Id |
Subject |
Object |
Predicate |
Lexical cue |
T779 |
0-342 |
Sentence |
denotes |
Using a primary human brain microvascular endothelial cell (BMEC) and astrocyte co-culture model, Mahajan et al. (2008) were among the first to demonstrate that co-exposure to morphine and HIV-1 Tat resulted in greater increases in TNF-α and IL-8 levels and decreases in barrier tightness (measured by TEER) than either morphine or Tat alone. |
T780 |
343-583 |
Sentence |
denotes |
Morphine and Tat co-exposure also additively increased JAM-2, while zonula occludens-1 (ZO-1) levels were decreased by morphine or by Tat individually, and occludin protein levels were decreased by morphine alone but not Tat (Mahajan et al. |
T781 |
584-590 |
Sentence |
denotes |
2008). |
T782 |
591-752 |
Sentence |
denotes |
Using the inducible Tat transgenic mouse model, Leibrand et al. (2019), also demonstrated that HIV-1 Tat and morphine act independently to disrupt BBB integrity. |
T783 |
753-926 |
Sentence |
denotes |
In these studies, morphine, and to a lesser extent Tat, exposure increased the leakage of fluorescently labeled dextrans from the circulation into the brain (Leibrand et al. |
T784 |
927-948 |
Sentence |
denotes |
2017, 2019) (Fig. 3). |
T785 |
949-1066 |
Sentence |
denotes |
Morphine exposure decreased the penetration of select ARVs in the brain, in a region-specific manner (Leibrand et al. |
T786 |
1067-1082 |
Sentence |
denotes |
2019) (Fig. 3). |
T787 |
1083-1286 |
Sentence |
denotes |
Morphine exposure also resulted in increased expression and function of the drug efflux transport protein, P-gp, suggesting a mechanism by which morphine decreased the ARV concentrations (Leibrand et al. |
T788 |
1287-1293 |
Sentence |
denotes |
2019). |
T789 |
1294-1440 |
Sentence |
denotes |
This finding suggests that morphine exposure could impact the efficient delivery of any therapeutic drug that is a substrate of P-gp into the CNS. |
T790 |
1441-1572 |
Sentence |
denotes |
Future research should also investigate morphine’s impact on other drug transport proteins important for ARV delivery to the brain. |
T791 |
1573-1674 |
Sentence |
denotes |
Fig. 3 Effects of HIV-1 Tat and morphine on BBB leakiness and on antiretroviral brain concentrations. |
T792 |
1675-1965 |
Sentence |
denotes |
After 14 days of Tat induction, there was a significant increase in the 10 kDa (Cascade Blue®) tracer leakage into the brain in Tat + placebo as compared to Tat − placebo mice (*p < 0.05) and in Tat − mouse brains upon exposure to morphine as compared to Tat − placebo mice (*p < 0.05) (a). |
T793 |
1966-2314 |
Sentence |
denotes |
There was a significant main effect of morphine, resulting in reduced integrity of the BBB and increased leakage of the higher molecular weight (40 kDa and 70 kDa) tracers in morphine-exposed groups as compared to the those groups (Tat + and Tat − together) not exposed to morphine (placebo) (#p < 0.05; significant main effect of morphine) (b, c). |
T794 |
2315-2474 |
Sentence |
denotes |
Data represent the fold change in mean fluorescence intensity ± SEM; n = 8 Tat−/placebo, n = 6 Tat+/placebo, n = 9 Tat−/morphine, and n = 7 Tat+/morphine mice. |
T795 |
2475-2650 |
Sentence |
denotes |
Additionally, morphine exposure increased horseradish peroxidase (HRP) extravasation from the vasculature into the perivascular space and/or parenchyma in the striatum (d, e). |
T796 |
2651-2888 |
Sentence |
denotes |
HRP antigenicity was detected by indirect immunofluorescence (red) in tissue sections counterstained with Hoechst 33342 (blue) to reveal cell nuclei and visualized by differential interference contrast (DIC)-enhanced confocal microscopy. |
T797 |
2889-3050 |
Sentence |
denotes |
HRP extravasation into the striatal perivascular space/parenchyma was especially prevalent in morphine-exposed mice (arrowheads; left-hand panels in e versus d). |
T798 |
3051-3321 |
Sentence |
denotes |
The dotted lines (············) indicate the approximate edge of the capillaries/post-capillary venules; while intermittent dotted lines (· · · · · · ·) indicate the approximate edge of a partly sectioned blood vessel that appears partially outside the plane of section. |
T799 |
3322-3389 |
Sentence |
denotes |
The asterisks (*) indicate white matter tracts within the striatum. |
T800 |
3390-3441 |
Sentence |
denotes |
Representative samples from ≥ n = 4 mice per group. |
T801 |
3442-3480 |
Sentence |
denotes |
All images are the same magnification. |
T802 |
3481-3499 |
Sentence |
denotes |
Scale bar = 10 μm. |
T803 |
3500-3557 |
Sentence |
denotes |
Antiretroviral tissue-to-plasma ratios in striatum (f–g). |
T804 |
3558-3776 |
Sentence |
denotes |
Irrespective of Tat exposure, morphine significantly reduced the levels of dolutegravir (f) and abacavir (g), but not lamivudine (h), within the striatum, as compared to placebo. (* p < 0.05; main effect for morphine). |
T805 |
3777-4002 |
Sentence |
denotes |
Data represent the tissue-to-plasma ratios ± SEM sampled from n = 9 Tat−/placebo, n = 9 Tat+/placebo, n = 6 Tat−/morphine, and n = 8 Tat+/morphine mice. (a–h) Modified and reprinted with permission from Leibrand et al. (2019) |