Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New compounds effective against Alzheimer’s disease onset and progression

09.11.2004


Drug discovery researchers at Northwestern University have developed a new class of compounds that have the potential to reduce the inflammation of brain cells and the neuron loss associated with Alzheimer’s disease.



The new class of compounds are aminopyridazines. The original compound, called MW01-070C, is used in an injectable form. More recently developed compounds, such as MW01-2-151WH and MW01-5-188WH, can be taken by mouth.

The compounds were designed and synthesized in the laboratory of D. Martin Watterson, J. G. Searle Professor of Molecular Biology and Biochemistry and professor of molecular pharmacology and biological chemistry, Northwestern University Feinberg School of Medicine, using a synthetic chemistry platform developed by the Northwestern Drug Discovery Program for the rapid discovery of new potential therapeutic targets.


The aminopyridazines are targeted for the potential treatment of certain neurodegenerative diseases that are characterized by neuroinflammation and neuronal loss, such as Alzheimer’s disease, Parkinson’s disease, stroke and traumatic brain injury. The compounds inhibit over-activation of glia, important cells of the central nervous system that normally help the body mount a response to injury or developmental change but are overactivated in certain neurodegenerative diseases.

The efficacy and safety of the compounds in an Alzheimer’s disease animal model was evaluated in collaboration with Linda J. Van Eldik, professor of cell and molecular biology at Feinberg.

The scientists described their Alzheimer’s disease drug discovery efforts in recent issues of the Journal of Molecular Neuroscience and the journal Neurobiology of Aging, and a publication that will appear in early 2005 in the journal Current Alzheimer Research. The studies have important implications for future drug development because they provide a proof of concept that targeting neuroinflammation with aminopyridazines is a viable Alzheimer’s disease drug discovery approach that has the potential to modulate disease onset and progression, Van Eldik said.

Deposition of the beta-amyloid plaques and neurofibrillary tangles of Alzheimer’s disease is associated with glial activation, loss of neurons and decline of cognitive function. Long-term or excessive activation of glia increases production of chemokines and cytokines, such as interleukin-1 beta (IL-1b), and oxidative stress-related enzymes, such as a highly active form of nitric oxide synthase (iNOS). The excessive production of the inflammation-related substances can, in turn, contribute to further exacerbation of the disease process.

IL-1b is involved in glial inflammatory and neuronal dysfunction responses, and variants of the IL-1 gene are associated with increased risk for Alzheimer’s disease. The iNOS induced as a result of glial activation generates nitric oxide (NO), which can exist in toxic forms that damage neurons. Therefore, development of new compounds that can modulate these disease-linked biological processes may represent alternative therapeutic approaches and lead to future identification of new drug discovery targets, Van Eldik said.

Van Eldik and co-researchers found that the aminopyridazines inhibited both oxidative and inflammatory cytokine pathways and reduced human amyloid beta (Ab)-induced glial activation in a mouse specially designed to develop many of the hallmarks of Alzheimer’s disease pathology, including neuroinflammation, neuronal and synaptic degeneration and amyloid disposition, often called plaques.

Inhibition of neuroinflammation correlated with a decreased neuron loss, restoration towards control levels of synaptic dysfunction biomarkers in the hippocampus and diminished amyloid plaque deposition. Consistent with the pathology changes, treatment with the aminopyridazines also attenuated behavioral deficits in the mice that are due to injury in the part of the brain called the hippocampus, a region that is gradually destroyed in neurodegenerative diseases such as Alzheimer’s. The Northwestern investigators are now seeking to raise the funding necessary for testing in humans.

Collaborating with Watterson and Van Eldik on this research were Jeffrey M. Craft, a medical scientist predoctoral student in the Drug Discovery Training Program, and Wenhui Hu and Hantamalala Ranay Ranaivo, postdoctoral scholars in the Drug Discovery Training Program.

Elizabeth Crown | EurekAlert!
Further information:
http://www.northwestern.edu

More articles from Life Sciences:

nachricht New application for acoustics helps estimate marine life populations
16.01.2018 | University of California - San Diego

nachricht Unexpected environmental source of methane discovered
16.01.2018 | University of Washington Health Sciences/UW Medicine

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

Im Focus: A thermometer for the oceans

Measurement of noble gases in Antarctic ice cores

The oceans are the largest global heat reservoir. As a result of man-made global warming, the temperature in the global climate system increases; around 90% of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

White graphene makes ceramics multifunctional

16.01.2018 | Materials Sciences

Breaking bad metals with neutrons

16.01.2018 | Materials Sciences

ISFH-CalTeC is “designated test centre” for the confirmation of solar cell world records

16.01.2018 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>