CONCLUSIONS: COX-2 expression was associated with dying oligodendrocytes in MS lesions and appeared to increase excitotoxic death of oligodendrocytes in culture. An understanding of how COX-2 expression influences oligodendrocyte death leading to demyelination may have important ramifications for future treatments for MS.
However, the side effects of spironolactone are significant while MCP is proven to achieve greater results without toxicity or side effects. Specifically, the MCP was shown to outperform spironolactone in a few key areas related to inflammation and fibrosis. MCP achieved better suppression of fibrotic markers. Importantly, MCP completely inhibited the cytokine interleukin-6 (IL-6) which plays a key role in inflammation, fibrosis, immune response and cancer/metastasis. Spironolactone only partially blocked the Aldo induced IL-6.
http://www.bizjournals.com/sacramento/p ... 20/AQ15591
Aldosterone and vascular damage
Daniel Duprez MD, DSc, PhD, Marc De Buyzere BSc, Ernst R. Rietzschel MD, Denis L. Clement MD, PhD
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Although the aldosterone escape mechanism is well known, aldosterone has often been neglected in the pathophysiologic consequences of the activated renin-angiotensinaldosterone system in arterial hypertension and chronic heart failure. There is now evidence for vascular synthesis of aldosterone aside from its secretion by the adrenal cortex. Moreover, aldosterone is involved in vascular smooth muscle cell hypertrophy and hyperplasia, as well as in vascular matrix impairment and endothelial dysfunction. The mechanisms of action of aldosterone may be either delayed (genomic) or rapid (nongenomic). Deleterious effects of aldosterone leading to vascular target-organ damage include (besides salt and water retention) decreased arterial and venous compliance, increased peripheral vascular resistance, and impaired autonomic vascular control due to baroreflex dysfunction.
http://link.springer.com/article/10.100 ... -z?LI=true
Galectin-3 Mediates Aldosterone-Induced Vascular Fibrosis.
Laurent C, Maria M, Pascal R, Victoria C, Ernesto MM, de Boer RA, Françoise P, Patrick L, Faiez Z, Patrick R, Natalia LA.
Aldosterone (Aldo) is involved in arterial stiffness and heart failure, but the mechanisms have remained unclear. Galectin-3 (Gal-3), a β-galactoside-binding lectin, plays an important role in inflammation, fibrosis, and heart failure. We investigated here whether Gal-3 is involved in Aldo-induced vascular fibrosis.
METHODS AND RESULTS:
In rat vascular smooth muscle cells Gal-3 overexpression enhanced specifically collagen type I synthesis. Moreover Gal-3 inhibition by modified citrus pectin or small interfering RNA blocked Aldo-induced collagen type I synthesis. Rats were treated with Aldo-salt combined with spironolactone or modified citrus pectin for 3 weeks. Hypertensive Aldo-treated rats presented vascular hypertrophy, inflammation, fibrosis, and increased aortic Gal-3 expression. Spironolactone or modified citrus pectin treatment reversed all the above effects. Wild-type and Gal-3 knock-out mice were treated with Aldo for 6 hours or 3 weeks. Aldo increased aortic Gal-3 expression, inflammation, and collagen type I in wild-type mice at both the short- and the long-term, whereas no changes occurred in Gal-3 knock-out mice.
Our data indicate that Gal-3 is required for inflammatory and fibrotic responses to Aldo in vascular smooth muscle cells in vitro and in vivo, suggesting a key role for Gal-3 in vascular fibrosis.
PMID: 23117656 [PubMed - as supplied by publisher]
United States Patent Application 20060014719
Kind Code A1
Chang; Yan January 19, 2006
Method for treating neurodegenerative diseases
The present invention is directed to methods and compositions for treatment of neurodegenerative diseases. In particular embodiments, the invention is directed to the treatment of Alzheimer's disease, MS, ALS, Huntington's Disease. In other embodiments, the invention is directed to the treatment of multiple sclerosis.
0017] Cell adhesion and activation of endothelial cell walls are important components of diseases such as MS or AD. The process involves a complex cascade of various molecules and mediators, including chemokines, adhesion molecules, and matrix metalloproteases. One important set of components is integrins, which may mediate the progression of these diseases.
 Integrins are the principal receptors on animal cells for binding most extracellular matrix proteins, including collagen, fibronectin, and laminin. Integrins form a large family of homologous transmembrane linker proteins, and are the main way that cells bind to and respond to the extracellular matrix. Integrins are heterodimers of .alpha. and .beta. subunits, and the ligand-binding site is composed of parts of both chains. In mammals, at least 22 integrin heterodimers, composed of 17 types of .alpha. subunits and 8 types of .beta. subunits, are known. A single .beta. chain can interact with multiple a chains, forming integrins that bind different ligands.
 .beta. integrins are generally believed to be directly associated with focal adhesion kinase (FAK). Constitutive activation of FAK is sufficient to rescue epithelial cells from anoikis, whereas apoptosis occurs if FAK is inhibited by, for example, a peptide representing the FAK-binding site of .beta.1 integrin. Several proteins that lie downstream to .beta.1 integrin in this signal transduction pathway have been identified, two of which are Akt and PI-3 kinase. Akt is a survival-promoting Ser-Thr protein kinase whose activity is regulated by a variety of growth factors in a PI 3-kinase-dependent manner. Activation of Akt has been shown to result in inhibition of apoptosis in several types of cells, including primary culture of cerebellar neurons, Rat-1, and COS-7 cells. P13 kinase and Akt both can be direct or indirect down stream effectors of FAK.
 There is evidence that the carbohydrate polymer for the use in the method of present invention interacts directly or indirectly with integrins, more specifically .beta. integrins, and prevents or attenuates the progression of the inflammatory neurodegenerative diseases. The carbohydrate useful to carry out the methods of the present invention has been shown to downregulate both FAK and Akt.
Fig. 1. Potential role for angiogenesis in MS. (1) Initially immune cells bind to the BBB through a variety of cell adhesion molecules. (2) Cells infiltrate the perivascular space. (3) Cytokine, immune and antibody mediated attack on the myelin in the perivascular space. (4) Infiltration of immune cells into the parenchyma. (5) Release of inflammatory and hypoxic mediators including VEGF, HIF-1, NO, ET-1 from various cell types. (6) Angiogenic signals cause the initiation of the formation of new blood vessels into the lesion area.
Vascular Endothelial Growth Factor Is Expressed in Multiple Sclerosis Plaques and Can Induce Inflammatory Lesions in Experimental Allergic Encephalomyelitis Rats
PROESCHOLDT, MARTIN A. MD; JACOBSON, STEVEN PHD; TRESSER, NANCY MD; OLDFIELD, EDWARD H. MD; MERRILL, MARSHA J. PHD
The active lesions in multiple sclerosis (MS) are characterized by blood-brain-barrier (BBB) breakdown, upregulation of adhesion molecules on capillary endothelial cells, and perivascular inflammation, suggesting that altered vessel permeability and activated endothelial cells are involved in the pathogenesis of the disease. Vascular endothelial growth factor (VEGF) mediates multiple aspects of blood vessel physiology, including regulation of growth, permeability, and inflammation. To investigate a possible relationship between VEGF expression and CNS autoimmune disease, we examined VEGF expression in MS plaques compared to normal white matter by immunohistochemistry and in situ hybridization. VEGF expression was consistently upregulated in both acute and chronic MS plaques. We also examined VEGF expression during the course of experimental allergic encephalomyelitis (EAE) in rats. VEGF-positive cells with astrocytic morphology increased in the spinal cord during the development of EAE and were found in association with inflammatory cells. Furthermore, intracerebral infusion of VEGF in animals previously immunized with myelin basic protein induced an inflammatory response in the brain, whereas infusion of vehicle, or infusion of VEGF in naive animals, did not. These results suggest that overexpression of VEGF may exacerbate the inflammatory response in autoimmune diseases of the CNS by inducing focal BBB breakdown and migration of inflammatory cells into the lesions.
The present invention recognizes the role of galectins in angiogenesis, and provides a therapeutic material which will advantageously interact with galectins so as to moderate or prevent the manifestations of angiogenesis-dependent disease. Specifically, the present invention recognizes that particular carbohydrate materials will bind to or otherwise interact with galectins and thereby modify their interaction with cellular structures, and thereby control angiogenesis.
Galectins comprise a family of proteins which are expressed by plant and animal cells, and which bind .beta.-galactoside sugars. These proteins can be found on cell surfaces, in cytoplasm, and in extracellular fluids. They have a molecular weight in the general range of 29-34 kd; they have an affinity for .beta.-galactoside containing materials, and have been found to play important roles in a number of biological processes. Galectin-1 and galectin-3 are specific members of this family which have been found to interact with various cellular structures, and galectin-3 has been demonstrated to promote angiogenesis in vitro.
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