Document Detail

Functional regulation of P-glycoprotein at the blood-brain barrier in proton-coupled folate transporter (PCFT) mutant mice.
MedLine Citation:
PMID:  23212123     Owner:  NLM     Status:  MEDLINE    
Folate deficiency has been associated with many adverse clinical manifestations. The blood-brain barrier (BBB), formed by brain capillary endothelial cells, protects the brain from exposure to neurotoxicants. The function of BBB is modulated by multiple ABC transporters, particularly P-glycoprotein. A proton-coupled folate transporter (PCFT)-deficient mouse has been previously described as a model for systemic folate deficiency. Herein, we demonstrate that exposing mouse brain capillaries to the antiepileptic drug, valproic acid (VPA; 5 μM), significantly increased P-glycoprotein transport function in the wild-type animals. A ligand to the aryl hydrocarbon receptor, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), produced a similar induction of P-glycoprotein, which tightened the BBB, thereby increasing the neuroprotection. However, VPA- or TCDD-induced P-glycoprotein transport was blocked in the PCFT-nullizygous mice, indicating that multiple neuroprotective mechanisms are compromised under folate-deficient conditions. Brain capillaries from S-folinic acid (SFA; 40 mg/kg)-treated PCFT-nullizygous mice exhibited increased P-glycoprotein transport following VPA exposure. This suggests that SFA supplementation restored the normal BBB function. In addition, we show that tight-junction proteins are disintegrated in the PCFT mutant mice. Taken together, these findings strongly suggest that folate deficiency disrupts the BBB function by targeting the transporter and tight junctions, which may contribute to the development of neurological disorders.
Xueqian Wang; Robert M Cabrera; Yue Li; David S Miller; Richard H Finnell
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2012-12-04
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  27     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-01     Completed Date:  2013-04-26     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1167-75     Citation Subset:  IM    
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MeSH Terms
Anticonvulsants / pharmacology
Biological Transport, Active / drug effects,  genetics
Blood-Brain Barrier / metabolism*,  pathology
Leucovorin / pharmacology
Mice, Mutant Strains
Nervous System Diseases / genetics,  metabolism,  pathology
P-Glycoprotein / genetics,  metabolism*
Proton-Coupled Folate Transporter / genetics,  metabolism*
Teratogens / pharmacology
Tetrachlorodibenzodioxin / pharmacology
Tight Junctions / genetics,  metabolism*,  pathology
Valproic Acid / pharmacology
Vitamin B Complex / pharmacology
Grant Support
Reg. No./Substance:
0/Anticonvulsants; 0/P-Glycoprotein; 0/Proton-Coupled Folate Transporter; 0/Slc46a1 protein, mouse; 0/Teratogens; 12001-76-2/Vitamin B Complex; 614OI1Z5WI/Valproic Acid; DO80M48B6O/Tetrachlorodibenzodioxin; Q573I9DVLP/Leucovorin

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