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Methods and compositions for the prevention and treatment of inflammatory diseases or conditions

An inflammatory disease, composition technology, applied in the field of biological sciences, can solve problems such as trouble

Inactive Publication Date: 2007-01-17
MUSC FOUND FOR RES DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This defect is particularly troublesome when iNOS-mediated nitric oxide toxicity results in overt cellular damage, especially in chronic inflammatory disease states

Method used

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  • Methods and compositions for the prevention and treatment of inflammatory diseases or conditions
  • Methods and compositions for the prevention and treatment of inflammatory diseases or conditions
  • Methods and compositions for the prevention and treatment of inflammatory diseases or conditions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] Materials and Methods I

[0164] reagent. Recombinant rat interferon gamma (IFN□) and antibodies against mouse macrophage iNOS were obtained from Calbiochem (CA). DMEM and FBS were from Life Technologies Inc. Lipopolysaccharide (from E. coli serotype 0111:B4) was from Sigma (MO). Glucosylceramide, lactosylceramide, galactosylceramide, ganglioside and D-PDMP (C 23 h 38 N 2 o 3 hydrochloride; D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol hydrochloride) from Matreya Inc (PA). 14 C-galactose and 3H UDP-galactose was obtained from American Radiolabeled Chemicals (MO).

[0165] cell culture. Primary astrocyte-enriched cultures were prepared from whole cortex of 1-day-old Sprague-Dawley rats as previously described (Pahan et al., 1998). Briefly, cortices were rapidly isolated in ice-cold Hanks balanced salt solution pH 7.4 (HBSS) (Gibco, Grand Island, NY) without calcium / magnesium, as previously described (Won et al., 2001). The ti...

Embodiment 2

[0185] Result I

[0186] GSL mediates LPS / IFN□-induced NO production and iNOS gene expression. It is a complex process that LPS / IFN□ stimulates primary astrocytes to cause iNOS gene expression. This trial investigates whether the GSL is somehow involved. After pretreating primary astrocytes with several concentrations of glycosphingolipid inhibitor D-PDMP (0, 10, 25 and 50 μM) for 0.5 h, they were treated with LPS / IFN□ (1□g / ml; 10U / ml ) stimulation indicates that nitric oxide (NO) production ( Figure 1A ) and iNOS mRNA and protein levels ( Figure 1B ) decreased in a dose-dependent manner. However, in the presence of increasing doses of LacCer, D-PDMP mediated NO production ( Figure 1C ) and iNOS gene expression ( Figure 1D ) inhibition is inactivated. To demonstrate that this is a LacCer-specific result, other glycosphingolipid derivatives were also exogenously supplemented. However, Glucer ( Figure 2A ), GalCer ( Figure 2B ) and vari...

Embodiment 3

[0195] Discussion I

[0196] Nitric oxide-mediated pathophysiology is common in many neuroinflammatory diseases, including stroke and spinal cord injury (SCI). Because it is not yet fully understood which factors induce and regulate iNOS gene expression in inflammatory diseases, this study investigated the role of glycosphingolipids in primary astrocytes and elucidated the role of LacCer-mediated events of the NF-κB pathway regulate a novel pathway of iNOS genes. These conclusions are based on the following findings. (1) D-PDMP (an inhibitor of glycosphingolipid synthesis) inhibits LPS / IFN□-induced iNOS gene expression and LacCer production. Addition of exogenous lactosylceramide, but not any other glycosphingolipids, reversed the inhibition of iNOS gene expression by D-PDMP. (2) LPS / IFN□ stimulated the activity of GalT-2 within 5 minutes and rapidly increased the level of intracellular lactosylceramide. Furthermore, knockdown of GalT-2 with ant...

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Abstract

The present invention relates to methods and compositions of treating or preventing inflammatory diseases or conditions in a patient comprising administering to the patient a therapeutically effective amount of a composition comprising a glutathione donor, 5-amino 4-i mid azolecarboxamide ribotide (AICAR), a 3-hydroxy-3-methylgluatryl-coenzymeA (HMG-CoA) reductase inhibitor, D-threo-1-Phenyl-2-decanoylamino-3-morpholino-1-propanol HCl (D-PDMP), and / or 1,5-(butylimino)-1,5-dideoxy-D-glucitol (Miglustat), or derivatives thereof.

Description

[0001] This application claims priority to US Provisional Application 60 / 559,112, filed April 2, 2004, and US Provisional Application 60 / 531,828, filed December 23, 2003. These provisional applications are incorporated herein by reference. Background of the invention [0002] A. Field of Invention [0003] The present invention relates generally to the field of biological sciences. More specifically, the present invention relates to compositions and methods of use for the treatment or prevention of inflammatory diseases. [0004] B. Description of related fields [0005] Inflammatory diseases and disorders constitute a serious health problem in modern society. Current methods of treating such diseases and conditions place a huge financial burden on patients as well as the health care system as a whole. When there are many different types of inflammatory diseases, such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, viral encephalitis, acquired immu...

Claims

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Application Information

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IPC IPC(8): A61K38/00
Inventor I·辛格
Owner MUSC FOUND FOR RES DEV
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