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

GLP-1 Receptor Agonists: A New Treatment in Parkinson’s Disease DOI Open Access
Kallirhoe Kalinderi, Vasileios Papaliagkas,

Liana Fidani

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3812 - 3812

Published: March 29, 2024

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Recent data highlight similarities between diseases, including PD and type 2 diabetes mellitus (T2DM), suggesting a crucial interplay gut–brain axis. Glucagon-like peptide-1 receptor (GLP-1R) agonists, known for their use in T2DM treatment, are currently extensively studied as novel modifying agents. For this narrative review article, we searched PubMed Scopus databases peer-reviewed research, articles clinical trials regarding GLP-1R agonists published English language with no time restrictions. We also screened references selected possible additional order to include key recent evidence. Many on animal models preclinical studies show that GLP1-R can restore dopamine levels, inhibit dopaminergic loss, attenuate neuronal degeneration alleviate motor non-motor features PD. Evidence from very promising, enhancing possibility adding current armamentarium drugs available treatment.

Language: Английский

Citations

18
Exenatide once a week versus placebo as a potential disease-modifying treatment for people with Parkinson's disease in the UK: a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial DOI Creative Commons
Nirosen Vijiaratnam, Christine Girges,

Grace Auld

et al.

The Lancet, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

GLP-1 receptor agonists have neurotrophic properties in in-vitro and in-vivo models of Parkinson's disease results epidemiological studies small randomised trials suggested possible benefits for risk progression disease. We aimed to establish whether the agonist, exenatide, could slow rate did a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial at six research hospitals UK. Participants were aged 25-80 years with diagnosis disease, Hoehn Yahr stage 2·5 or less when on dopaminergic treatment, treatment least 4 weeks before enrolment. randomly assigned (1:1) using web-based system minimisation according study site receive extended-release exenatide 2 mg by subcutaneous pen injection once per week over 96 weeks, visually identical placebo. All participants all team members sites masked randomisation allocation. The primary outcome was Movement Disorder Society-sponsored revision Unified Disease Rating Scale (MDS-UPDRS) part III score, off medication analysed intention-to-treat population linear mixed modelling approach. This is registered ISRCTN (14552789), EudraCT (2018-003028-35), ClinicalTrials.gov (NCT04232969). Between Jan 23, 2020, April 2022, 215 screened eligibility, whom 194 (n=97) placebo (n=97). 56 (29%) female 138 (71%) male. 92 group had one follow-up visit included analyses. At MDS-UPDRS OFF-medication scores increased (worsened) mean 5·7 points (SD 11·2) group, 4·5 11·4) (adjusted coefficient effect 0·92 [95% CI -1·56 3·39]; p=0·47). Nine (9%) serious adverse event compared 11 (11%) group. Our findings suggest that safe well tolerated. found no evidence support as disease-modifying people Studies agents show better target engagement specific subgroups patients are needed there any use National Institute Health Care Research Cure Parkinson's.

Language: Английский

Citations

8
Glucose-dependent insulinotropic polypeptide (GIP) DOI Creative Commons
Timo D. Müller, Alice E. Adriaenssens,

Bo Ahrén

et al.

Molecular Metabolism, Journal Year: 2025, Volume and Issue: 95, P. 102118 - 102118

Published: Feb. 28, 2025

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in maintenance of glucose tolerance healthy humans. Until recently GIP had not been developed as a therapeutic thus has overshadowed by other incretin, glucagon-like peptide 1 (GLP-1), which is basis for several successful drugs to treat diabetes obesity. However, there rekindling interest biology recent years, great part due pharmacology demonstrating that both GIPR agonism antagonism may be beneficial treating obesity diabetes. This apparent paradox reinvigorated field, led new lines investigation, deeper understanding GIP. In this review, we provide detailed overview on multifaceted nature discuss implications signal modification various diseases. Following its classification hormone, emerged pleiotropic hormone with variety metabolic effects outside endocrine pancreas. The numerous render interesting candidate development pharmacotherapies obesity, diabetes, drug-induced nausea bone neurodegenerative disorders.

Language: Английский

Citations

2
Exploring the Potential Impact of GLP-1 Receptor Agonists on Substance Use, Compulsive Behavior, and Libido: Insights from Social Media Using a Mixed-Methods Approach DOI Creative Commons
Davide Arillotta, Giuseppe Floresta,

Guy Pelletier

et al.

Brain Sciences, Journal Year: 2024, Volume and Issue: 14(6), P. 617 - 617

Published: June 20, 2024

Glucagon-like peptide-1 (GLP-1) is involved in a range of central and peripheral pathways related to appetitive behavior. Hence, this study explored the effects glucagon-like receptor agonists (GLP-1 RAs) on substance behavioral addictions, including alcohol, caffeine, nicotine, cannabis, psychostimulants, compulsive shopping, sex drive/libido. Data were collected from various social platforms. Keywords GLP-1 RAs substance/behavioral addiction used extract relevant comments. The employed mixed-methods approach analyze online discussions posted December 2019 June 2023 using specialized web application. Reddit entries focus here due limited data other platforms, such as TikTok YouTube. A total 5859 threads comments extracted six subreddits, which included about drugs associated brand names. To obtain posts, keywords potential use behavior selected. Further analysis two main steps: (1) manually coding posts based users’ references impact non-substance habits, excluding irrelevant or unclear comments; (2) performing thematic dataset keywords, AI-assisted techniques followed by manual revision generated themes. Second, was performed keyword-related dataset, In total, 29.75% alcohol-related; 22.22% caffeine-related; 23.08% nicotine-related clearly stated cessation intake these substances following start prescription. Conversely, mixed results found for cannabis intake, only limited, anecdotal made available cocaine, entactogens, dissociative drugs’ misuse. Regarding 21.35% reported shopping interruption, whilst sexual drive/libido elements reportedly increased several users. current appeared be useful tool gaining insight into complex topics addiction-related disorders; some RA-related mental health benefits could also inferred here. Overall, it that may show target both craving maladaptive/addictive behaviors, although further empirical research needed.

Language: Английский

Citations

12
Peptides Are Cardioprotective Drugs of the Future: The Receptor and Signaling Mechanisms of the Cardioprotective Effect of Glucagon-like Peptide-1 Receptor Agonists DOI Open Access
Alla A. Boshchenko, Л. Н. Маслов, А. V. Mukhomedzyanov

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4900 - 4900

Published: April 30, 2024

The high mortality rate among patients with acute myocardial infarction (AMI) is one of the main problems modern cardiology. It quite obvious that there an urgent need to create more effective drugs for treatment AMI than those currently used in clinic. Such could be enzyme-resistant peptide analogs glucagon-like peptide-1 (GLP-1). GLP-1 receptor (GLP1R) agonists can prevent ischemia/reperfusion (I/R) cardiac injury. In addition, chronic administration GLP1R alleviate development adverse remodeling infarction, hypertension, and diabetes mellitus. protect heart against oxidative stress reduce proinflammatory cytokine (IL-1β, TNF-α, IL-6, MCP-1) expression myocardium. stimulation inhibits apoptosis, necroptosis, pyroptosis, ferroptosis cardiomyocytes. activation augments autophagy mitophagy downregulate reactive species generation through Epac GLP1R/PI3K/Akt/survivin pathway. GLP1R, kinases (PKCε, PKA, Akt, AMPK, PI3K, ERK1/2, mTOR, GSK-3β, PKG, MEK1/2, MKK3), enzymes (HO-1 eNOS), transcription factors (STAT3, CREB, Nrf2, FoxO3), KATP channel opening, MPT pore closing are involved cardioprotective effect agonists.

Language: Английский

Citations

11
Type 2 diabetes mellitus/obesity drugs: A neurodegenerative disorders savior or a bridge too far? DOI
Katherine O. Kopp, Elliot J. Glotfelty, Yazhou Li

et al.

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 98, P. 102343 - 102343

Published: May 16, 2024

Language: Английский

Citations

8
Exploring the Role of GLP-1 Receptor Agonists in Alzheimer’s Disease: A Review of Preclinical and Clinical Evidence DOI Creative Commons
Lívia Cristina Ribeiro Teixeira, Marcelo R. Luizon, Karina Braga Gomes

et al.

Receptors, Journal Year: 2025, Volume and Issue: 4(1), P. 2 - 2

Published: Jan. 26, 2025

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including dulaglutide, liraglutide, semaglutide, and exenatide, are effective treatments for type 2 diabetes mellitus (T2DM) obesity. These agents mimic the action of endogenous incretin glucagon-like (GLP-1) by enhancing insulin secretion, inhibiting glucagon release, promoting weight loss through appetite suppression. GLP-1RAs have recently been suggested to neuroprotective effects, suggesting their potential as treatment neurodegenerative disorders, such Alzheimer’s disease (AD). AD T2DM share several common pathophysiological mechanisms, resistance, chronic inflammation, oxidative stress, mitochondrial dysfunction. shared mechanisms suggest that therapeutic targeting metabolic dysfunction may also be beneficial conditions. Preclinical studies on in models, both vitro vivo, demonstrated promising reductions amyloid-beta accumulation, decreased tau hyperphosphorylation, improved synaptic plasticity, enhanced neuronal survival. Despite encouraging results from preclinical challenges need addressed before can widely used treatment. Ongoing clinical trials investigating cognitive benefits patients, aiming establish role a option AD. This review aimed examine current literature GLP-1

Language: Английский

Citations

1
Neuropsychiatric adverse events associated with Glucagon-like peptide-1 receptor agonists: a pharmacovigilance analysis of the FDA Adverse Event Reporting System database DOI Creative Commons
Wenchao Lu, Shihan Wang, Huilin Tang

et al.

European Psychiatry, Journal Year: 2025, Volume and Issue: 68(1)

Published: Jan. 1, 2025

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used due to their profound efficacy in glycemic control and weight management. Real-world observations have revealed potential neuropsychiatric adverse events (AEs) associated with GLP-1RAs. This study aimed comprehensively investigate characterize these AEs Methods We analyzed GLP-1RA reaction reports using the FDA Adverse Event Reporting System database. Disproportionality analysis reporting odds ratio (ROR) identified eight categories of conducted descriptive time-to-onset (TTO) analyses explored AE signals among individual GLP-1RAs for loss diabetes mellitus (DM) indications. Results 25,110 cases GLP-1RA-related AEs. showed an association headache (ROR 1.74, 95% confidence interval [CI] 1.65–1.84), migraine 1.28, 95%CI 1.06–1.55), olfactory sensory nerve abnormalities 2.44, 1.83–3.25; ROR 1.69, 1.54–1.85). Semaglutide a moderate suicide-related signal population 2.55, 1.97–3.31). The median TTO was 16 days (interquartile range: 3–66 days). Conclusions In this study, we and, first time, detected positive migraine, abnormalities, abnormalities. also observed semaglutide, population. provides reliable basis further investigation However, as exploratory our findings require confirmation through large-scale prospective studies.

Language: Английский

Citations

1
Tirzepatide shows neuroprotective effects via regulating brain glucose metabolism in APP/PS1 mice DOI
Shaobin Yang,

Xiaoqian Zhao,

Yimeng Zhang

et al.

Peptides, Journal Year: 2024, Volume and Issue: 179, P. 171271 - 171271

Published: July 11, 2024

Language: Английский

Citations

7
IUPHAR review – Glucagon-like peptide-1 (GLP-1) and substance use disorders: An emerging pharmacotherapeutic target DOI Creative Commons

Nicolaus Bruns,

Elizabeth H. Tressler,

Leandro F. Vendruscolo

et al.

Pharmacological Research, Journal Year: 2024, Volume and Issue: 207, P. 107312 - 107312

Published: July 18, 2024

Addiction is a chronic relapsing disease with high morbidity and mortality. Treatments for addiction include pharmacological psychosocial interventions; however, currently available medications are limited in number efficacy. The glucagon-like-peptide-1 (GLP-1) system emerging as potential novel pharmacotherapeutic target alcohol other substance use disorders (ASUDs). In this review, we summarize discuss the wealth of evidence from testing GLP-1 receptor (GLP-1R) agonist preclinical models humans ASUDs, possible mechanisms underlying impact GLP-1R agonists on alcohol/substance use, gaps knowledge, future directions. Most research has been conducted relation to use; psychostimulants, opioids, nicotine have also investigated. Preclinical suggests that reduce related outcomes. main proposed reward processing, stress, cognitive function, well broader satiety, changes gastric motility, glucose homeostasis. More in-depth mechanistic studies warranted. Clinical their findings less conclusive; most support safety efficacy ASUD treatment. Identifying preferred compounds, subgroups who responsive some key questions translate promising data into clinical settings. Several trials underway test people ASUDs.

Language: Английский

Citations

6