Comparing regional brain uptake of incretin receptor agonists after intranasal delivery in CD-1 mice and the APP/PS1 mouse model of Alzheimer’s disease DOI Creative Commons
Noor Abdulhameed,

Alice Babin,

Kim M. Hansen

et al.

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: Aug. 1, 2024

Abstract Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer’s disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven reverse BIR improve cognition in mouse models AD. We previously showed that many, but not all, IRAs can cross blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread uptake could be achieved by circumventing BBB using intranasal (IN) delivery, which added advantage minimizing adverse gastrointestinal effects systemically delivered IRAs. Of 5 radiolabeled tested (exenatide, dulaglutide, semaglutide, DA4-JC, DA5-CH) CD-1 mice, exenatide, DA4-JC were successfully distributed throughout following IN observed significant sex differences DA4-JC. Dulaglutide exhibited high hippocampus multiple neocortical areas. further found presence AD-associated Aβ pathology minimally affected dulaglutide IRAs, are best capable accessing regions most vulnerable AD (neocortex hippocampus) administration. Future studies will need performed determine IRA delivery reduce animal disorder.

Language: Английский

Mapping the effectiveness and risks of GLP-1 receptor agonists DOI Creative Commons
Yan Xie,

Taeyoung Choi,

Ziyad Al‐Aly

et al.

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 20, 2025

Language: Английский

Citations

15
The pharmacodynamics-based prophylactic benefits of GLP-1 receptor agonists and SGLT2 inhibitors on neurodegenerative diseases: evidence from a network meta-analysis DOI Creative Commons
Ping‐Tao Tseng,

Bing‐Yan Zeng,

Chih-Wei Hsu

et al.

BMC Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 6, 2025

Abstract Background Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors represent a new generation of antihyperglycemic agents that operate through mechanisms distinct from conventional diabetes treatments. Beyond their metabolic effects, these medications have demonstrated neuroprotective properties in preclinical studies. While clinical trials explored therapeutic potential established neurodegenerative conditions, role disease prevention remains unclear. We conducted network meta-analysis (NMA) to comprehensively evaluate the prophylactic benefits across multiple diseases identify most promising preventive strategies. Methods systematically searched PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ProQuest, ScienceDirect, Web Science, ClinicalTrials.gov October 24th, 2024, for randomized controlled (RCTs) GLP-1 or SGLT2 inhibitors. Our primary outcome was incidence seven major diseases: Parkinson’s disease, Alzheimer’s Lewy body dementia, sclerosis, amyotrophic lateral frontotemporal Huntington’s disease. Secondary outcomes included safety profiles assessed dropout rates. performed frequentist-based NMA evaluated risk bias with Risk Bias tool. The main result current study would be re-affirmed via sensitivity test Bayesian-based NMA. Results analysis encompassed 22 RCTs involving 138,282 participants (mean age 64.8 years, 36.4% female). Among all investigated medications, only dapagliflozin significant benefits, specifically preventing (odds ratio = 0.28, 95% confidence intervals 0.09 0.93) compared controls. Neither nor other showed effects any conditions. Drop-out rates were comparable Conclusions This comprehensive reveals novel specific effect against representing breakthrough neurology. specificity dapagliflozin’s protective might rely on its highly selective inhibition SGLT2. These findings provide important direction future research could inform strategies populations at Trial registration PROSPERO CRD42021252381.

Language: Английский

Citations

1
Sweet Solutions: Unlocking the Diabetes-Dementia Connection for Better Outcomes DOI Creative Commons

Emőke Pósán

Journal of Insurance Medicine, Journal Year: 2025, Volume and Issue: 52(1), P. 14 - 20

Published: March 6, 2025

Type 2 diabetes and Alzheimer's dementia represent important health challenges in our society today. Understanding the relationship between these conditions is crucial. This article explores research on whether they share common risk factors or if may influence each other's development, which could lead to more effective prevention treatment strategies.

Language: Английский

Citations

0
Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway DOI Creative Commons
Yanyu Zhai, Kaili Lu, Yuan Yuan

et al.

Journal of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

Background Alzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting function. However, research about mechanism semaglutide as a therapeutic intervention in AD is sparse. Objective This study was to investigate efficacy transgenic mouse model pathology explored detailed by modulated neuroinflammatory processes. Methods Male amyloid precursor protein/presenilin 1 (APP/PS1) mice were treated with or vehicle for 8 weeks. Morris water maze test used assess recognition Pathology analysis performed detect deposition plaques. High-throughput sequencing applied specify mechanism. Microglia astrocyte activation assessed immunofluorescent staining. Inflammation cytokine levels evaluated enzyme-linked immunosorbent assay (ELISA). Related proteins pathway western blot. Results Semaglutide treatment attenuated Aβ accumulation enhanced APP/PS1 mice. Through transcriptomic profiling, immunohistochemical staining, ELISA, substantiated inhibit overactivation microglia astrocytes, well curtail secretion inflammatory mediators. Furthermore, robustly activated AMP-activated protein kinase (AMPK) suppressed toll-like 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing dampening cascade. Conclusions The results demonstrated that mitigated neuroinflammation decelerated advance

Language: Английский

Citations

0
GLP-1/Sigma/RAGE receptors: An evolving picture of Alzheimer's disease pathology and treatment DOI

Neha Neha,

Zitin Wali,

Pinky Pinky

et al.

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 93, P. 102134 - 102134

Published: Nov. 25, 2023

Language: Английский

Citations

7
Beyond blood sugar: exploring the anti-inflammatory frontier of antidiabetic medications to alleviate diabetic complications DOI Creative Commons
khalil Amjad Hadid, Fawaz A. Alassaf, Mohammed N. Abed

et al.

Romanian Journal of Medical Practice, Journal Year: 2024, Volume and Issue: 19(1), P. 92 - 99

Published: March 31, 2024

Background and objective. Inflammation is closely correlated with diabetes diabetic complications. Research has shown that individuals exhibit an upregulation of circulatory proinflammatory cytokines, resulting in a chronic state low-grade inflammation. The participation inflammation the pathogenesis complications, particularly cardiovascular renal well-established. Targeting may produce prominent effects improving clinical condition patients, reducing progression promoting glucose uptake by insulin-sensitive tissues. This review article aimed to explore anti-inflammatory effect antidiabetics beyond their hypoglycemic action potential such Materials methods. Based on relevant online publications using terms anti-diabetics, anti-inflammatory, inflammatory mediators up February 2024 PubMed Google Scholar were utilized construct this review. Results. majority antidiabetic drugs pose indirect through hypogly­cemic effect. However, many have additional mechanism independently effects, which augments effects. Conclusion. Suppression response anti-diabetics achieving homeostatic control effective approach for preventing

Language: Английский

Citations

2
Incretin-Based Multi-Agonist Peptides Are Neuroprotective and Anti-Inflammatory in Cellular Models of Neurodegeneration DOI Creative Commons
Katherine O. Kopp, Yazhou Li, Elliot J. Glotfelty

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(7), P. 872 - 872

Published: July 19, 2024

Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) are widely used to treat type 2 diabetes mellitus (T2DM) obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors ("multi-agonists"), including glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) glucagon (Gcg) (GcgR), emerged with aim enhancing drug benefits. In this study, we utilized human mouse microglial cell lines, HMC3 IMG, respectively, together neuroblastoma SH-SY5Y line as cellular models neurodegeneration. Using these studied neuroprotective anti-inflammatory capacity several multi-agonists in comparison a single GLP-1 (GLP-1R) agonist, exendin-4. Our data demonstrate that two selected GLP-1R/GIPR dual agonists GLP-1R/GIPR/GcgR triple agonist not only neurotrophic effects but also anti-neuroinflammatory properties, indicated decreased cyclooxygenase (COX2) expression, nitrite production, pro-inflammatory cytokine release. addition, our results indicate potential outperform commercially available GLP-1R neurodegenerative disease treatment.

Language: Английский

Citations

2
Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, anti-diabetic drugs in heart failure and cognitive impairment: potential mechanisms of the protective effects DOI Creative Commons
Maria Antonietta Riemma, Elena Mele, Maria Donniacuo

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: June 14, 2024

Heart failure and cognitive impairment emerge as public health problems that need to be addressed due the aging global population. The conditions often coexist are strongly related advancing age multimorbidity. Epidemiological evidence indicates cardiovascular disease neurodegenerative processes shares similar aspects, in term of prevalence, distribution, mortality. Type 2 diabetes increasingly represents a risk factor associated not only cardiometabolic pathologies but also neurological conditions. pathophysiological features type its metabolic complications (hyperglycemia, hyperinsulinemia, insulin resistance) play crucial role development progression both heart dysfunction. This connection has opened potential new strategy, which classes anti-diabetic medications, such glucagon-like peptide-1 receptor (GLP-1R) agonists sodium-glucose cotransporter (SGLT2) inhibitors, able reduce overall events neuronal damage, showing additional protective effects beyond glycemic control. pleiotropic GLP-1R SGLT2 inhibitors have been extensively investigated. They exert direct indirect cardioprotective neuroprotective actions, by reducing inflammation, oxidative stress, ions overload, restoring signaling. Nonetheless, specificity pathways their contribution fully elucidated, this underlines urgency for more comprehensive research.

Language: Английский

Citations

2
Dipeptidyl peptidase-4 inhibitors alleviate cognitive dysfunction in type 2 diabetes mellitus DOI Creative Commons

Jie Meng,

Rui Yan, Chen Zhang

et al.

Lipids in Health and Disease, Journal Year: 2023, Volume and Issue: 22(1)

Published: Dec. 11, 2023

Patients with type 2 diabetes mellitus (T2DM) are commonly at high risk for developing cognitive dysfunction. Antidiabetic agents might be repurposed targeting dysfunction in addition to modulation on glucose homeostasis. This study aimed evaluate the impact of dipeptidyl peptidase-4 inhibitors (DPP-4i) function T2DM.PubMed, Embase, Cochrane Library and Web Science were systematically searched from inception September 30, 2023. Weighted mean differences calculated using Mantel-Haenszel (M-H) fixed or random effects model based degree heterogeneity among studies. Heterogeneity was evaluated a Chi-squared test quantified Higgins I2. Sensitivity analysis performed leave-one-out method, publication bias according Begg's Egger's tests.Six clinical trials involving 5,178 participants included pooled analysis. Administration DPP-4i generally correlated an increase Mini-Mental State Examination (MMSE) scores (1.09, 95% CI: 0.22 1.96). alleviated impairment copying skill subdomain MMSE (0.26, 0.12 0.40). Treatment also resulted Instrumental Activities Daily Living (IADL) (0.82, 0.30 1.34). However, produced no significant Barthel (BADL) (0.37, -1.26 1.99) other scores.DPP-4i treatment favourably improved patients T2DM. Further larger samples should confirm these estimates investigate association different diabetic patients.CRD42023430873.

Language: Английский

Citations

5
The Association of Circulating Glucagon-Like Peptide-1 with Cognitive Functions and Biomarkers in Alzheimer’s Disease DOI

Mengqing Liu,

Nenghong Ma,

Xiao Yang

et al.

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 99(2), P. 525 - 533

Published: April 26, 2024

Background: Alzheimer’s disease (AD) is an age-related neurodegenerative that clinically characterized by progressive cognitive decline. Glucagon-like peptide-1 (GLP-1) a hormone belongs to the incretin family and released in response nutrient intake. It plays role maintaining metabolic homeostasis has been suggested be involved brain microenvironment. However, of GLP-1 AD pathogenesis not fully illustrated. Objective: This study aims investigate clinical relevance effects amyloid-β (Aβ) metabolism vitro. Methods: In this study, 39 patients 120 cognitively intact controls were included. Plasma levels measured using ELISA. SH-SY5Y cells overexpressing human amyloid precursor protein (APP) treated with GLP-1. Western blot analysis was used assess on Aβ. Results: decreased aging. lower comparison healthy older adults. positively associated Mini-Mental State Examination scores but negatively plasma pTau181 levels. dose-dependently increased area fraction mitochondrial staining Furthermore, promoted α-cleavage APP, thus reducing generation Conclusions: neuroprotective AD, therefore decrease during aging might contribute development AD.

Language: Английский

Citations

1