Nicotine and cotinine modulate cerebral microvascular permeability and protein expression of ZO-1 through nicotinic acetylcholine receptors expressed on brain endothelial cells

Thomas J. Abbruscato, Steve P. Lopez, Karen S. Mark, Brian T. Hawkins, Thomas P. Davis

Research output: Contribution to journalArticle

106 Scopus citations


The blood-brain barrier (BBB) adapts to a variety of pathological processes. Little is known about the effects of nicotine exposure on BBB function and the ability to adapt to stroke conditions. We have demonstrated, using a well-characterized in vitro BBB model, bovine brain microvessel endothelial cells (BBMEC) model, that nicotine and its major metabolite, cotinine, modulate BBB integrity by opening the paracellular route of solute entry into the brain. Additionally, nicotine and cotinine together increase the permeability change observed after 6 h of hypoxia/aglycemia, an in vitro model of stroke. This has important implications for how the BBB initially adapts to stroke in an environment that is previousely exposed to nicotine. Nicotine and cotinine exposure also resulted in reduced ZO-1 immunoreactivity (tight junctional protein) that occurred in a time-dependent manner. Interestingly, attenuation of bovine brain microvessel endothelial cell (BBMEC) ZO-1 protein expression was reversed using 10 nM BGT, an α7 nicotinic acetycholine receptor (nAChR) antagonist, suggesting that the effects of nicotine on BBMEC protein expression of ZO-1 protein are mediated by nAChR expressed on brain endothelial cells. In addition to α7, we found that BBMEC also contain positive immunoreactivity for the α3, α5, β2, β3 nAChR subunit. Both α7 and β2 nAChR subunit protein levels decreased with prior nicotine and cotinine exposure. These data provide evidence that nicotine and cotinine alter BBB permeability and tight junctional protein expression of ZO-1, thereby altering the BBB response to stroke conditions. These changes in brain endothelial cell paracellular permeability are believed to be associated with nicotine binding to nAChRs present at the BBB.

Original languageEnglish (US)
Pages (from-to)2525-2538
Number of pages14
JournalJournal of pharmaceutical sciences
Issue number12
StatePublished - Dec 2002



  • Blood-brain barrier
  • Cotinine
  • Endothelial cell
  • Nicotine
  • Tight junction
  • ZO-1

ASJC Scopus subject areas

  • Pharmaceutical Science

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