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.
The compound is also 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 overactivated 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.
Northwestern University patented the compound designated 188WH and has exclusively licensed the patent rights to NeuroMedix, Inc., for clinical development.
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.
