The new 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 which are overactivated in certain neurodegenerative diseases or after traumatic brain injury or stroke.
An article describing an early phase study of the new class of compounds was published in the online version of the Journal of Medicinal Chemistry and in the print version on January 31.
The report has potential impact on future drug development in these disease areas because it provides a proof of principle that excessive glia activation can be controlled by a new class of compounds that work via mechanisms distinct from inflammatory response enzyme cyclooxygenase (COX-2) inhibitors and from a promising new class of experimental anti-inflammatory drugs called p38 MAP kinase inhibitors.
The study was led by D. Martin Watterson, John G. Searle Professor of Molecular Biology and Biochemistry, professor of molecular pharmacology and biological chemistry and director of the Drug Discovery Program at Northwestern University.
Recent studies on the use of antiinflammatory drugs in persons with Alzheimer's disease and related neurodegenerative disorders suggest that modulating glial inflammation may be an effective therapeutic approach to delaying onset or slowing progression of neurodegeneration.
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 combine with other chemicals such as superoxide to damage neurons.
Therefore, development of new compounds that can modulate these disease-linked biological processes might provide insight into alternative therapeutic approaches and future identification of drug discovery targets, Watterson said.
The new compounds described in the report selectively block production of IL-1B, iNOS and NO by activated glia without diminishing the production of other glial proteins, such as apolipoprotein E, or of COX-2, the target of new anti-inflammatory drugs used in the treatment of arthritis and other inflammatory disorders.
The results of this study demonstrate the selectivity of the compounds and suggest that the mechanism of action is different from that of currently available anti-inflammatory compounds that target peripheral inflammation.
"The direct linkage of glial activation to disease pathology underscores the importance of understanding the signal transduction pathways that mediate these critical glial cellular responses and of the need for discovery of cell-permeable drugs that can modulate disease-relevant pathways," Watterson said.
Northwestern researchers who collaborated on the study were Linda J. Van Eldik, professor of cell and molecular biology, and undergraduate chemistry students and post-doctoral fellows in the Drug Discovery Training Program. The group at the Universite' Louis Pasteur, Strasbourg, France, was led by Jacques Haiech in the drug discovery Institute Gilbert Laustriat. Dr. Haiech is also a program administrator in genomics at the Ministere de la Recherche in Paris.