Cu(ATSM) Increases P-Glycoprotein Expression and Function at the Blood-Brain Barrier in C57BL6/J Mice

• Main Authors: Jae Pyun (Author), HuiJing Koay (Author), Pranav Runwal (Author), Celeste Mawal (Author), Ashley I. Bush (Author), Yijun Pan (Author), Paul S. Donnelly (Author), Jennifer L. Short (Author), Joseph A. Nicolazzo (Author)
• Format: Bog
• Udgivet: MDPI AG, 2023-08-01T00:00:00Z.
• Fag: article
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• Notes: 10.3390/pharmaceutics15082084; 1999-4923
• Keywords: blood-brain barrier; P-glycoprotein; copper; bis(thiosemicarbazone); CNS drug delivery; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 15, Iss 8, p 2084 (2023)

P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), is critical in preventing brain access to substrate drugs and effluxing amyloid beta (Aβ), a contributor to Alzheimer's disease (AD). Strategies to regulate P-gp expression therefore may impact central nervous system (CNS) drug delivery and brain Aβ levels. As we have demonstrated that the copper complex copper diacetyl bis(4-methyl-3-thiosemicarbazone) (Cu(ATSM)) increases P-gp expression and function in human brain endothelial cells, the present study assessed the impact of Cu(ATSM) on expression and function of P-gp in mouse brain endothelial cells (mBECs) and capillaries in vivo, as well as in peripheral organs. Isolated mBECs treated with Cu(ATSM) (100 nM for 24 h) exhibited a 1.6-fold increase in P-gp expression and a 20% reduction in accumulation of the P-gp substrate rhodamine 123. Oral administration of Cu(ATSM) (30 mg/kg/day) for 28 days led to a 1.5 & 1.3-fold increase in brain microvascular and hepatic expression of P-gp, respectively, and a 20% reduction in BBB transport of [3H]-digoxin. A metallomic analysis showed a 3.5 and 19.9-fold increase in Cu levels in brain microvessels and livers of Cu(ATSM)-treated mice. Our findings demonstrate that Cu(ATSM) increases P-gp expression and function at the BBB in vivo, with implications for CNS drug delivery and clearance of Aβ in AD.