Assessing the Impact of Lithium Chloride on the Expression of P-Glycoprotein at the Blood-Brain Barrier
| Autor: | Yijun Pan, Jennifer L. Short, Stephanie A. Newman, Joseph A. Nicolazzo |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Drug ATP Binding Cassette Transporter Subfamily B Lithium (medication) media_common.quotation_subject Blotting Western Cell Culture Techniques Pharmaceutical Science Down-Regulation Gene Expression Pharmacology Blood–brain barrier Transfection Protein expression 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Alzheimer Disease medicine Gene and protein expression Animals Humans Rhodamine 123 ATP Binding Cassette Transporter Subfamily B Member 1 media_common P-glycoprotein Amyloid beta-Peptides biology Dose-Response Relationship Drug Brain Endothelial Cells Biological Transport 030104 developmental biology medicine.anatomical_structure Biochemistry chemistry Blood-Brain Barrier biology.protein Chlorates Lithium chloride Efflux Lithium Chloride 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of pharmaceutical sciences. 106(9) |
| ISSN: | 1520-6017 |
| Popis: | In addition to extruding drugs from the brain, P-glycoprotein (P-gp) at the blood-brain barrier (BBB) facilitates the brain-to-blood clearance of beta-amyloid (Aβ) and is down-regulated in Alzheimer's disease. Studies suggest that the mood-stabilizing drug lithium exerts a protective effect against Alzheimer's disease. Although the mechanisms underlying this effect are not fully understood, evidence suggests that lithium chloride (LiCl) increases P-gp expression in vitro , albeit at concentrations substantially outside the therapeutic window. Therefore, we investigated the effects of pharmacologically-relevant concentrations of LiCl on P-gp expression using in vitro and in vivo approaches. Swiss outbred mice administered LiCl (300 mg/kg/day, 21 days) showed no change in brain microvascular P-gp protein expression. Furthermore, P-gp transcript and protein levels were unaltered by LiCl (1.25-5 mM, 24 h) in human immortalized brain endothelial cells, while both gene and protein expression were significantly enhanced by the P-gp up-regulator, SR12813 by 1.5-fold and 2.0-fold, respectively. P-gp efflux function was also unaffected by LiCl in vitro , by measuring accumulation of the fluorescent P-gp substrate rhodamine-123. This suggests therefore that LiCl is unlikely to affect the BBB efflux of Aβ or other P-gp substrates at pharmacologically-relevant concentrations, suggesting that the Aβ-lowering effects of LiCl are unrelated to elevated BBB P-gp expression. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|