. 101 In this model, liraglutide delayed the ageassociated progressive decline in spatial memory function associated with hippocampal neuronal loss. Compared with age-matched vehicledosed SAMP8 mice, liraglutide also significantly increased the number and the density of cornu ammonis 1 (CA1; Latin for 'horn shaped)' pyramidal neurons, which appear to be critical for object differentiation in long-term memory. ...
... Hippocampal neurons are, therefore, preserved in these mice with AD treated with liraglutide. 101 Other preclinical studies showed that liraglutide prevents key neurodegenerative developments found in AD. 90,92 Evidence from clinical trials In a pilot study where liraglutide was administered in people with longstanding AD (n=18), no difference in terms of cognition or Aβ deposition was found compared with those on placebo (n=20) after 26 weeks. 102 The individuals in this clinical assay were not diabetic. ...
From an epidemiological and pathophysiological point of view, Alzheimer’s disease (AD) and type 2 diabetes (T2DM) should be considered 'sister' diseases. T2DM significantly increases the risk of developing AD, and the mechanisms of neuronal degeneration themselves worsen peripheral glucose metabolism in multiple ways. The pathophysiological links between the two diseases, particularly cerebral insulin resistance, which causes neuronal degeneration, are so close that AD is sometimes referred to as 'type 3 diabetes'. Although the latest news on the therapeutic front for AD is encouraging, no treatment has been shown to halt disease progression permanently. At best, the treatments slow down the progression; at worst, they are inactive, or cause worrying side effects, preventing their use on a larger scale. Therefore, it appears logical that optimizing the metabolic milieu through preventive or curative measures can also slow down the cerebral degeneration that characterizes AD. Among the different classes of hypoglycaemic drugs, glucagon-like peptide 1 receptor agonists, which are widely used in the treatment of T2DM, were shown to slow down, or even prevent, neuronal degeneration. Data from animal, preclinical, clinical phase II, cohort and large cardiovascular outcomes studies are encouraging. Of course, randomized clinical phase III studies, which are on-going, will be essential to verify this hypothesis. Thus, for once, there is hope for slowing down the neurodegenerative processes associated with diabetes, and that hope is the focus of this review.
... 28 According to a mouse model of AD, treatment with the GLP-1 analog liraglutide can prevent the progression of memory decline. 29 Another recent study found that liraglutide can reduce associated brain complications when T2DM and AD occur simultaneously. 30 In 2019, Femminella et al. conducted the Evaluating Liraglutide in Alzheimer's Disease (ELAD) study to assess the effect of the novel GLP-1 analog liraglutide on AD, but they have not yet published their conclusions. ...
Background:
Alzheimer's disease (AD) is the most common type of dementia. At present, some drug and non-drug therapies can be used to slow disease progression or prevent cognitive deterioration. More treatment options still need to be explored.
Objectives:
A meta-analysis was performed to compile the relevant evidence for the use of glucagon-like peptide-1 (GLP-1) receptor agonists in preventing AD.
Material and methods:
We systematically searched English and Chinese databases, including Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, and Weipu website (VIP), based on the PICOS (Participants, Interventions, Comparisons, Outcomes, Study design) principles. The reviewers evaluated the search results and conducted the analysis; 5 articles with a total sample size of 184 patients were included. Changes in cognitive function, body mass index (BMI), blood glucose level, and insulin content were analyzed.
Results:
A low risk of bias and no publication bias were found in these studies. The following results were obtained: 1) cognitive function: mean difference (MD) = 2.16, 95% confidence interval (95% CI): 1.45-2.88; 2) BMI change: MD = -1.16, 95% CI: -1.71--0.61; and 3) blood glucose change: standard MD (SMD) = -0.64, 95% CI: -1.21--0.88. No statistically significant difference was found in insulin content.
Conclusion:
In this review, we showed that GLP-1 receptor agonists can effectively change cognitive function, BMI and blood glucose levels in patients with AD. This provides relevant clues for the prevention of AD. However, more studies are needed to refine these conclusions.
... It was suggested in Porter et al.'s study that Liraglutide administration improves cognitive function by increasing the number of hippocampal CA1 neurons in the mouse model of Alzheimer's disease [16]. The effects of Liraglutide on learning and memory have also been reported in a mouse model of Alzheimer's disease after four weeks of treatment [47]. Another study showed that GLP-1R knockout mice demonstrated decreased learning-memory performance and LTP in the hippocampal CA1 region during novel object recognition and MWM [48]. ...
Glucagon-like peptide 1 (GLP-1) agonists are among the agents that can be used to treat type 2 diabetes mellitus, and they have also been reported to have neuroprotective effects. This study examined the effects of GLP-1 agonist Liraglutide on CREB, BDNF, Trk-B expression and emotional/cognitive behaviors in an experimental schizophrenia-like behavior model induced by MK-801. MK-801 (0.25 mg/kg, 0.1 ml/kg body weight) and/or Liraglutide (300 mcg/kg) were injected intraperitoneally once a day for 7 weeks into 8-10 weeks old male Balb/c mice (n = 78). Mice were randomly divided into 5 groups: Saline+Saline, MK-801 +Saline, Liraglutide+Saline, MK-801 +Liraglutide co-treatment, and Liraglutide+MK-801 co-treatment. A Morris water maze test, an elevated plus maze test, and an open field test were performed after injection. Western blots were performed on mice' hippocampus and PFC for BDNF, Trk-B, CREB, and p-CREB expression. Our study found that MK-801 impaired emotional and cognitive functions in mice. MK-801 administration did not affect Liraglutide's positive effects on spatial learning and memory activity in the Liraglutide+MK-801 group. Liraglutide administration (Liraglutide+MK-801 group) improved the BDNF/Trk-B and p-CREB/CREB ratio in the hippocampus, and the p-CREB/CREB ratio in the PFC to the control group level. The negative effects of MK-801 on cognitive behavior were not reversed by Liraglutide in the MK-801 +Liraglutide group. In conclusion, Liraglutide does not affect NMDA receptor blockade-induced emotional and cognitive behaviors. However, it has a protective effect against cognitive impairment. Furthermore, it is possible that the GLP-1 receptors in the hippocampus and PFC are involved in the modulation of NMDA receptor activity through CREB activation/deactivation.
... The pathogenesis of AD has also been associated with a decreased expression of GLUT1, the major glucose transporter in the BBB. Liraglutide, a GLP1 analog, has showed to delay memory decline in a mouse model of AD (Hansen et al., 2015). Recently, it was demonstrated that the same drug slowed down memory decline in a group of patients with obesity and type 2 diabetes (Vadini et al., 2020) and more recently, GLP1 receptor agonists were shown to prevent glucose transport decline through BBB in AD patients, although no conclusions were drawn on cognitive decline (Gejl et al., 2016). ...
The existence of a selective blood-brain barrier (BBB) and neurovascular coupling are two unique central nervous system vasculature features that result in an intimate relationship between neurons, glia, and blood vessels. This leads to a significant pathophysiological overlap between neurodegenerative and cerebrovascular diseases. Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease whose pathogenesis is still to be unveiled but has mostly been explored under the light of the amyloid-cascade hypothesis. Either as a trigger, bystander, or consequence of neurodegeneration, vascular dysfunction is an early component of the pathological conundrum of AD. The anatomical and functional substrate of this neurovascular degeneration is the BBB, a dynamic and semi-permeable interface between blood and the central nervous system that has consistently been shown to be defective. Several molecular and genetic changes have been demonstrated to mediate vascular dysfunction and BBB disruption in AD. The isoform ε4 of Apolipoprotein E is at the same time the strongest genetic risk factor for AD and a known promoter of BBB dysfunction. Low-density lipoprotein receptor–related protein 1 (LRP-1), P-glycoprotein, and receptor for advanced glycation end products (RAGE) are examples of BBB transporters implicated in its pathogenesis due to their role in the trafficking of amyloid-β. This disease is currently devoid of strategies that change the natural course of this burdening illness. This unsuccess may partly be explained by our misunderstanding of the disease pathogenesis and our inability to develop drugs that are effectively delivered to the brain. BBB may represent a therapeutic opportunity as a target itself or as a therapeutic vehicle. In this review, we aim to explore the role of BBB in the pathogenesis of AD including the genetic background and detail how it can be targeted in future therapeutic research.
