Nicotinic modulation of cerebral microvascular permeability

Abstract

The blood-brain barrier (BBB) is the regulated interface between the peripheral circulation and the central nervous system (CNS), formed primarily by the cerebral microvascular endothelium. Tight junctions (TJ) between BBB endothelial cells restrict paracellular diffusion from blood to brain. Expression and localization of TJ proteins are modulated by multiple pathways. Disruption of TJ by disease or drugs can impair BBB function and compromise the CNS. Therefore, understanding how BBB TJ are affected by various factors is useful for the prevention and treatment of neurological diseases. Smoking is associated with increased risk of disease, including neurological disease. The effects of nicotine on endothelial cells are profound, and nicotinic acetylcholine receptors (nAChR) have been characterized in peripheral endothelial cells. However, relatively little is known about the specific effect of nicotine on the BBB. The hypothesis of this study is that nicotine increases BBB permeability by alteration of TJ via a nAChR-mediated pathway. To test this hypothesis, studies were undertaken to (1) explore the effects of nicotine on the expression and distribution of TJ proteins in cerebral microvessels; (2) determine the effect of nicotine on BBB permeability in an intact animal model; and (3) investigate the role of nAChR in the effects of nicotine on the BBB. Rats were given nicotine at a dosage designed to mimic the exposure experienced by heavy smokers. While nicotine did not alter the expression of the TJ proteins investigated, changes in their distribution were observed. Nicotine was found to increase BBB permeability to sucrose without significant changes in its initial volume of distribution. These data suggest that nicotine increases the permeability of the BBB via modulation of TJ proteins. Positive immunoreactivity was found for nAChR subunits α3, α5, α7, and β2, but not α4, β3, or β4. Nicotine was co-administered with the nicotinic antagonists mecamylamine, which readily crosses the BBB, and hexamethonium, which does not. Both of these antagonists attenuated the effect of nicotine on BBB permeability, indicating that this effect is receptor-mediated and that receptors within the CNS are probably not involved. Taken together, these data suggest a novel role for endothelial nAChR in regulation of BBB TJ and permeability.