Purpose: The aim of this study was to assess the influence of age on the functional activity of the multidrug efflux transporter P-glycoprotein (P-gp) at the human blood-brain barrier.
Methods: Seven young (mean age: 27 +/- 4 years) and six elderly (mean age: 69 +/- 9 years) healthy volunteers underwent dynamic (R)-[(11)C]verapamil (VPM) positron emission tomography (PET) scans and arterial blood sampling. Parametric distribution volume (DV) images were generated using Logan linearisation, and age groups were compared with statistical parametric mapping (SPM). Brain regions that SPM analysis had shown to be most affected by age were analysed by a region of interest (ROI)-based approach using a maximum probability brain atlas, before and after partial volume correction (PVC).
Results: SPM analysis revealed significant clusters of DV increases in cerebellum, temporal and frontal lobe of elderly compared to younger subjects. In the ROI-based analysis, elderly subjects showed significant DV increases in amygdala (+30%), insula (+26%) and cerebellum (+25%) before PVC, and in insula (+33%) after PVC.
Conclusions: Increased VPM DV values in the brains of elderly subjects suggest a decrease in cerebral P-gp function with increasing age.
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http://dx.doi.org/10.1007/s00228-009-0709-5 | DOI Listing |
Front Pharmacol
January 2025
Key Research Laboratory for Prevention and Treatment of Cerebrospinal diseases, Shaanxi Provincial Administration of Traditional Chinese Medicine, Xianyang, China.
Purpose: Xixin Decoction (XXD) is a classical formula that has been used to effectively treat dementia for over 300 years. Modern clinical studies have demonstrated its significant therapeutic effects in treating Alzheimer's disease (AD) without notable adverse reactions. Nevertheless, the specific mechanisms underlying its efficacy remain to be elucidated.
View Article and Find Full Text PDFEur J Pharm Sci
January 2025
Centre for Applied Pharmacokinetic Research, University of Manchester, UK.
Access of drugs to the central nervous system is limited by the blood-brain barrier, and this in turn affects drug efficacy/toxicity. To date, most drug discovery optimization paradigms have relied heavily on in vitro transporter assays and preclinical species pharmacokinetic evaluation to provide a qualitative assessment of human brain penetration. Because of the lack of human brain pharmacokinetic data, mechanistic models for preclinical species, combined with in vitro and in silico data, are useful for translation to human.
View Article and Find Full Text PDFMol Imaging Biol
January 2025
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Purpose: This preclinical study explored the feasibility of assessing P-glycoprotein (P-gp) function in both brain and gastrointestinal (GI) tract of rats using positron emission tomography (PET) following oral administration of [F]MC225. Different oral administration protocols were evaluated, and radioactivity uptake was compared with uptake following intravenous administration.
Procedures: Twelve male Wistar rats were divided into four groups and subjected to intravenous or oral [F]MC225 administration protocols: G (intravenous route), G (oral administration without fasting), G (oral administration with fasting), and G (oral administration with fasting following administration of the P-gp inhibitor tariquidar).
Eur J Med Chem
January 2025
Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA, 30322, United States. Electronic address:
Monoacylglycerol lipase (MAGL) is a 33 kDa cytosolic serine hydrolase that is widely distributed in the central nervous system and peripheral tissues. MAGL hydrolyzes monoacylglycerols into fatty acids and glycerol, playing a crucial role in endocannabinoid degradation. Inhibition of MAGL in the brain elevates levels of 2-arachidonoylglycerol and leads to decreased pro-inflammatory prostaglandin and thromboxane production.
View Article and Find Full Text PDFVet Q
December 2025
Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada.
This review examines the role of the canine blood-brain barrier (BBB) in health and disease, focusing on the impact of the multidrug resistance (MDR) transporter P-glycoprotein (P-gp) encoded by the gene. The BBB is critical in maintaining central nervous system homeostasis and brain protection against xenobiotics and environmental drugs that may be circulating in the blood stream. We revise key anatomical, histological and functional aspects of the canine BBB and examine the role of the gene mutation in specific dog breeds that exhibit reduced P-gp activity and disrupted drug brain pharmacokinetics.
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