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

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
Semaglutide promotes the transition of microglia from M1 to M2 type to reduce brain inflammation in APP/PS1/tau mice DOI
Zhaojun Wang, Wei-Na Han,

Shi-Fan Chai

et al.

Neuroscience, Journal Year: 2024, Volume and Issue: 563, P. 222 - 234

Published: Nov. 14, 2024

Language: Английский

Citations

2
Special Issue “Pathophysiology and Treatment of Alzheimer’s Disease” DOI Open Access
Jeffrey Fessel

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(11), P. 6015 - 6015

Published: May 30, 2024

The majority of clinical trials, whose primary aims were to moderate Alzheimer’s dementia (AD), have been based upon the prevailing paradigm, i [...]

Language: Английский

Citations

1
Investigational and emerging gastric inhibitory polypeptide (GIP) receptor-based therapies for the treatment of obesity DOI

Robert H. Gaffey,

Afua K. Takyi,

Alpana P. Shukla

et al.

Expert Opinion on Investigational Drugs, Journal Year: 2024, Volume and Issue: 33(8), P. 757 - 773

Published: July 10, 2024

One billion people live with obesity. The most promising medications for its treatment are incretin-based therapies, based on enteroendocrine peptides released in response to oral nutrients, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). mechanisms by which GLP-1 receptor agonism cause weight reduction becoming increasingly understood. However, the GIP receptor-modulating loss remain be clarified.

Language: Английский

Citations

1
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

Citations

1