Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders

作者：Yazhou Li, Kelli L. Vaughan, Yun Wang, Seong‐Jin Yu, Eun-Kyung Bae, Ian A. Tamargo, Katherine O. Kopp, David Tweedie, Cheng‐Chuan Chiang, Keith T. Schmidt, Debomoy K. Lahiri, Michael A. Tones, Margaret M. Zaleska, Barry J. Hoffer, Julie A. Mattison, Nigel H. Greig · 发表于：GeroScience · 年份：2024 · DOI：10.1007/s11357-024-01120-4 · 被引用次数：10 · 研究领域：Alzheimer's disease research and treatments、Neuroscience and Neuropharmacology Research、Pharmacological Effects and Toxicity Studies

The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, and anti-neuroinflammatory actions. The dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of endogenous GLP-1 and GIP, and, thereby, extends the circulation of these protective peptides. The current nonhuman primate (NHP) study evaluates whether human translational sitagliptin doses can elevate systemic and central nervous system (CNS) levels of GLP-1/GIP in naive, non-lesioned NHPs, in line with our prior rodent studies that demonstrated sitagliptin efficacy in preclinical models of Parkinson's disease (PD). PD is an age-associated neurodegenerative disorder whose current treatment is inadequate. Repositioning of the well-tolerated and efficacious diabetes drug sitagliptin provides a rapid approach to add to the therapeutic armamentarium for PD. The pharmacokinetics and pharmacodynamics of 3 oral sitagliptin doses (5, 20, and 100 mg/kg), equivalent to the routine clinical dose, a tolerated higher clinical dose and a maximal dose in monkey, were evaluated. Peak plasma sitagliptin levels were aligned both with prior reports in humans administered equivalent doses and with those in rodents demonstrating reduction of PD associated neurodegeneration. Although CNS uptake of sitagliptin was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), both plasma and CSF concentrations of GLP-1/GIP were elevated in line w...