Treatment of neurodegeneration and neuroinflammation

A technology for neuroinflammation and neurodegeneration, which is applied in the field of neurodegeneration and neuroinflammation treatment, and can solve problems such as new recurrence and increased stability

Inactive Publication Date: 2012-04-25
BIOGEN MA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

On the other hand, patients with progressive MS exhibit increased stability of deficits as defined above, either from onset or after the acute phase, but this designation does not exclude the further occurrence of new relapses

Method used

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  • Treatment of neurodegeneration and neuroinflammation
  • Treatment of neurodegeneration and neuroinflammation
  • Treatment of neurodegeneration and neuroinflammation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] BG00012, an orally available formulation of dimethyl fumarate (DMF), is in Phase III testing for relapsing-remitting multiple sclerosis (RRMS). In phase IIb testing, BG-12 significantly reduced gadolinium-enhancing brain lesions and reduced T1 hypointense black holes. The active ingredient of BG00012, dimethyl fumarate (DMF), was tested in a rat model of EAE. Such as Figure 1A As shown, treatment of experimentally induced EAE rats with various doses of DMF alleviated EAE symptoms in a dose-dependent manner. Treatment with 200 mg / kg DMF completely eliminated the disease. ( Figure 1A ).

[0095] Figure 1B Cross-sections of spinal cords of rats treated with vehicle or BG00012 are shown. Panels a–f were processed and stained as follows:

[0096] a.Luxol Fast Blue / vehicle

[0097]b.Luxol Fast Blue / BG00012

[0098] c. GFAP / vehicle

[0099] d. GFAP / BG00012

[0100] e.IBA1 / vehicle

[0101] f.IBA1 / BG00012

[0102] Such as Figure 1B As shown, the activated astro...

Embodiment 2

[0104] This example shows that BG00012 reduces astrocyte activation in vivo. Specifically, there were fewer activated astrocytes in the gray matter of the spinal cords of DMF-treated rats than in the spinal cords of rats that received vehicle alone. Figure 3A Shown is a cross-section of the spinal cord stained with GFAP antibody to identify activated astrocytes. Panels (a) and (b) are from rats treated with vehicle only at 5x and 20x magnification, respectively, while panels (c) and (d) are from rats treated with 100 mg / kg DMF at 5x magnification, respectively and 20 times the display.

[0105] Figure 3B Morphometric quantification using Apeiro color deconvolution is shown.

[0106] Figure 3C A cross-section of the rat spinal cord is shown, with ventral gray and white matter areas indicated. These regions were selected for morphometric assays. Figure 3D Morphometric quantification of positive GFAP staining in ventral gray and white matter is shown.

Embodiment 3

[0108] This experiment shows that BG00012 reduces the activation of primary cultured astrocytes. Figure 4A Quantitative PCR analysis of GFAP expression is shown after 6 and 24 hours of stimulation with the indicated concentrations of DMF. As shown, DMF inhibited GFAP expression in a concentration-dependent manner.

[0109] Figure 4B Quantitative PCR analysis of TNF expression is shown after 24 h stimulation with the indicated concentrations of DMF with 0, 10 and 30 ng / ml LPS added 4 h before harvest. As shown, LPS induced TNF expression in a dose-dependent manner, and the induced TNF expression was inhibited by DMF in a dose-dependent manner.

[0110] Figure 4C Quantitative PCR analysis of NQO1 expression is shown after 6 and 24 hours of stimulation with the indicated concentrations of DMF. As shown, DMF induced Nqo1 expression in a concentration-dependent manner. It is also evident from the data that Nqo1 is induced at a higher level by 24 hours exposure to DMF than b...

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Abstract

Methods of treating a subject having a condition characterized by at least one of neurodegeneration and neuroinflammation are provided. Methods of reducing astrogliosis in a subject having a condition characterized by increased astrogliosis are also provided. Methods of providing neuroprotection to a subject in need thereof are also provided.

Description

[0001] Related Application Cross Reference [0002] This application claims priority to US Provisional Patent Application No. 61 / 173,797, filed April 29, 2009, and US Provisional Patent Application No. 61 / 175,270, filed May 4, 2009. The entire disclosures of these two applications are hereby incorporated by reference herein. technical field [0003] The present invention provides a method of treating a subject suffering from a condition characterized by at least one of neurodegeneration and neuroinflammation by administering to the subject a therapeutically effective amount of at least one compound of formula I or its pharmaceutical acceptable salt. The present invention also provides a method of reducing astrogliosis in a subject suffering from a condition characterized by increased astrogliosis, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof. The pres...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N37/12A01N37/44A61K31/195
CPCA61K9/2072A61K9/00A61K9/2846A61K31/225A61P25/28Y02A50/30A61K2300/00C12Q1/6876C12Q2600/136C12Q2600/158G01N33/5023G01N33/5058G01N2500/10
Inventor 马特维·卢卡舍夫
Owner BIOGEN MA INC
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