Chronic exposure to nicotine and saquinavir decreases endothelial Notch-4 expression and disrupts blood-brain barrier integrity.
Since the advent of HAART, there have been substantial improvements in HIV patient survival; however, the prevalence of HIV associated dementia has increased. Importantly, HIV positive individuals who smoke progress to HIV associated neurological conditions faster than those who do not. Recent in vitro data have shown that pharmacological levels of saquinavir causes endothelial oxidative stress and significantly decreases Notch-4 expression, a primary protein involved in maintaining stability of blood-brain barrier (BBB) endothelium. This is concerning as nicotine can also generate reactive oxygen species in endothelium. It is largely unknown if pharmacological doses of these drugs can cause a similar in vivo down-regulation of Notch-4 and if there is a concurrent destabilization of the integrity of the BBB. The data herein show: (i) nicotine and protease inhibitors cause an additive oxidative stress burden in endothelium; (ii) that the integrity of the BBB is disrupted after concurrent chronic nicotine and protease inhibitor administration; and (iii) that BBB endothelial dysfunction is correlated with a decrease in Notch-4 and ZO-1 expression. Considering the high prevalence of smoking in the HIV infected population (3- to 4-fold higher than in the general population) this data must be followed up to determine if all protease inhibitors cause a similar BBB disruption or if there is a safer alternative. In addition, this data may suggest that the induced BBB disruption may allow foreign molecules to gain access to brain and be a contributing factor to the slow progression of HIV associated dementia.
Manda
Vamshi K
VK
Texas Tech University Health Sciences Center, School of Pharmacy, Department of Pharmaceutical Sciences, Amarillo, Texas 79106-1712, USA.
Mittapalli
Rajendar K
RK
Geldenhuys
Werner J
WJ
Lockman
Paul R
PR
D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000166:cytology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D004347:Drug Interactions; D042783:Endothelial Cells / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage* / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D019258:Saquinavir / Q000008:administration & dosage*; D012907:Smoking; D014810:Vitamin E / Q000494:pharmacology; D062826:Zonula Occludens-1 Protein
D017320:HIV Protease Inhibitors; D008565:Membrane Proteins; C106075:NOTCH4 protein, human; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D000074562:Receptor, Notch4; D051880:Receptors, Notch; C569042:TJP1 protein, human; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D014810:Vitamin E; D009538:Nicotine; D019258:Saquinavir