Nicotine increases in vivo blood-brain barrier permeability and alters cerebral microvascular tight junction protein distribution.
The blood-brain barrier (BBB) is critical to the health of the central nervous system. The BBB is formed primarily by the presence of tight junctions (TJ) between cerebral microvessel endothelial cells. In light of the known effects of nicotine on endothelial cell biology, the specific effects of nicotine on the in vivo BBB were examined. Using in situ brain perfusion, it was found that continuous administration of nicotine (4.5 mg free base x kg(-1) x day(-1)) for 1 and 7 days led to increased permeability of the BBB to [14C]-sucrose without significant changes in its initial volume of distribution. The expression and distribution of the TJ-associated proteins actin, occludin, claudin-1, -3, and -5, and ZO-1 and -2 were analyzed by Western blot and immunofluorescence microscopy. Though no changes in total protein expression were observed, nicotine treatment was associated with altered cellular distribution of ZO-1 and diminished junctional immunoreactivity of claudin-3. It is proposed that nicotine leads to changes in BBB permeability via the modulation of TJ proteins.
Hawkins
Brian T
BT
Program in Neuroscience, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA.
Abbruscato
Thomas J
TJ
Egleton
Richard D
RD
Brown
Rachel C
RC
Huber
Jason D
JD
Campos
Christopher R
CR
Davis
Thomas P
TP
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D015153:Blotting, Western / Q000379:methods; D002199:Capillary Permeability / Q000187:drug effects*; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D008565:Membrane Proteins / Q000378:metabolism; D016253:Microscopy, Immunoelectron / Q000379:methods; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009538:Nicotine / Q000097:blood / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013395:Sucrose / Q000493:pharmacokinetics; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D013997:Time Factors
D002247:Carbon Isotopes; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D013395:Sucrose; D009538:Nicotine