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New Compound Stops Brain Cell Degeneration in
Alzheimer's Disease
The study has important implications for drug
discovery in neurodegenerative diseases in general
Jan. 19, 2006 - Drug discovery researchers at
Northwestern University have developed a novel orally administered
compound specifically targeted to suppress brain cell inflammation and
neuron loss associated with Alzheimer's disease. Northwestern has
patented the compound designated 188WH and has exclusively licensed the
patent rights to NeuroMedix, Inc., for clinical development.
The compound is rapidly absorbed by the brain and
is non-toxic – important considerations for a central nervous system
drug that might need to be taken for extended periods.
As described in the Jan. 11 issue of the Journal of
Neuroscience, the compound, called MW01-5-188WH, selectively inhibits
production of pro-inflammatory proteins called cytokines by glia,
important cells of the central nervous system that normally help the
body mount a response, but are over activated in certain
neurodegenerative diseases, such as Alzheimer's disease, Parkinson's
disease, stroke and traumatic brain injury.
The compound was designed and synthesized in the
laboratory of D. Martin Watterson at Northwestern University Feinberg
School of Medicine, using a synthetic chemistry platform developed in
his lab by researchers at the Northwestern University Center for Drug
Discovery and Chemical Biology (CDDCB) for the rapid discovery of new
potential therapeutic compounds.
Watterson is co-director of the CDDCB, the J.G.
Searle Professor of Molecular Biology and Biochemistry and professor of
molecular pharmacology and biological chemistry at the Feinberg School.
The efficacy and safety of the compound in an
animal model of Alzheimer's disease was evaluated in collaboration with
Linda J. Van Eldik, co-director of the CDDCB and professor of cell and
molecular biology at Feinberg.
Besides providing a lead compound for drug
development, the study has important implications for drug discovery in
neurodegenerative diseases in general because it provides proof of
concept that targeting over-production of cytokines by activated glia is
a viable approach that has the potential to modulate disease onset and
progression, the researchers said.
Decline of cognitive functions linked to the part
of the brain called the hippocampus is a clinical hallmark of
Alzheimer's disease. The report demonstrates that targeting excessive
glial activation can suppress brain inflammation and neuron dysfunction
in the hippocampus and protect against cognitive decline in an animal
model.
Neuron dysfunction can lead to further glia
activation and contribute to further exacerbation of the disease
process. The Northwestern researchers found that 188WH and related
compounds slowed or reversed the progression of the neuroinflammatory
cascade and reduced human amyloid beta-induced glia activation in a
mouse specially designed to develop many of the signs of Alzheimer's
disease, including neuroinflammation, neuronal and synaptic degeneration
and behavioral deficits.
The compound also restored normal levels of markers
of synaptic dysfunction in the hippocampus, the area of the brain that
helps regulate memory and is gradually destroyed in neurodegenerative
diseases such as Alzheimer's. Treatment with the compound also
attenuated Alzheimer's-like behavioral deficits in the mice that are due
to injury to the hippocampus.
While previous research by the authors and many
other investigators in the field has linked plaques, tangles and
neuronal injury to synaptic dysfunction and cognitive decline, the
direct linkage of glia to these processes and their potential as a
selective target for new therapies has not previously been implicated so
directly.
There are three key aspects of the report,
Watterson said.
"First, a novel compound for development into a new
class of Alzheimer's disease therapeutics that target disease has been
described.
"Second, an innovative approach was used for the
rapid and cost-effective discovery of orally bioavailable, safe and
efficacious compounds, and this approach can be extended to other
disease areas," Watterson said.
"Third, the design, synthesis and in vivo analyses
were carried out by a new generation of young scientists trained in our
educational program to instruct the next generation of interdisciplinary
scientists," Watterson said.
About source:
Co-authors with Watterson and Van Eldik on this
report were senior staff biologist Ling Guao; post-doctoral trainees
Hantamalala Ralay Ranaivo and Wenhui Hu; and pre-doctoral trainees
Jeffrey M. Craft and Laura K. Wing, Center for Drug Discovery and
Chemical Biology, Northwestern University.
This research was supported in part by funds from
the Institute for the Study of Aging; from the National Institutes of
Health (AG013939; NS047586; AG021184; N0S46942; and AG000260); from the
PhRMA Foundation; and from NeuroMedix, Inc.
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