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Modulation of the Phospholipase A2 Pathway as a Therapeutic

a phospholipase and pathway technology, applied in the field of phospholipase a2 pathway modulation as a therapeutic, can solve the problems of unconventional detection of such neurotoxic effects, the role of alzheimer's disease and other diseases, and the mechanism of action of alzheimer's disease, etc., and achieve the effects of enhancing et-1 induced vasoconstriction

Inactive Publication Date: 2010-12-30
PARIS DANIEL C +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods for modifying vasoactivity, treating vascular disease, and regulating inflammatory reactions in microglia and neurons by targeting a soluble Aβ pro-inflammatory pathway. A pharmaceutical composition containing an effective amount of an Aβ pro-inflammatory pathway regulator is also provided.

Problems solved by technology

However, its role in the disease process of Alzheimer's disease and other diseases, as well as its mechanism of action, remains in dispute.
However, there has been no consistent detection of such neurotoxic effects and there are conflicting reports (Price et al.

Method used

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  • Modulation of the Phospholipase A2 Pathway as a Therapeutic
  • Modulation of the Phospholipase A2 Pathway as a Therapeutic
  • Modulation of the Phospholipase A2 Pathway as a Therapeutic

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0066]The following example demonstrates that soluble Alzheimer's β-amyloid peptides mediate vasoactivity through a pro-inflammatory pathway, the phospholipase A2 / arachidonic acid / 5-lipoxygenase / cyclo-oxygenase-2 cascade. Furthermore, this example shows that blocking specific target molecules on this pathway oppose the effect of soluble Aβ peptides (1-40 and 1-42) in the vasculature.

Materials and Methods

[0067]The compounds used in vasoactivity assays include: Porcine pancreatic PLA2 (sPLA2), melittin, mastoparan and ET-1 were purchased from Sigma. Isotetrandrine, MK-886, RHC-80267, diacylglycerol (DAG), oleyloxyethylphosphocholine (oleylox.), bisindolylmaleimide I (bisindol.), PD98059, SB202190, methyl arachidonyl fluophosphonate (MAFP), quercetin, haloenol lactone suicide substrate (HELSS), AACOCF3 and NS-398 were obtained from Calbiochem. Aβ1-40 and Aβ1-42 were obtained from QCB. MK-886, RHC-80267, DAG, bisindol., PD98059, SB202190, MAFP, quercetin, HELSS, AACOCF3, NS-398, Aβ1-40 ...

example 2

[0115]The following example serves to illustrate that the sPLA2 / AA / 5-LOX / COX-2 pathway is also activated by soluble Aβ peptides in microglia, providing for an additional system where Aβ peptides stimulate this pathway. Additionally, this example illustrates that substances which inhibit this pathway block the effect of Aβ in microglia.

Methods

[0116]Leukotriene B4 (LTB4) enzyme-linked immunoabsorbant assay (ELISA). Quantitative determination of LTB4 levels was made using a competitive binding ELISA (R&D Systems, Minneapolis, Minn.) designed to measure LTB4 in cell culture supernatants (as described in Paris et al., Exp Neurol 1999). A murine microglial cell line (N9) was provided by Dr. Paola Ricciardi-Castagnoli (Cellular Pharmacology Center, Milan, Italy) and were grown in RPMI medium supplemented with five percent fetal calf serum, 2 mM glutamine, 100 U / mL penicillin, 0.1 μg / mL streptomycin and 0.05 mM 2-mercaptoethanol. Microglial cells were seeded at 50,000 cells / well in 6-well p...

example 3

[0123]This example illustrates the effect of soluble Aβ on a neuronal model (NGF-β differentiated PC12 cells). The data presented here, like those in example 2, demonstrate that soluble Aβ peptides stimulate the sPLA2 / AA / 5-LOX / COX-2 pathway. In this example it is further highlighted that soluble Aβ peptides are able to trigger the pathway in various cell types.

Methods

[0124]Measurement of [3H]AA release in neuronal cells (cultured differentiated PC12 cells). A rat pheochromocytoma cell line (PC12) was grown in Kahn's modification of F12 medium supplemented with 10% fetal calf serum, 100 U / mL penicillin and 0.1 gg / mL streptomycin. PC12 cells were seeded at 35,000 cells / well and differentiated with 60 ng / mL NGF-β for 5-6 days and then maintained with 5 ng / mL NGF-β thereafter. PC12 cells were treated with 0.4 μCi / mL of [3H]AA for 18 h and were washed multiple times with 1 mL of complete medium to remove unincorporated [3H] AA. Cells were then treated with 1 μM of Aβ1-40 or 40 U / mL of sP...

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Abstract

There is provided a method of modifying vasoactivity by regulating a soluble Aβ pro-inflammatory pathway. Also provided is a method of modifying inflammatory reactions in microglia and neurons by regulating a soluble Aβ pro-inflammatory pathway. A method of treating patients with vascular disease by modifying an intracellular soluble Aβ pro-inflammatory pathway is also provided. A pharmaceutical composition consisting essentially of an effective amount of a soluble Aβ pro-inflammatory pathway regulator in a pharmaceutically effective carrier is also provided.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The present invention relates to methods and compositions to reduce the neuronal cell death associated with the pro-inflammatory pathway and vasoactivity. More specifically, the present invention relates to specific modulation of signal transduction pathways, such as the sPLA2 / MAPK / cPLA2 / AA / LOX / COX pathway, to reduce the pro-inflammatory response that leads to an enhanced production of eicosanoids.[0003]2. Description of Related Art[0004]The protein β-amyloid (A4, Aβ, Aβ1-39-42) has long been central to the neuropathology of Alzheimer's disease (Glenner and Wong, 1984). However, its role in the disease process of Alzheimer's disease and other diseases, as well as its mechanism of action, remains in dispute.[0005]It is undisputed that β-amyloid protein is a major component of the neuritic plaques which, along with the neurofibrillary tangles, provide the neuropathological diagnostic markers for Alzheimer's disease (Matts...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/685A61K31/662A61K31/121A61K31/405A61K31/415A61K31/18G01N33/567A61P9/00G01N33/53C12N5/02A61K31/00A61K31/165A61K31/27A61K31/352A61K31/36A61K31/366A61K31/4045A61K31/4439
CPCA61K31/00A61K31/121A61K31/165A61K31/18A61K31/27A61K31/352A61K31/685A61K31/366A61K31/4045A61K31/405A61K31/415A61K31/4439A61K31/683A61K31/36A61P9/00
Inventor PARIS, DANIEL C.TOWN, TERRENCE C.MULLAN, MICHAEL J.
Owner PARIS DANIEL C
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