Are the levels of Soluble CD44 increased in ALS?

Mary

7 June 2001, Volume 20, Number 26, Pages 3399-3408
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Original Paper
Soluble CD44 inhibits melanoma tumor growth by blocking cell surface CD44 binding to hyaluronic acid

Thomas Ahrens1, Jonathan P Sleeman2, Christoph M Schempp1, Norma Howells2, Martin Hofmann3, Helmut Ponta2, Peter Herrlich2 and Jan C Simon1

1Department of Dermatology, University of Freiburg, Hauptstrasse 7, D-79104, Freiburg, Germany

2Forschungszentrum Karlsruhe, Institute of Genetics, D-76021 Karlsruhe, Germany

3Lion Bioscience AG, Im Neuenheimer Feld 515-517, D-69120 Heidelberg, Germany


Correspondence to: J C Simon, Department of Dermatology, University of Freiburg, Hauptstrasse 7, D-79104, Freiburg, Germany


Abstract

Proteolytic cleavage of the extracellular domain of CD44 from the surface of cells has been observed recently in different cell types. In cell culture supernatants of human melanoma cell lines a 70 kDa soluble CD44 protein (solCD44) was detected at concentrations of 250-300 ng/ml. Protease inhibitor studies revealed that serine proteases and metalloproteases are involved in the cleavage of CD44 from the surface of melanoma cells. To analyse a possible function of soluble CD44 a human malignant melanoma cell line was stably transfected with cDNAs encoding either wild type soluble CD44s or mutated forms with defective HA binding properties (CD44sR41A and CD44sR150A/R154A). Soluble CD44s almost completely inhibited hyaluronic acid binding by melanoma cells, whereas soluble CD44 mutated in the HA binding domain had no effect. When cultivated on hyaluronic acid, melanoma cell proliferation was induced by 30% for both the parental and the control transfected cells. This increase in proliferation was blocked completely in solCD44s-secreting transfectants, whereas solCD44sR41A and solCD44sR150A/R154A-secreting cells again showed hyaluronic acid-induced cell proliferation. These cell lines were subcutaneously injected into MF1 nu/nu mice to compare their growth as tumors in vivo. Compared to tumors derived from parental and control transfected cells, we observed a dramatic reduction of primary tumor growth with solCD44s expressing MM cells. Transfectants expressing solCD44s mutated in the HA binding domain in contrast developed fast-growing primary tumors. These results provide strong evidence that direct solCD44 interactions with hyaluronic acid interfere competively with processes induced by hyaluronic acid binding to surface CD44. Autocrine, or drug-induced secretion of solCD44 by human melanoma cells may thus exert potent antitumoral effects in vivo. Oncogene (2001) 20, 3399

Plasmapheresis did not work but I often wonder if a straight (regular) transfusion from a young blood relative would carry the 'factors' necessary as an ALS therapeutic?

We've seen a recent study in which chronic cerebrospinal venous insufficiency has been suggested to result in the deposition of iron in multiple sclerosis. It would appear that Calcium Dobesilate (Doxium) may benefit both ALS and MS.

Mary

ANGIOLOGY
Calcium Dobesilate for Chronic Venous Insufficiency: A Systematic Review
Agustín Ciapponi, MD
Family and Preventive Medicine Division, Hospital Italiano de Buenos Aires, agustin.ciapponi@hospitalitaliano.org.ar

Enrique Laffaire, MD

Programa de Efectividad Clínica, Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Argentina

Marta Roqué, BSc

Department of Clinic Epidemiology and Public Health, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Chronic venous insufficiency (CVI) causes much discomfort and sick leave. Many randomized clinical trials (RCTs) have shown a beneficial effect of calcium dobesilate, but consensus is lacking about efficacy and safety. The authors report a meta-analysis of the effectiveness and safety of calcium dobesilate in CVI. Ten RCTs (778 patients) in which calcium dobesilate for CVI was compared with placebo met the inclusion criteria. Only 3 trials (608 patients) were of good methodological quality. Calcium dobesilate significantly improved night cramps and discomfort nearly twice as well as placebo, with the number needed to treat (NNT) being 8 (95% CI 4-50) and 4 (95% CI 3-7), respectively. Frequency of adverse events was not significantly different from placebo. Subgroup analysis found a differential response with respect to disease severity, with greater improvements in pain, heaviness, and malleolar swelling being seen in the severe group than in the mild group. Calcium dobesilate improved paresthesias significantly more than placebo in the severe but not in the mild group and the effect on leg volume was also significantly better in the severe group (-7.2% vs -1.6%). No difference in effect was found for different doses of calcium dobesilate (1,000 or 1,500 mg/day). Sensitivity analyses did not affect the results. Current evidence suggests that calcium dobesilate is more effective than placebo in improving some CVI symptoms, that there is higher efficacy in more severe disease, and that a dose of 1,000 mg/day is as effective and safe as 1,500 mg/day. Further adequately powered trials are needed to further evaluate these hypotheses

http://www.pharmaforte.com.my/images/pdf/OM%20Pharma.pdf

PROPERTIES

Doxium corrects capillary hyperpermeability and increases capillary resistance. It antagonises the effect of

vasoactive substances (histamine, serotonin, bradykinin, prostaglandins and PAF), acts against collagen breakdown,

reduces blood hyperviscosity, increases red cell flexibility, diminishes platelet hyperaggregation and improves

lymphatic drainage.

Hyperphosphorylation of tau protein in superficial CNS siderosis
Journal of the Neurological Sciences, Volume 273, Issue 1, Pages 130-132
D. Kondziella, H. Zetterberg

Abstract
In superficial CNS siderosis chronic subarachnoidal hemorrhage leads to hemosiderin deposits in the subpial layers of the brain and spinal cord. Many years usually pass between the initial event causing chronic bleedings and the development of cerebellar ataxia, sensory hearing loss and various sensorimotor deficits. The only therapeutic option is to identify and eliminate the bleeding source. Otherwise slow relentless decline to a bedridden state and dementia is usually unavoidable. However, it is not known how precisely leptomeningeal hemosiderin deposits induce progressive neurodegeneration. Here we present the first report of a patient with superficial CNS siderosis in whom cerebrospinal fluid biomarkers of brain damage were assessed. Levels of neurofilament light protein, glial fibrillary acidic protein, total tau protein and, most importantly, hyperphosphorylated tau protein were increased. The results indicate that in superficial CNS siderosis neurodegeneration may be secondary to iron toxicity and oxidative stress. Similar mechanisms have been suggested for other neurodegenerative disorders such as Alzheimer's disease.

NEUROLOGY 2006;66:1770-1771
© 2006 American Academy of Neurology

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Brief Communications


Tau protein hyperphosphorylation in sporadic ALS with cognitive impairment
M. J. Strong, MD, W. Yang, MD, W. L. Strong, BSc, C. Leystra-Lantz, BSc, H. Jaffe, PhD and H. C. Pant, PhD

From the Cell Biology Research Group (M.J.S., W.Y., W.L.S., C.L.-L.), Robart’s Research Institute, London, Ontario, Canada; Department of Clinical Neurological Sciences (M.J.S.), Schulich School of Medicine, The University of Western Ontario, London, Ontario, Canada; and National Institute of Neurological Disorders and Stroke (H.J., H.C.P.), National Institutes of Health, Bethesda, MD.

Address correspondence and reprint requests to Dr. Michael J. Strong, Room C7-120, UH-LHSC, London, Ontario, Canada, N6A 5A5; e-mail: mstrong@uwo.ca

The authors have characterized frontal cortical tau protein in cognitively intact (4) and cognitively impaired (ALSci, 4) ALS patients and compared it with control (2) or Alzheimer disease (AD, 1)- derived tau. The authors observed expression of both 3R and 4R tau isoforms; increased insoluble tau protein; phosphatase resistance; and hyperphosphorylation at T175, S208, and S210. Soluble tau from both AD and ALSci was also phosphorylated at S237. Tau hyperphosphorylation is associated with ALS.

Just summarizing here. I've asked whether you may expect hyperviscosity due to the increased serum hyaluronic acid in ALS. Hyaluronic acid binds CD44. If so, then calcium dobesilate (Doxium) may be beneficial. Further to that, it corrects capillary hyperpermeability which is a problem in the SOD1 mice. With increased permeability you have depostition of hemosiderin. APC has been found to reduce this, but is too expensive.

Doxium has been reported to be beneficial in venous insufficiency, therefore may be expected to be beneficial for those reporting swelling of legs and ankles. Hemosiderin deposits have been found in the inguinal lymph nodes in venous insufficiency. Hyperphosphorylated tau is reported in superficial CNS siderosis. Hyperphosphorylated tau is reported in SALS with dementia. Are the soccer players more likely to suffer a subarachnoid haemorrage?

The study "Superficial siderosis associated with anterior horn cell dysfunction" above is most interesting.

Deposition of hemosiderin is reported in Wegener's Granulomatosis and hemochromatosis, both of which have been associated with ALS. I see they also mention its association with Goodpasture's syndrome. The autoantigen in Goodpasture's syndrome ( GPBP/CERT) is a ceramide transporter. Increased accumulation of sphingomyelin, ceramides, and cholesterol esters is reported in the SOD1 mice?

Should anyone think that Doxium may be beneficial, the good news is that is out there now. Has anyone tried this, or know of any trials with this drug for ALS?

Mary

http://en.wikipedia.org/wiki/Hemosiderosis

http://en.wikipedia.org/wiki/Wikipedia:Text_of_Creative_Commons_Attribution-ShareAlike_3.0_Unported_License

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This article is about accumulation of hemosiderin. For other uses, see Iron overload#Terminology.
Hemosiderosis
Classification and external resources

Image of a kidney viewed under a microscope. The brown areas contain hemosiderin
MeSH D006486

Hemosiderosis (AmE) or haemosiderosis (BrE) is a form of iron overload disorder resulting in the accumulation of hemosiderin.

Types include:

Transfusion hemosiderosis
Idiopathic pulmonary haemosiderosis
Hemosiderin deposition in the lungs is often seen after diffuse alveolar hemorrhage, which occurs in diseases such as Goodpasture's syndrome, Wegener's granulomatosis, and idiopathic pulmonary haemosiderosis. Mitral stenosis can also lead to pulmonary hemosiderosis. Hemosiderin collects throughout the body in hemochromatosis. Hemosiderin deposition in the liver is a common feature of hemochromatosis and is the cause of liver failure in the disease. Deposition in the pancreas leads to diabetes and in the skin leads to hyperpigmentation. Hemosiderin deposition in the brain is seen after bleeds from any source, including chronic subdural hemorrhage, Cerebral arteriovenous malformations, cavernous hemangiomata. Hemosiderin collects in the skin and is slowly removed after bruising; hemosiderin may remain in some conditions such as stasis dermatitis. Hemosiderin in the kidneys have been associated with marked hemolysis and a rare blood disorder called Paroxysmal Nocturnal Hemoglobinuria.

Hemosiderin may deposit in diseases associated with iron overload. These diseases are typically diseases in which chronic blood loss requires frequent blood transfusions, such as sickle cell anemia and thalassemia.

[edit] Treatment
Treatment for hemosiderin focuses on limiting the effects of the underlying disease leading to continued deposition. In hemochromatosis, this entails frequent phlebotomy. In diseases such as Wegener's granulomatosis, immune suppression is required. Limiting blood transfusions and institution of iron chelation therapy when iron overload is detected are important when managing sickle-cell anemia and other chronic hemolytic anemias.

Journal of Chemical Neuroanatomy
Volume 38, Issue 2, October 2009, Pages 97-105

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doi:10.1016/j.jchemneu.2009.06.005 | How to Cite or Link Using DOI
Copyright © 2009 Elsevier B.V. All rights reserved.
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The expression of the Goodpasture antigen-binding protein (ceramide transporter) in adult rat brain


Chiara Mencarellia, b, 1, Caroline Hammelsa, b, 1, Joost Van Den Broecka, b, Mario Losena, b, Hellen Steinbuscha, b, Francisco Revertc, Juan Sausc, David A. Hopkinsd, Marc H. De Baetsa, b, e, Harry W. Steinbuscha, b and Pilar Martinez-Martineza, b, ,

aDepartment of Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands

bEuropean Graduate School of Neuroscience (EURON), The Netherlands

cCentro de Investigación Príncipe Felipe and Departamento de Bioquímica y Biología Molecular, Universidad de Valencia, Valencia, Spain

dDepartment of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada

eNeuroimmunology Group, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium

Received 19 January 2009; revised 11 June 2009; accepted 12 June 2009. Available online 23 June 2009.

Abstract
The Goodpasture antigen-binding protein (GPBP) plays a critical role in brain development. Knockdown of GPBP leads to loss of myelinated tracts in the central nervous system and to extensive apoptosis in the brain during early embryogenesis. GPBP was initially identified as a protein associated with the autoantigen in Goodpasture autoimmune syndrome, where it was shown to be a kinase that regulates type IV collagen organization. GPBP isoforms bind and transport ceramide from the endoplasmic reticulum to the Golgi apparatus and are therefore also known as ceramide transporters (CERT). Ceramide dysregulation is involved in autoimmunity and neurodegenerative disorders.

In order to analyze the possible role of GPBP in neuroinflammation and neurodegeneration we studied the basal GPBP expression in normal rat brain. High levels of immunoreactivity were detected in neurons of the cerebral cortex, hippocampal formation, the basal ganglia, the olfactory bulb and nuclei of the thalamus, the hypothalamus and the septal area. Lower expression levels of GPBP were observed widely throughout the brain, suggesting that GPBP plays an important role in central nervous system neuron function.

Ann Neurol. 2002 Oct;52(4):448-57.

Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis.
Cutler RG, Pedersen WA, Camandola S, Rothstein JD, Mattson MP.

Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, MD, USA.

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons in the spinal cord resulting in progressive paralysis and death. The pathogenic mechanism of ALS is unknown but may involve increased oxidative stress, overactivation of glutamate receptors, and apoptosis. We report abnormalities in sphingolipid and cholesterol metabolism in the spinal cords of ALS patients and in a transgenic mouse model (Cu/ZnSOD mutant mice), which manifest increased levels of sphingomyelin, ceramides, and cholesterol esters; in the Cu/ZnSOD mutant mice, these abnormalities precede the clinical phenotype. In ALS patients and Cu/Zn-SOD mutant mice, increased oxidative stress occurs in association with the lipid alterations, and exposure of cultured motor neurons to oxidative stress increases the accumulation of sphingomyelin, ceramides, and cholesterol esters. Pharmacological inhibition of sphingolipid synthesis prevents accumulation of ceramides, sphingomyelin, and cholesterol esters and protects motor neurons against death induced by oxidative and excitotoxic insults. These findings suggest a pivotal role for altered sphingolipid metabolism in the pathogenesis of ALS.

PMID: 12325074 [PubMed - indexed for MEDLINE]

OXYSTEROL BINDING PROTEIN (OSBP) AND VAMP-ASSOCIATED

PROTEIN (VAP) ARE REQUIRED FOR STEROL-DEPENDENT ACTIVATION

OF THE CERAMIDE TRANSPORT PROTEIN (CERT)

? hemosiderosis or Superficial siderosis of the CNS.

http://www.usatoday.com/sports/baseball/2007-06-18-focus-concussions_N.htm

Baseball taking note of concussions

http://news.google.com/newspapers?nid=2206&dat=19410602&id=BzYuAAAAIBAJ&sjid=qtQFAAAAIBAJ&pg=4880,748344

Concussion From Beaning Failed To Bench Lou .Gehrig

This study below posted by majestik12


In 1976, the journal Neurology suggested that Lou Gehrig's
disease might be induced by an autoimmune response to bovine
proteins (Volume 26:2, 167-172).

Frank Oski, M.D., once Chief of Pediatrics at Johns Hopkins
Medical School wrote on page 63 of his best selling book,
"Don't Drink Your Milk":

"It may be more than coincidence that a group of
investigators from the Baylor College of Medicine in
Houston, Texas, also identified milk consumption as a factor
in...amyotrophic lateral scleroses--also popularly known as
Lou Gehrig's Disease after the famous athlete who was a
victim of this disorder. The neurologists analyzed many
variables in twenty-five patients with this disease and
compared the patient's histories with twenty-five healthy
individuals of similar sex, age, racial background, economic
status, and education. The factors that set aside the
patients with amyotrophic lateral scleroses from their
normal counterparts was that the patients reported an
increased incidence of exposure to lead and mercury, more
participation in sports, and higher ingestion of cow's milk.More food for thought."

Are you more likely to develop an allergy to protein in cow's milk with greater consumption?

Image Name: minocycline_pigmentation_1_041027 File Type: jpg
Diagnosis: HYPERPIGMENTATION /
DRUG REACTION, HYPERPIGMENTATION /
MINOCYCLINE REACTION Category: drug reaction /
hyperpigmentation /
treatment complication
Body Site: leg / shin Age: 54 years
Contributor: Bernard Cohen, MD
Description: subtle generalized hyperpigmentation and irregular patchy bronze-brown hyperpigmentation around scar
Comments: This 54-year-old man with a history of recurrent acne was treated intermittently with oral minocycline. He developed subtle generalized hyperpigmentation and patchy bronze-brown patches on his left leg. He had chronic edema and a well healed scar on the left leg from an old injury. A skin biopsy showed increased melanin and hemosiderin-like pigment consistent with the melanin-iron complex found in some patients with minocycline hyperpigmentation.
Related Images: minocycline_pigmentation_2_041027



http://dermatlas.med.jhmi.edu/derm/result.cfm?Diagnosis=1579193659

JAMA. 1980 Sep 5;244(10):1103-6.

Minocycline-induced pigmentation at sites of cutaneous inflammation.
Fenske NA, Millns JL, Greer KE.

In four cases of minocycline hydrochloride-induced cutaneous pigmentation, blue-gray discoloration in sites of cutaneous inflammation was seen in all cases. An additional finding of generalized, brown hyperpigmentation with accentuation in sun-exposed areas was noted in one. Although all of the patients had used relatively high doses of medication, the variable duration of therapy before pigmentary changes and dearth of similar reports suggest an idiosyncratic response to this commonly used medication. Histochemical stains and electron microscopic studies suggest hemosiderin or a pigment with similar staining properties; a minocycline degradation product, however, cannot be discounted.

PMID: 6447805 [PubMed - indexed for MEDLINE]

J Clin Neuromuscul Dis. 2010 Mar;11(3):137-44.

Superficial siderosis mimicking amyotrophic lateral sclerosis.
Driver-Dunckley ED, Hoxworth JM, Patel NP, Bosch EP, Goodman BP.

From the *Departments of Neurology; daggerRadiology; and double daggerNeurosurgery, Mayo Clinic, AZ.

We report a case of superficial siderosis erroneously diagnosed as amyotrophic lateral sclerosis. The patient's symptoms began 18 years prior with unilateral upper extremity weakness, fasciculations, and hyperreflexia. The patient then developed ataxia and hearing loss 15 years after his original symptoms. The magnetic resonance images revealed superficial siderosis involving the spinal cord and brain. We want to attract attention to superficial siderosis as a rare amyotrophic lateral sclerosis mimic disorder.

PMID: 20215988 [PubMed - in process]

Hi Donna,

I see that roflumilast diminished microvascular permeability in histamine sensitive postcapillary venules in this study.

Mary


Br J Pharmacol. 2007 Oct;152(4):481-92. Epub 2007 Aug 20.

Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability.
Sanz MJ, Cortijo J, Taha MA, Cerdá-Nicolás M, Schatton E, Burgbacher B, Klar J, Tenor H, Schudt C, Issekutz AC, Hatzelmann A, Morcillo EJ.

Department of Pharmacology, University of Valencia, Valencia, Spain.

BACKGROUND AND PURPOSE: The present study addressed the effects of the investigational PDE4 inhibitor roflumilast on leukocyte-endothelial cell interactions and endothelial permeability in vivo and in vitro. EXPERIMENTAL APPROACH: In vivo, intravital video-microscopy was used to determine effects of roflumilast p.o. on leukocyte-endothelial cell interactions and microvascular permeability in rat mesenteric venules. In vitro, the effects of roflumilast N-oxide, the active metabolite of roflumilast in humans, and other PDE4 inhibitors on neutrophil adhesion to tumour necrosis factor alpha (TNFalpha)-activated human umbilical vein endothelial cells (HUVEC), E-selectin expression and thrombin-induced endothelial permeability was evaluated. Flow cytometry was used to determine the effect of roflumilast on N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced CD11b upregulation on human neutrophils. KEY RESULTS: In vivo, roflumilast, given 1 h before lipopolysaccharide (LPS), dose-dependently reduced leukocyte-endothelial cell interactions in rat mesenteric postcapillary venules. It also diminished histamine-induced microvascular permeability. Immunohistochemical analyses revealed that roflumilast prevented LPS-induced endothelial P- and E-selectin expression. In vitro, roflumilast N-oxide concentration-dependently suppressed neutrophil adhesion to TNFalpha-activated HUVEC and CD11b expression on fMLP-stimulated neutrophils. It also reduced TNFalpha-induced E-selectin expression on HUVEC, when PDE3 activity was blocked. HUVEC permeability elicited by thrombin was concentration-dependently suppressed by roflumilast N-oxide. While roflumilast N-oxide was as potent as roflumilast at inhibiting stimulated endothelial cell and neutrophil functions, both compounds were significantly more potent than the structurally unrelated PDE4 inhibitors, rolipram or cilomilast. CONCLUSIONS AND IMPLICATIONS: These findings further support earlier observations on the inhibition of inflammatory cell influx and protein extravasation by roflumilast in vivo.

PMID: 17704822 [PubMed - indexed for MEDLINE]