Diseases involving the blood-brain barrier

Meningitis
Meningitis is an inflammation of the membranes that surround the brain and spinal cord (these membranes are also known as meninges). Meningitis is most commonly caused by infections with various pathogens, examples of which are Streptococcus pneumoniae and Haemophilus influenzae. When the meninges are inflamed, the blood-brain barrier may be disrupted. This disruption may increase the penetration of various substances (including either toxins or antibiotics) into the brain. Antibiotics used to treat meningitis may aggravate the inflammatory response of the central nervous system by releasing neurotoxins from the cell walls of bacteria-like lipopolysaccharide (LPS) [9] Treatment with third-generation or fourth-generation cephalosporin is usually preferred.
Epilepsy
Epilepsy is a common neurological disease that is characterized by recurrent and sometimes untreatable seizures. Several clinical and experimental data have implicated the failure of blood-brain barrier function in triggering chronic or acute seizures,[10][11] some studies implicate the interactions between a common blood protein - albumin and astrocytes.[12] These findings have shown that acute seizures are a predictable consequence of disruption of the BBB by either artificial or inflammatory mechanisms. In addition, expression of drug resistance molecules and transporters at the BBB are a significant mechanism of resistance to commonly used anti-epileptic drugs.[13]
Multiple sclerosis (MS)
Multiple sclerosis (MS) is considered to be an auto-immune and neurodegenerative disorder in which the immune system attacks the myelin that protects and electrically insulates the neurons of the central and peripheral nervous systems. Normally, a person's nervous system would be inaccessible to the white blood cells due to the blood-brain barrier. However, it has been shown using Magnetic Resonance Imaging, that when a person is undergoing an MS "attack," the blood-brain barrier has broken down in a section of the brain or spinal cord, allowing white blood cells called T lymphocytes to cross over and attack the myelin. It has sometimes been suggested that, rather than being a disease of the immune system, MS is a disease of the blood-brain barrier.[14] A recent study suggests that the weakening of the blood-brain barrier is a result of a disturbance in the endothelial cells on the inside of the blood vessel, due to which the production of the protein P-glycoprotein is not working well.
There are currently active investigations into treatments for a compromised blood-brain barrier. It is believed that oxidative stress plays an important role into the breakdown of the barrier. Anti-oxidants such as lipoic acid may be able to stabilize a weakening blood-brain barrier.[15]
Neuromyelitis optica
Neuromyelitis optica, also known as Devic's disease, is similar to and is often confused with multiple sclerosis. Among other differences from MS, a different target of the autoimmune response has been identified. Patients with neuromyelitis optica have high levels of antibodies against a protein called aquaporin 4 (a component of the astrocytic foot processes in the blood-brain barrier).[16]
Late-stage neurological trypanosomiasis (Sleeping sickness)
Late-stage neurological trypanosomiasis, or sleeping sickness, is a condition in which trypanosoma protozoa are found in brain tissue. It is not yet known how the parasites infect the brain from the blood, but it is suspected that they cross through the choroid plexus, a circumventricular organ.
Progressive multifocal leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system that is caused by reactivation of a latent papovavirus (the JC polyomavirus) infection, that can cross the BBB. It affects immune-compromised patients and it is usually seen with patients suffering from AIDS.
[edit] De Vivo disease
De Vivo disease (also known as GLUT1 deficiency syndrome) is a rare condition caused by inadequate transportation of the sugar, glucose, across the blood-brain barrier, resulting in mental retardation and other neurological problems. Genetic defects in glucose transporter type 1 (GLUT1) appears to be the primary cause of De Vivo disease.[17][18]
Alzheimer's Disease
Some new evidence indicates [19] that disruption of the blood-brain barrier in Alzheimer's Disease patients allows blood plasma containing amyloid beta (Aβ) to enter the brain where the Aβ adheres preferentially to the surface of astrocytes. These findings have led to the hypotheses that (1) breakdown of the blood-brain barrier allows access of neuron-binding autoantibodies and soluble exogenous Aβ42 to brain neurons and (2) binding of these auto-antibodies to neurons triggers and/or facilitates the internalization and accumulation of cell surface-bound Aβ42 in vulnerable neurons through their natural tendency to clear surface-bound autoantibodies via endocytosis. Eventually the astrocyte is overwhelmed, dies, ruptures, and disintegrates, leaving behind the insoluble Aβ42 plaque. Thus, in some patients, Alzheimer’s disease may be caused (or more likely, aggravated) by a breakdown in the blood-brain barrier. [1]
The herpes virus produces the amyloid beta (Aβ), and this virus has been found to be the pathogen responsible for being a major cause of the disease. [2]
HIV Encephalitis
It is believed [20] that latent HIV can cross the blood-brain barrier inside circulating monocytes in the bloodstream ("Trojan horse theory") within the first 14 days of infection. Once inside, these monocytes become activated and are transformed into macrophages. Activated macrophages release virions into the brain tissue proximate to brain microvessels. These viral particles likely attract the attention of sentinel brain microglia and perivascular macrophages initiating an inflammatory cascade that may cause a series of intracellular signaling in brain microvascular endothelial cells and damage the functional and structural integrity of the BBB. This inflammation is HIV encephalitis (HIVE). Instances of HIVE probably occur throughout the course of AIDS and are a precursor for HIV-associated dementia (HAD). The premier model for studying HIV and HIVE is the simian model.
References
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^ Lina Stern: Science and fate by A.A. Vein. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
^ Silva, GA (December 2008). "Nanotechnology approaches to crossing the blood-brain barrier and drug delivery to the CNS". BMC Neuroscience 9 (Suppl. 3): S4. doi:10.1186/1471-2202-9-S3-S4. PMID 19091001. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19091001.
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^ Hashizume, H; Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM (April 2000). "Openings between defective endothelial cells explain tumor vessel leakiness". American Journal of Pathology 156 (4): 1363–1380. PMID 10751361.
^ Schneider, SW; Ludwig T, Tatenhorst L, Braune S, Oberleithner H, Senner V, Paulus W (March 2004). "Glioblastoma cells release factors that disrupt blood-brain barrier features". Acta Neuropathologica 107 (3): 272–276. doi:10.1007/s00401-003-0810-2. PMID 14730455.
^ Beam, TR Jr.; Allen, JC (December 1977). "Blood, brain, and cerebrospinal fluid concentrations of several antibiotics in rabbits with intact and inflamed meninges". Antimicrobial agents and chemotherapy 12 (6): 710–6. PMID 931369.
^ E. Oby and D. Janigro, The Blood-brain barrier and epilepsy. Epilepsia. 2006 Nov;47(11):1761-74
^ Marchi,N. et al. Seizure-Promoting Effect of Blood-Brain Barrier Disruption. Epilepsia 48(4), 732-742 (2007). Seiffert,E. et al. Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J. Neurosci. 24, 7829-7836 (2004). Uva,L. et al. Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood-brain barrier permeability. Neuroscience (2007). van Vliet,E.A. et al. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130, 521-534 (2007).
^ Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O et al. (2007). "TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis.". Brain 130 (Pt 2): 535–47. doi:10.1093/brain/awl317. PMID 17121744. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17121744.
^ Awasthi,S. et al. RLIP76, a non-ABC transporter, and drug resistance in epilepsy. BMC. Neurosci. 6, 61 (2005). Loscher,W. & Potschka,H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat. Rev. Neurosci. 6, 591-602 (2005).
^ Waubant E (2006). "Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis". Disease Markers 22 (4): 235–44. PMID 17124345. http://iospress.metapress.com/openurl.asp?genre=article&issn=0278-0240&volume=22&issue=4&spage=235.
^ Schreibelt G, Musters RJ, Reijerkerk A, et al. (August 2006). "Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity". J. Immunol. 177 (4): 2630–7. PMID 16888025. http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=16888025.
^ Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR (August 2005). "IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel". J. Exp. Med. 202 (4): 473–7. doi:10.1084/jem.20050304. PMID 16087714.
^ Pascual, JM; Wang D, Lecumberri B, Yang H, Mao X, Yang R, De Vivo DC (May 2004). "GLUT1 deficiency and other glucose transporter diseases". European journal of endocrinology 150 (5): 627–33. doi:10.1530/eje.0.1500627. PMID 15132717.
^ Klepper, J; Voit T (June 2002). "Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain-- a review". European journal of pediatrics 161 (6): 295–304. doi:10.1007/s00431-002-0939-3. PMID 12029447.
^ Microvascular injury and blood–brain barrier leakage in Alzheimer’s disease - Zipser et al 2006
^ http://arjournals.annualreviews.org/doi/pdf/10.1146/annurev.neuro.25.112701.142822?cookieSet=1