Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders DOI Creative Commons
Yazhou Li, Kelli L. Vaughan, Yun Wang

et al.

GeroScience, Journal Year: 2024, Volume and Issue: 46(5), P. 4397 - 4414

Published: March 27, 2024

The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, anti-neuroinflammatory actions. dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of GLP-1 GIP, and, thereby, extends the circulation these protective peptides. current nonhuman primate (NHP) study evaluates whether human translational doses can elevate systemic central nervous system (CNS) levels GLP-1/GIP in naive, non-lesioned NHPs, line with our prior rodent studies that demonstrated efficacy preclinical models Parkinson's disease (PD). PD is an age-associated neurodegenerative disorder whose treatment inadequate. Repositioning well-tolerated efficacious diabetes drug provides a rapid approach to add therapeutic armamentarium for PD. pharmacokinetics pharmacodynamics 3 oral (5, 20, 100 mg/kg), equivalent routine clinical dose, tolerated higher dose maximal monkey, were evaluated. Peak plasma aligned both reports humans administered those rodents demonstrating reduction associated neurodegeneration. Although CNS uptake was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), CSF concentrations elevated studies. Additional cellular evaluating SH-SY5Y primary rat ventral mesencephalic cultures challenged 6-hydroxydopamine, established PD, joint + GIP mitigated cell death, particularly when combined DPP-4 inhibition maintain incretin levels. In conclusion, this supportive step towards evaluation other disorders which aging, similarly, greatest risk factor.

Language: Английский

Microglia Involvement into Acute and Chronic Brain Damage in Diabetic Rats: Impact of GLP-1RA and SGLT-2i DOI Creative Commons
А. В. Симаненкова,

Oksana Fuks,

Н. В. Тимкина

et al.

Frontiers in Bioscience-Landmark, Journal Year: 2024, Volume and Issue: 29(7)

Published: July 24, 2024

Background: Acute and chronic brain damage in type 2 diabetes mellitus (DM) determines the need to investigate neuroprotective potential of glucose-lowering drugs. The purpose was directly compare effects glucagon-like peptide-1 receptor agonists (GLP-1RAs) with different duration action sodium-glucose cotransporter-2 inhibitors (SGLT-2i) diabetic rats without stroke. Methods: DM modelled using high-fat diet nicotinamide+streptozotocin protocol. following groups (n = 15 each) were formed: treatment, treatment liraglutide, dulaglutide, canagliflozin as well control group treatment. After 8 weeks, 10 from each underwent middle cerebral artery occlusion. In reperfusion period neurological deficit, neuroglial markers necrosis evaluated. Brain slices remaining 5 animals histologically examined for microglial activation neuronal damage. Results: similar “DM” “Control” (17.53 [14.23; 26.58] 15.87 [13.40; 22.68] % total volume, respectively). All study drugs diminished volume comparing whereas “DM+Liraglutide” smaller than “DM+Canagliflozin” did not significantly differ “DM+Dulaglutide” (2.9 [1.83; 4.71], 6.17 [3.88; 8.88] 4.57 [3.27; 7.90] %). deficit more prominent “Control”, while all demonstrated positive effect. Neurofilament light chains (NLC) between “Control”. Dulaglutide caused a marked decrease NLC. Protein S100BB level Liraglutide largest decrease, influence it. ischaemia, increased number normal neurons, but GLP-1RAs had pronounced accompanied by activated cells Cornu Ammonis (CA)1 hippocampal region. Both reduced Iba-1-positive cells, dulaglutide being effective affect this parameter. Conclusions: SGLT-2i have properties against acute rats, although infarct-limiting effect may be pronounced. exert their protective influencing survival, also microglia.

Language: Английский

Citations

2
Melatonin-mediated IGF-1/GLP-1 activation in experimental OCD rats: Evidence from CSF, blood plasma, brain and in-silico investigations DOI
Aditi Giri, Sidharth Mehan, Zuber Khan

et al.

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 217, P. 115831 - 115831

Published: Sept. 28, 2023

Language: Английский

Citations

6
Designer GLP1 poly-agonist peptides in the management of diabesity DOI Creative Commons
Laura Statham,

Melina Pelling,

Petra Hanson

et al.

Expert Review of Endocrinology & Metabolism, Journal Year: 2023, Volume and Issue: 18(3), P. 231 - 240

Published: April 20, 2023

To date, the 21st Century has witnessed key developments in management of diabesity (a conflation obesity and Type 2 Diabetes Mellitus [T2D]), including Glucagon Like Peptide 1 (GLP1) receptor agonist therapies, recently 'designer' GLP1 Poly-agonist Peptides (GLP1PPs).A PubMed search published data on GLP1PP class therapies was conducted. The gut-brain axis forms complex multi-directional interlinks that include autonomic nervous signaling, components gut microbiota (including metabolic by-products gram-negative cell wall [e.g. endotoxinaemia]), incretin hormones are secreted from response to ingestion nutrients. development dual-incretin includes combinations peptide with Glucose-dependent Insulinotropic Polypeptide (GIP), (Gcg), Cholecystokinin (CCK), YY (PYY), Glucagon-Like (GLP2). Triple also under development.At dawn a new era therapeutic diabesity, designer holds great promise, each novel combination building preexisting palimpsest clinical insights. Future innovations will likely enable medically induced weight loss glycemic control rival or even out-perform those resulting bariatric surgery.

Language: Английский

Citations

4
Photomodulatory effects in the hypothalamus of sleep-deprived young and aged rats DOI

Radwa H Lutfy,

Shérine Abdel Salam, Haitham S. Mohammed

et al.

Behavioural Brain Research, Journal Year: 2023, Volume and Issue: 458, P. 114731 - 114731

Published: Oct. 26, 2023

Language: Английский

Citations

4
Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders DOI Creative Commons
Yazhou Li, Kelli L. Vaughan, Yun Wang

et al.

GeroScience, Journal Year: 2024, Volume and Issue: 46(5), P. 4397 - 4414

Published: March 27, 2024

The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, anti-neuroinflammatory actions. dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of GLP-1 GIP, and, thereby, extends the circulation these protective peptides. current nonhuman primate (NHP) study evaluates whether human translational doses can elevate systemic central nervous system (CNS) levels GLP-1/GIP in naive, non-lesioned NHPs, line with our prior rodent studies that demonstrated efficacy preclinical models Parkinson's disease (PD). PD is an age-associated neurodegenerative disorder whose treatment inadequate. Repositioning well-tolerated efficacious diabetes drug provides a rapid approach to add therapeutic armamentarium for PD. pharmacokinetics pharmacodynamics 3 oral (5, 20, 100 mg/kg), equivalent routine clinical dose, tolerated higher dose maximal monkey, were evaluated. Peak plasma aligned both reports humans administered those rodents demonstrating reduction associated neurodegeneration. Although CNS uptake was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), CSF concentrations elevated studies. Additional cellular evaluating SH-SY5Y primary rat ventral mesencephalic cultures challenged 6-hydroxydopamine, established PD, joint + GIP mitigated cell death, particularly when combined DPP-4 inhibition maintain incretin levels. In conclusion, this supportive step towards evaluation other disorders which aging, similarly, greatest risk factor.

Language: Английский

Citations

1