Compound Suppresses Brain Deterioration in Alzheimer's

Drug-discovery researchers have devised a unique orally administered compound specifically targeted to halt brain cell inflammation and neuron loss associated with Alzheimer's disease (AD).

The substance is also quickly absorbed by the brain and is non-toxic--important characteristics for a central nervous system (CNS) drug that might need to be taken for extended periods. The study, published in the January 11, 2006, issue of the Journal of Neuroscience, describes the compound, called MW01-5-188WH, which selectively inhibits production of pro-inflammatory proteins called cytokines by glia, key cells of the CNS that normally help the body prepare a response but are overactivated in specific neurodegenerative diseases, such as AD, Parkinson's disease, stroke, and traumatic brain injury.

The compound was developed and synthesized in the laboratory of Dr. D. Martin Watterson at Northwestern University Feinberg School of Medicine (Evanston, IL, USA), 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 quick discovery of new potential therapeutic compounds.

The efficacy and safety of the compound in an animal model of Alzheimer's disease was assessed. As well as providing a lead compound for drug development, the study has significant implications for drug discovery in neurodegenerative diseases in general because it provides proof of concept that targeting overproduction of cytokines by activated glia is a feasible approach that has the potential to modulate disease onset and progression, according to the researchers.

Decline of cognitive functions associated with the hippocampus part of the brain is a clinical hallmark of AD. The study 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 additional glia activation and contribute to further progression of the disease process. The Northwestern researchers discovered that 188WH and related compounds slowed or reversed the progression of the neuroinflammatory cascade and decreased human amyloid beta-induced glia activation in a mouse specially designed to develop many of the signs of AD, including neuroinflammation, neuronal and synaptic degeneration, and behavioral deficits.

The compound also re-established normal levels of markers of synaptic dysfunction in the hippocampus, the region of the brain that helps regulate memory and is gradually destroyed in neurodegenerative diseases such as AD. Treatment with the compound also attenuated Alzheimer's-like behavioral problems in the mice that are due to injury to the hippocampus.

Whereas earlier studies by these investigators and many others in the field have 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 clearly.

There are three major features of the report, according to Dr. Watterson. "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,” Dr. 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.”

Northwestern University patented the compound designated 188WH and has exclusively licensed the patent rights to NeuroMedix, Inc. (Toronto, Canada), for clinical development.