Highly Enhanced Permeability of Blood‐Brain Barrier Induced by Repeated Administration of Endothelin‐1 in Dogs and Rats

Narushima, Itaru; Kita, Taizo; Kubo, Kaoru; Yonetani, Yukio; Momochi, C.; Yoshikawa, I.; Ohno, Nobutada; Nakashima, Toshikatsu

doi:10.1034/j.1600-0773.2003.920104.x

Cited by 40 publications

(24 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, ET-1 interactions with endothelin A receptors may lead to disruption of the blood-brain barrier (41). HIV-infected astrocytes are most often present at the blood-brain barrier or close to brain capillaries (6,7).…”

Section: Discussionmentioning

confidence: 99%

Molecular programming of endothelin‐1 in HIV‐infected brain: role of Tat in up‐regulation of ET‐1 and its inhibition by statins

Chauhan¹,

Hahn²,

Gartner³

et al. 2006

FASEB j.

View full text Add to dashboard Cite

Human Immune Deficiency Virus-1 (HIV-1) infection can induce severe and debilitating neurological problems, including behavioral abnormalities, motor dysfunction, and dementia. HIV can persistently infect astrocytes, during which viral accessory proteins are produced that are unaffected by current antiretroviral therapy. The effect of these proteins on astrocyte function remains unknown. Astrocytes are the predominant cells within the brain; thus, disruption of astrocyte function could influence the neuropathogenesis of HIV infection. To explore further these effects, we constitutively expressed HIV-Tat protein in astrocytes. Since the nuclear presence of Tat protein leads to alteration of host gene expression, we further analyzed the effects of Tat on host gene transcripts. Endothelin-1 (ET-1) was a significantly elevated transcript as verified by reverse transcription-polymerase chain reaction (RT-PCR), and it was subsequently released extracellularly in Tat-expressing and HIV-infected astrocytes. ET-1 expression was also prominent in reactive astrocytes and neurons in brain tissues from basal ganglia and frontal lobes of HIV encephalitic patients. HIV-Tat regulated ET-1 at the transcriptional level through NF-κB (NF-κB)-responsive sites in the ET-1 promoter. Intriguingly, simvastatin (10 µM) down-regulated HIV-Tat-induced ET-1 and also inhibited activation of NF-κB in astrocytes. Our findings suggest that ET-1 may be critical in mediating the neuropathogenesis of HIV dementia and that statins may have therapeutic potential in these patients. KeywordsHIV-neuropathogenesis; nuclear Tat; ET-1 transcriptional regulation; NF-κB; simvastatin Before the introduction of highly active antiretroviral therapy (HAART), ~30% of HIVinfected patients developed cognitive, behavioral, and motor symptoms, collectively known as HIV-associated dementia (HAD) (1). However, with the continued use of HAART, the severe form of HAD has dramatically decreased. Instead, a more subtle form of central nervous system (CNS) dysfunction, minor cognitive motor disorder, is more common in HAART-treated patients (2,3 HIV has been shown to remain in the brain resident cells productively or unproductively. Brain cells, including astrocytes, microglia, and perivascular macrophages, are susceptible to HIV infection (4); however, the latter two types are most productively infected (5). Astrocytes are the most numerous cell type within the brain, outnumbering neurons by 10:1, and provide an important reservoir for HIV infection within the brain (6-9). The virus causes a noncytopathic infection in these cells (10,11). HIV infection in astrocytes may lead to production of accessory viral proteins but may not produce fully replicative viral particles, resulting in a restricted or unproductive infection (9, 12-5). In contrast, some studies, including ours, showed productive HIV infection in human astrocytes in vitro (16,17).During HIV infection, Tat is the first viral protein produced and it subsequently induces the production of other early as ...

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular programming of endothelin‐1 in HIV‐infected brain: role of Tat in up‐regulation of ET‐1 and its inhibition by statins

Chauhan¹,

Hahn²,

Gartner³

et al. 2006

FASEB j.

View full text Add to dashboard Cite

show abstract

“…The literature contains conflicting reports as to the effects of ET-1 on brain capillary permeability. Thus, injection of ET into the brain has been reported to increase permeability (Narushima et al, 2003) or to have no significant effect (Hughes et al, 2003). In these in vivo studies, permeability measurements were made after many hours to days of ET-1 treatment.…”

Section: Regulation Of P-glycoprotein At the Blood-brain Barrier 391mentioning

confidence: 99%

Rapid Regulation of P-Glycoprotein at the Blood-Brain Barrier by Endothelin-1

Hartz

Bauer²,

Fricker³

et al. 2004

Mol Pharmacol

151

218

View full text Add to dashboard Cite

The ATP-driven xenobiotic transporter P-glycoprotein is a critical element of the blood-brain barrier. To study regulation of P-glycoprotein function, we measured specific transport [(3Ј-oxo-4-butenyl-4-methyl-threonine(1), (valine(2)) cyclosporin (PSC833)-sensitive] of the fluorescent cyclosporin A derivative [N-⑀(4-nitrobenzofurazan-7-yl)-D-Lys 8 ]-cyclosporin A (NBDL-CSA) into the lumens of isolated rat brain capillaries using confocal microscopy and quantitative image analysis. Luminal NBDL-CSA accumulation was rapidly and reversibly reduced in a concentration-dependent manner by 0.1 to 100 nM endothelin-1 (ET-1). In this concentration range, ET-1 did not affect junctional permeability. The ET B receptor agonist sarafotoxin 6c also reduced transport. An ET B receptor antagonist blocked effects of ET-1 and sarafotoxin 6c; an ET A receptor antagonist was without effect. Consistent with this, immunostaining and Western blotting showed expression of the ET B receptor in brain capillary membranes. NBDL-CSA transport was also reduced by sodium nitroprusside, a NO donor, and by phorbol ester, a protein kinase C (PKC) activator. Inhibition of NO synthase (NOS) or PKC abolished the ET-1 effects. Thus, ET-1, acting through an ET B receptor, NOS, and PKC rapidly and reversibly reduced transport mediated by P-glycoprotein at the blood-brain barrier.The structural basis of the blood-brain barrier is the nonfenestrated, brain capillary endothelium. Functionally, low passive permeability and the expression of selective, plasma membrane-bound transporters define this barrier tissue. These combine to both nourish the central nervous system (CNS) and protect it from potentially toxic chemicals. One critical selective component of the blood-brain barrier is Pglycoprotein, an ATP-driven, drug-efflux pump (Schinkel et al., 1994). This multispecific, primary active transporter, located at the luminal membrane of the brain capillary endothelium, is considered to be an important "gatekeeper" of the blood-brain barrier (Schinkel, 1999). As such, it protects the CNS from neurotoxicants and also limits brain penetration of a large number of drugs used to treat CNS disorders (Schinkel et al., 1996). In this regard, reduced P-glycoprotein function, whether the result of pump inhibition, genetic manipulation, or pathological change, substantially increases brain levels of administered drugs, including chemotherapeutics, human immunodeficiency virus protease inhibitors, anticonvulsants, antipsychotics, and glucocorticoids (Schinkel et al., 1996;Fellner et al., 2002;Goralski et al., 2003).For CNS therapy, it would clearly be advantageous to be able to modulate P-glycoprotein function over the short term while still retaining its protection over the longer term. One strategy that may accomplish this would be to transiently decrease specific efflux to the blood through rapid regulation. Unfortunately, we know little about the regulation of Pglycoprotein at the blood-brain barrier, and what we do know concerns mechanisms that take fro...

show abstract

“…In dogs, treatment with EDN1 resulted in increased permeability of the blood-brain-barrier; treatment with an EDN1 receptor antagonist reversed this and also ameliorated EAE in rats. 20,21 Furthermore, inhibition of the EDN1 receptor by antagonists or gene knockdown reduced the transmigration of monocytes through brain endothelium in vitro. 22 In this study we found increased mRNA levels of EDN1 in the CNS-infiltrating leukocytes from patients compared with controls, which are in line with the previous observations of increased plasma and CSF levels of EDN1 in MS. 23,24 Together, these results indicate that local production of EDN1 in the infiltrating leukocytes may be important for the passage of leukocytes across the bloodbrain-barrier in MS. CXCL11 is a potent chemoattractant for activated T-cells and also a ligand for CXCR3.…”

Section: Discussionmentioning

confidence: 99%