Copper bis(thiosemicarbazone) complexes modulate P-glycoprotein expression and function in human brain microvascular...

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• P-glycoprotein (P-gp) is a crucial efflux transporter at the blood-brain barrier (BBB), regulating brain entry of drugs and clearance of molecules like amyloid beta (Aβ).
• Biometals, particularly copper (Cu), influence P-gp regulation through various neuronal signaling pathways.

Purpose of the Study:

• To investigate the effects of bis(thiosemicarbazone) (BTSC) copper complexes, specifically Cu^II[GTSM] and Cu^II[ATSM], on P-gp expression and function at the BBB.
• To determine if Cu^II[ATSM], which releases Cu under hypoxia, modulates P-gp differently than Cu^II[GTSM].

Main Methods:

• Human brain endothelial cells (hCMEC/D3) were treated with varying concentrations of Cu^II[GTSM] and Cu^II[ATSM].
• P-gp mRNA and protein expression were quantified using RT-qPCR and Western blot.
• P-gp function was assessed by measuring rhodamine 123 accumulation, and intracellular Cu levels were measured via ICP-MS.

Main Results:

• Cu^II[ATSM] significantly increased P-gp expression (2-fold) and function (1.3-fold).
• Cu^II[GTSM] reduced P-gp expression (0.5-fold) and function (by 200%).
• Cu^II[ATSM]-mediated P-gp enhancement involved the extracellular signal-regulated kinase 1 and 2 pathway.

Conclusions:

• Cu^II[ATSM] and Cu^II[GTSM] differentially modulate P-gp expression and function at the BBB.
• Cu^II[ATSM] shows potential for enhancing brain drug delivery and Aβ clearance.
• The study highlights the role of copper complexes in regulating BBB transporter activity.