New research published on how increased levels of glutamate are found in cerebrospinal fluid and blood of pwMS--and how that may contribute to death of oligodendocytes. If you're interested in how this ties in to CCSVI, check out Dr. Hubbard's "theory of MS"....it is the primary death of the oligodendocytes that he believes initiates the immune response. This is also covered in research compiled by Marie Rhodes in her new book....www.ccsvibook.com
As readers of this page can already probably guess...the same reaction of excitotoxicity due to increased release of glutamate is found in cerebrovascular disease, ischemia, hypoxia and oxytosis-- or lack of oxygen in the brain related to hypoperfusion, or slowed blood flow.
Neuronal injury caused by ischemia after occlusion of cerebral arteries is believed to be mediated by excessive activation of glutamate receptors. In the ischemic brain, extracellular glutamate is elevated rapidly after the onset of ischemia and declines following reperfusion.
http://www.ncbi.nlm.nih.gov/pubmed/11459428?dopt=Abstract
Here's a wonderful article in Nature regarding excitotoxic cell death and glutamate
http://www.nature.com/nrn/journal/v4/n8/box/nrn1174_BX1.html
The research linking MS to other cerebrovascular diseases continues to grow.
Here's the new paper--note the similar mechanisms found in MS and ischemia.
These researchers found higher levels of glutamate and also xCT, a cysteine/glutamate transporting protein, in the blood of pwMS. Here are selections from the paper, with the full link below.
Glutamate excitotoxicity contributes to oligodendrocyte and tissue damage in multiple sclerosis (MS). Intriguingly, glutamate level in plasma and cerebrospinal fluid of MS patients is elevated, a feature which may be related to the pathophysiology of this disease.
In addition to glutamate transporters, levels of extracellular glutamate are controlled by cystine/glutamate antiporter xc-, an exchanger that provides intracellular cystine for production of glutathione, the major cellular antioxidant. The objective of this study was to analyze the role of the system xc- in glutamate homeostasis alterations in MS pathology.
Methods: Primary cultures of human monocytes and the cell line U-937 were used to investigate the mechanism of glutamate release.
Expression of xCT was quantified by quantitative PCR, Western blot, flow cytometry and immunohistochemistry in monocytes in vitro, in animals with experimental autoimmune encephalomyelitis (EAE),the animal model of MS, and in samples of MS patients.Results and discussion We show here that human activated monocytes release glutamate through cystine/glutamate antiporter xc- and that the expression of the catalytic subunit xCT is upregulated as a consequence of monocyte activation. In addition, xCT expression is also increased in EAE and in the disease proper.
In the later (MS in humans), high expression of xCT occurs both in the CNS and in peripheral blood cells. In particular, cells from monocyte-macrophage-microglia lineage have higher xCT expression in MS and in EAE, indicating that immune activation upregulates xCT levels, which may result in higher glutamate release and contribution to excitotoxic damage to oligodendrocytes.
Consistent with the findings in the EAE model, MS patients show an increased xCT expression in spinal cord macrophages which are located in blood vessels and form cell clusters. Moreover, higher xCT expression in leukocytes during the course of MS relapses suggests dynamic changes in response to inflammatory activity. An increased expression of xCT or an altered function of xc other CNS disorders [40]. In malignant brain tumors, glutamate release by glioma cells through the xc - system contributes to glioma-induced peritumoral cell death, and inhibition of its activity lessens neurodegeneration and alleviates perifocal edema [41]. In addition, an increased expression of xCT has been described in an animal model of
Parkinson´s disease [42] and in reactive microglia located in amyloid plaques of transgenic mice expressing mutant human amyloid precursor protein, as well as in wild-type mice injected with amyloid-ß [26]. Altogether data indicate that xc - system expression is altered as a consequence of inflammation and oxidative stress in CNS disorders with an important inflammatory component. Because system xc plays an
essential role in the antioxidant defense of the cell [38, 43], more detailed studies are
needed to determine whether the system constitutes a new therapeutic target for these
disorders.
Conclusions: Together, these results reveal that increased expression of the cystine/glutamate antiporter system xc- in MS provides a link between inflammation and excitotoxicity in demyelinating diseases.
Author: Olatz PampliegaMaria DomercqFedercio SoriaPablo VillosladaAlfredo Rodriguez-AntiguedadCarlos Matute
Credits/Source: Journal of Neuroinflammation 2011, 8:63
Full paper:
http://www.jneuroinflammation.com/content/pdf/1742-2094-8-63.pdf
onward!
Joan