Hi Ron,

Tysabri

Tysabri has some effect on the BBB but it doesn't close it down completely. I think we'd die if it was closed down completely since we still need many components to pass our BBB in order to nourish/protect our brains.

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

Neurology.
2004 Jun 8;62(11):2038-43.
Comment in:
Neurology. 2005 Jan 11;64(1):174-5; author reply 174-5.

Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects.

O'Connor PW, Goodman A, Willmer-Hulme AJ, Libonati MA, Metz L, Murray RS, Sheremata WA, Vollmer TL, Stone LA; Natalizumab Multiple Sclerosis Trial Group.

St. Michael's Hospital, Toronto, Ontario, Canada. oconnorp@smh.toronto.on.ca

BACKGROUND: Relapses in multiple sclerosis (MS) can cause significant neurologic disability. Natalizumab (Antegren) is a humanized anti-alpha4-integrin antibody that inhibits the trafficking of leukocytes across endothelium by blocking binding of alpha4beta1-integrin to vascular cell adhesion molecule-1.

OBJECTIVE: To assess the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses.

METHODS: In this randomized, double-blind, multicenter trial, the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses were assessed. MS patients (n = 180) in acute relapse were randomly assigned to receive a single dose of natalizumab 1 or 3 mg/kg or placebo and were followed for 14 weeks.

RESULTS: There was no difference in Expanded Disability Status Scale (EDSS) score change over time between treatment and placebo groups. In all three groups, approximately half of patients showed EDSS improvement after 2 weeks, rising to 67% by 8 weeks. EDSS improved by a mean value of 0.8 point at week 1, 1.2 points at week 4, and 1.6 points at week 8 in the natalizumab group compared with EDSS improvement of 1.0 point at week 1, 1.6 points at week 4, and 1.6 points at week 8 in the placebo group. A significant decrease in Gd-enhancing lesion volume was seen in both active treatment groups at weeks 1 and 3 compared with placebo.

CONCLUSIONS: A single dose of IV natalizumab did not hasten clinical recovery after relapse, although a significant decrease in Gd-enhancing lesion volume was observed at 1 and 3 weeks after treatment. These MRI findings are consistent with prior studies of natalizumab and support its further investigation as an agent for the treatment of MS.

PMID: 15184611 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

Mult Scler.

2004 Oct;10(5):540-8.

Macrophage brain infiltration in experimental autoimmune encephalomyelitis is not completely compromised by suppressed T-cell invasion: in vivo magnetic resonance imaging illustration in effective anti-VLA-4 antibody treatment.

Deloire MS, Touil T, Brochet B, Dousset V, Caille JM, Petry KG.
EA 2966 Neurobiology of Myelin Diseases Laboratory, University Victor Segalen Bordeaux 2, Bordeaux, France.

Large inflammatory infiltrates of T cells, macrophages and B cells in the central nervous system (CNS) contribute to the pathogenesis of multiple sclerosis (MS). The passage of T cells through the blood-brain barrier can be suppressed with antibodies directed against alpha-4 integrins (VLA-4) that mediate T-cell adherence. This treatment, in phase III of clinical trial evaluation, reduces lesion development in MS patients.

In the ongoing inflammatory disease process the consequences of T-cell inhibitory anti-VLA-4 antibodies on inflammatory compounds are still poorly investigated. We show that anti-VLA-4 antibody treatment during the late preclinical phase of the acute experimental autoimmune encephalomyelitis (EAE) MS rat model interrupts T-cell egress out of the vascular compartment and suppresses clinical disease and histological alterations but macrophage recruitment in the CNS is not fully compromised.

Among the treated EAE animals not developing disease, none presented foci of T-cell infiltration in CNS. However, in 75% of the treated EAE rats monocyte ingress in CNS was observed in vivo by magnetic resonance imaging with the ultrasmall superparamagnetic iron oxide contrast agent. Our data shed new light on the role of remaining macrophage brain infiltration in an induced but interrupted T-cell-mediated EAE disease process.

PMID: 15471371 [PubMed - indexed for MEDLINE]

ALA and Curcumin (turmeric)

Alpha lipoic acid does seem to help maintain BBB integrity. Curcumin (turmeric) has been found to have anti-inflammatory properties that have suppressed the mouse model of MS.

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

J Immunol.

2006 Aug 15;177(4):2630-7.

Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity.

Schreibelt G, Musters RJ, Reijerkerk A, de Groot LR, van der Pol SM, Hendrikx EM, Dopp ED, Dijkstra CD, Drukarch B, de Vries HE.
Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.

Reactive oxygen species (ROS) play an important role in various events underlying multiple sclerosis (MS) pathology. In the initial phase of lesion formation, ROS are known to mediate the transendothelial migration of monocytes and induce a dysfunction of the blood-brain barrier (BBB). In this study, we describe the beneficial effect of the antioxidant alpha-lipoic acid (LA) on these phenomena.

In vivo, LA dose-dependently prevented the development of clinical signs in a rat model for MS, acute experimental allergic encephalomyelitis (EAE). Clinical improvement was coupled to a decrease in leukocyte infiltration into the CNS, in particular monocytes. Monocytes isolated from the circulation of LA-treated rats revealed a reduced migratory capacity to cross a monolayer of rat brain endothelial cells in vitro compared with monocytes isolated from untreated EAE controls.

Using live cell imaging techniques, we visualized and quantitatively assessed that ROS are produced within minutes upon the interaction of monocytes with brain endothelium. Monocyte adhesion to an in vitro model of the BBB subsequently induced enhanced permeability, which could be inhibited by LA. Moreover, administration of exogenous ROS to brain endothelial cells induced cytoskeletal rearrangements, which was inhibited by LA. In conclusion, we show that LA has a protective effect on EAE development not only by affecting the migratory capacity of monocytes, but also by stabilization of the BBB, making LA an attractive therapeutic agent for the treatment of MS.

PMID: 16888025 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

J Immunol.

2002 Jun 15;168(12):6506-13.

Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes.

Natarajan C, Bright JJ.
Division of Neuroimmunology, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.

Experimental allergic encephalomyelitis (EAE) is a CD4(+) Th1 cell-mediated inflammatory demyelinating autoimmune disease of the CNS that serves as an animal model for multiple sclerosis (MS). IL-12 is a proinflammatory cytokine that plays a crucial role in the induction of neural Ag-specific Th1 differentiation and pathogenesis of CNS demyelination in EAE and MS. Curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant Curcuma longa. It has profound anti-inflammatory activity and been traditionally used to treat inflammatory disorders.

In this study we have examined the effect and mechanism of action of curcumin on the pathogenesis of CNS demyelination in EAE. In vivo treatment of SJL/J mice with curcumin significantly reduced the duration and clinical severity of active immunization and adoptive transfer EAE.

Curcumin inhibited EAE in association with a decrease in IL-12 production from macrophage/microglial cells and differentiation of neural Ag-specific Th1 cells. In vitro treatment of activated T cells with curcumin inhibited IL-12-induced tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4 transcription factors. The inhibition of Janus kinase-STAT pathway by curcumin resulted in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that curcumin inhibits EAE by blocking IL-12 signaling in T cells and suggest its use in the treatment of MS and other Th1 cell-mediated inflammatory diseases.

PMID: 12055272 [PubMed - indexed for MEDLINE]

For full article:

http://www.jimmunol.org/cgi/content/full/168/12/6506

Inosine

With respect to inosine, its effects are not direct, but on its impact on uric acid levels. Since uric acid is a Peroxynitrite scavenger (which, like nitric oxide, is a bad actor in the CNS), its ability to increase peroxynitrite scavenging levels is a good thing. Nitric Oxide increases permeability of the BBB, so decreasing NO levels and peroxynitrite levels by increasing UA levels would help reduce disruption of the BBB.

http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16410551

Full article:

http://jcs.biologists.org/cgi/content/full/119/2/339

J Cell Sci. 2006 Jan 15;119(Pt 2):339-49.

Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice.

Parathath SR, Parathath S, Tsirka SE.

Program in Molecular and Cellular Biology, Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA.

Stroke and many neurodegenerative diseases culminate in neuronal death through a mechanism known as excitotoxicity. Excitotoxicity proceeds through a complex signaling pathway that includes the participation of the serine protease tissue plasminogen activator (tPA). tPA mediates neurotoxic effects on resident central nervous system cells as well alters blood-brain barrier (BBB) permeability, which further promotes neurodegeneration. Another signaling molecule that promotes neurodegeneration and BBB dysfunction is nitric oxide (NO), although its precise role in pathological progression remains unclear. We examine here the potentially interrelated roles of tPA, NO and peroxynitrite (ONOO-), which is the toxic metabolite of NO, in BBB breakdown and neurodegeneration following intrahippocampal injection of the glutamate analog kainite (KA). We find that NO and ONOO- production are linked to tPA-mediated excitotoxic injury, and demonstrate that NO provision suffices to restore the toxic effects of KA in tPA-deficient mice that are normally resistant to excitotoxicity. NO also promotes BBB breakdown and excitotoxicity. Interestingly, BBB breakdown in itself does not suffice to elicit neurodegeneration; a subsequent ONOO(-)-mediated event is required. In conclusion, NO and ONOO- function as downstream effectors of tPA-mediated excitotoxicity.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

PMID: 16410551 [PubMed - indexed for MEDLINE]



http://cat.inist.fr/?aModele=afficheN&cpsidt=3622581

Titre du document / Document title

Role of nitric oxide in disruption of the blood-brain barrier during acute hypertension

Auteur(s) / Author(s)
MAYHAN W. G. ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
Univ. Nebraska medical cent., dep. physiology biophysics, Omaha NE 68198-4575, ETATS-UNIS

Résumé / Abstract
The goal of this study was to determine the role of nitric oxide in disruption of the blood-brain barrier during acute hypertension. We examined the microcirculation of the cerebrum in vivo. Permeability of the blood-brain barrier was quantitated by the formation of venular leaky sites and clearance of fluorescent-labeled albumin (FITC-albumin) before and during phenylephrine-induced acute hypertension.

We compared disruption of the blood-brain barrier during acute hypertension in untreated rats and in rats treated for 1 h with topical application of N[G]-monomethyl-L-arginine (L-NMMA ; 100 μM) or N[G]-nitro-L-arginine methyl ester (L-NAME ; 100 μM). Under control conditions, no venular leaky sites were visible and clearance of FITC-albumin was minimal in untreated rats and in rats treated with topical application of nitric oxide synthase inhibitors. Phenylephrine (20 μg/kg/min for 5 min) infusion increased systemic arterial pressure by a similar magnitude in all groups of rats and produced disruption of the blood-brain barrier in venules. However, the magnitude of disruption of the blood-brain barrier during acute hypertension was significantly less in rats treated with L-NMMA (52% reduction in the clearance of FITC-albumin) and L-NAME (47% reduction in clearance of FITC-albumin). The findings of the present study suggest that synthesis/release of nitric oxide contributes to disruption of the blood-brain barrier during acute hypertension.


http://www.fasebj.org/cgi/content/abstract/14/5/691

(The FASEB Journal. 2000;14:691-698.)
© 2000 FASEB

Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood–CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis

D. C. HOOPER1, G. S. SCOTT, A. ZBOREK2, T. MIKHEEVA, R. B. KEAN, H. KOPROWSKI and S. V. SPITSIN
Department of Microbiology and Immunology, Kimmel Cancer Institute, and the Biotechnology Foundation Laboratories, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA

1Correspondence: Department of Microbiology and Immunology, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107-6799, USA. E-mail douglas.c.hooper@mail.tju.edu

Peroxynitrite (ONOO-), a toxic product of the free radicals nitric oxide and superoxide, has been implicated in the pathogenesis of CNS inflammatory diseases, including multiple sclerosis and its animal correlate experimental autoimmune encephalomyelitis (EAE).

In this study we have assessed the mode of action of uric acid (UA), a purine metabolite and ONOO- scavenger, in the treatment of EAE. We show that if administered to mice before the onset of clinical EAE, UA interferes with the invasion of inflammatory cells into the CNS and prevents development of the disease. In mice with active EAE, exogenously administered UA penetrates the already compromised blood–CNS barrier, blocks ONOO--mediated tyrosine nitration and apoptotic cell death in areas of inflammation in spinal cord tissues and promotes recovery of the animals. Moreover, UA treatment suppresses the enhanced blood–CNS barrier permeability characteristic of EAE.

We postulate that UA acts at two levels in EAE: 1) by protecting the integrity of the blood–CNS barrier from ONOO--induced permeability changes such that cell invasion and the resulting pathology is minimized; and 2) through a compromised blood–CNS barrier, by scavenging the ONOO- directly responsible for CNS tissue damage and death.—Hooper, D. C., Scott, G. S., Zborek, A., Mikheeva, T., Kean, R. B., Koprowski, H., Spitsin, S. V. Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood–CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis.