scholarly journals Efavirenz and Metabolites in Cerebrospinal Fluid: Relationship withCYP2B6c.516G→T Genotype and Perturbed Blood-Brain Barrier Due to Tuberculous Meningitis

2016 ◽  
Vol 60 (8) ◽  
pp. 4511-4518 ◽  
Author(s):  
Sam Nightingale ◽  
Tran Thi Hong Chau ◽  
Martin Fisher ◽  
Mark Nelson ◽  
Alan Winston ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Neuronal Damage ◽  
Brain Barrier ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Toxic Concentration ◽  
Metabolite Concentrations ◽  
Blood Brain Barrier Integrity

ABSTRACTEfavirenz (EFZ) has been associated with neuropsychiatric side effects. Recently, the 8-hydroxy-EFZ (8OH-EFZ) metabolite has been shown to be a potent neurotoxinin vitro, inducing neuronal damage at concentrations of 3.3 ng/ml. EFZ induced similar neuronal damage at concentrations of 31.6 ng/ml. We investigated the effect of genotype and blood-brain barrier integrity on EFZ metabolite concentrations in cerebrospinal fluid (CSF). We measured CSF drug concentrations in subjects from two separate study populations: 47 subjects with tuberculous meningitis (TBM) coinfection in Vietnam receiving 800 mg EFZ with standard antituberculous treatment and 25 subjects from the PARTITION study in the United Kingdom without central nervous system infection receiving 600 mg EFZ. EFZ and metabolite concentrations in CSF and plasma were measured and compared with estimates of effectiveness and neurotoxicity from available publishedin vitroandin vivodata. The effect of theCYP2B6c.516G→T genotype (GG genotype, fast EFV metabolizer status; GT genotype, intermediate EFV metabolizer status; TT genotype, slow EFV metabolizer status) was examined. The mean CSF concentrations of EFZ and 8OH-EFZ in the TBM group were 60.3 and 39.3 ng/ml, respectively, and those in the no-TBM group were 15.0 and 5.9 ng/ml, respectively. Plasma EFZ and 8OH-EFZ concentrations were similar between the two groups. CSF EFZ concentrations were above thein vitrotoxic concentration in 76% of samples (GG genotype, 61%; GT genotype, 90%; TT genotype, 100%) in the TBM group and 13% of samples (GG genotype, 0%; GT genotype, 18%; TT genotype, 50%) in the no-TBM group. CSF 8OH-EFZ concentrations were above thein vitrotoxic concentration in 98% of the TBM group and 87% of the no-TBM group; levels were independent of genotype but correlated with the CSF/plasma albumin ratio. Potentially neurotoxic concentrations of 8OH-EFZ are frequently observed in CSF independently of theCYP2B6genotype, particularly in those with impaired blood-brain barrier integrity.

scholarly journals Mice deficient in endothelial α5 integrin are profoundly resistant to experimental ischemic stroke

2016 ◽  
Vol 37 (1) ◽  
pp. 85-96 ◽  
Author(s):  
Jill Roberts ◽  
Leon de Hoog ◽  
Gregory J Bix
Keyword(s):  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Infarct Volume ◽  
Ischemic Injury ◽  
Glucose Deprivation ◽  
Brain Barrier ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity

Stroke is a disease in dire need of better therapies. We have previously shown that a fragment of the extracellular matrix proteoglycan, perlecan, has beneficial effects following cerebral ischemia via the α5β1 integrin receptor. We now report that endothelial cell selective α5 integrin deficient mice (α5 KO) are profoundly resistant to ischemic infarct after transient middle cerebral artery occlusion. Specifically, α5 KOs had little to no infarct 2–3 days post-stroke, whereas controls had an increase in mean infarct volume over the same time period as expected. Functional outcome is also improved in the α5 KOs compared with controls. Importantly, no differences in cerebrovascular anatomy or collateral blood flow were noted that could account for this difference in ischemic injury. Rather, we demonstrate that α5 KOs have increased blood-brain barrier integrity (increased expression of claudin-5, and absent brain parenchymal IgG extravasation) after stroke compared with controls, which could explain their resistance to ischemic injury. Additionally, inhibition of α5 integrin in vitro leads to decreased permeability of brain endothelial cells following oxygen-glucose deprivation. Together, these findings indicate endothelial cell α5 integrin plays an important role in stroke outcome and blood-brain barrier integrity, suggesting that α5 integrin could be a novel therapeutic target for stroke.

The Identification and Investigation of In-vitro Blood-Brain Barrier Integrity Enhancers

2016 ◽  
Author(s):  
Quoc-Viet Andrew Duong ◽  
Hisham Qosa ◽  
Ashley DePaula ◽  
Courtney Flick ◽  
Trista LeBeouf ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity

CEREBROSPINAL FLUID MEASURES OF BLOOD BRAIN BARRIER INTEGRITY IN PSEN1-RELATED ALZHEIMER’S DISEASE

2017 ◽  
Vol 13 (7) ◽  
pp. P918
Author(s):  
John M. Ringman ◽  
Melanie D. Sweeney ◽  
Abhay Sagare ◽  
Helena Chang Chui ◽  
Berislav Zlokovic
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity

scholarly journals MiR-34a regulates blood–brain barrier permeability and mitochondrial function by targeting cytochrome c

2015 ◽  
Vol 36 (2) ◽  
pp. 387-392 ◽  
Author(s):  
Mimi Bukeirat ◽  
Saumyendra N Sarkar ◽  
Heng Hu ◽  
Dominic D Quintana ◽  
James W Simpkins ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Blood Brain Barrier ◽  
Critical Role ◽  
Cell Monolayer ◽  
Brain Barrier ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Cerebrovascular Endothelial Cells ◽  
Blood Brain Barrier Integrity

The blood–brain barrier is composed of cerebrovascular endothelial cells and tight junctions, and maintaining its integrity is crucial for the homeostasis of the neuronal environment. Recently, we discovered that mitochondria play a critical role in maintaining blood–brain barrier integrity. We report for the first time a novel mechanism underlying blood–brain barrier integrity: miR-34a mediated regulation of blood–brain barrier through a mitochondrial mechanism. Bioinformatics analysis suggests miR-34a targets several mitochondria-associated gene candidates. We demonstrated that miR-34a triggers the breakdown of blood–brain barrier in cerebrovascular endothelial cell monolayer in vitro, paralleled by reduction of mitochondrial oxidative phosphorylation and adenosine triphosphate production, and decreased cytochrome c levels.

scholarly journals Functional NHE1 expression is critical to blood brain barrier integrity and sumatriptan blood to brain uptake

2019 ◽  
Author(s):  
Erika Liktor-Busa ◽  
Kiera T. Blawn ◽  
Kathryn L. Kellohen ◽  
Beth M. Wiese ◽  
Vani Verkhovsky ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ion Homeostasis ◽  
Early Time ◽  
Female Rats ◽  
Brain Barrier ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity

AbstractDisruption of blood-brain barrier integrity and dramatic failure of brain ion homeostasis including fluctuations of pH occurs during cortical spreading depression (CSD) events associated with several neurological disorders, including migraine with aura, traumatic brain injury and stroke. NHE1 is the primary regulator of pH in the central nervous system. The goal of the current study was to investigate the role of sodium-hydrogen exchanger type 1 (NHE1) in blood brain barrier (BBB) integrity during CSD events and the contributions of this antiporter on xenobiotic uptake. Using immortalized cell lines, pharmacologic inhibition and genetic knockdown of NHE1 mitigated the paracellular uptake of radiolabeled sucrose implicating functional NHE1 in BBB maintenance. In contrast, loss of functional NHE1 in endothelial cells facilitated uptake of the anti-migraine therapeutic, sumatriptan. In female rats, cortical KCl but not aCSF selectively reduced total expression of NHE1 in cortex and PAG with limited impact on trigeminal ganglia or trigeminal nucleus caudalis suggesting in vitro observations may have a significance in vivo. Pharmacological inhibition of NHE1 prior to cortical manipulations enhanced the efficacy of sumatriptan at early time-points but induced facial sensitivity alone. Overall, our results suggest that dysregulation of NHE1 contributes to breaches in BBB integrity, drug penetrance, and the behavioral sensitivity to the antimigraine agent, sumatriptan.

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