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

Autor: Li Y; Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA., Vaughan KL; Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA., Wang Y; Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan, 35053., Yu SJ; Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan, 35053., Bae EK; Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan, 35053., Tamargo IA; Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA., Kopp KO; Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA., Tweedie D; Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA., Chiang CC; Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA., Schmidt KT; Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Lahiri DK; Departments of Psychiatry and Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA., Tones MA; Cadre Bioscience, Saint Louis, MO, 63110, USA., Zaleska MM; Neuro-D Consulting LLC, Penn Valley, PA, 19072, USA., Hoffer BJ; Department of Neurosurgery, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA., Mattison JA; Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA., Greig NH; Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA. Greign@grc.nia.nih.gov.
Jazyk: angličtina
Zdroj: GeroScience [Geroscience] 2024 Oct; Vol. 46 (5), pp. 4397-4414. Date of Electronic Publication: 2024 Mar 27.
DOI: 10.1007/s11357-024-01120-4
Abstrakt: 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 with efficacy in prior rodent PD studies. Additional cellular studies evaluating human SH-SY5Y and primary rat ventral mesencephalic cultures challenged with 6-hydroxydopamine, established cellular models of PD, demonstrated that joint treatment with GLP-1 + GIP mitigated cell death, particularly when combined with DPP-4 inhibition to maintain incretin levels. In conclusion, this study provides a supportive translational step towards the clinical evaluation of sitagliptin in PD and other neurodegenerative disorders for which aging, similarly, is the greatest risk factor.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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