Alzheimer Disease: Behanna HA

Van Eldik LJ, Thompson WL, Ralay Ranaivo H, Behanna HA, Martin Watterson D. · Center for Drug Discovery and Chemical Biology, Northwestern University Chicago, Illinois 60611, USA. · Int Rev Neurobiol. · Pubmed #17678967 No free full text.

Abstract: Inflammation is the body's defense mechanism against threats such as bacterial infection, undesirable substances, injury, or illness. The process is complex and involves a variety of specialized cells that mobilize to neutralize and dispose of the injurious material so that the body can heal. In the brain, a similar inflammation process occurs when glia, especially astrocytes and microglia, undergo activation in response to stimuli such as injury, illness, or infection. Like peripheral immune cells, glia in the central nervous system also increase production of inflammatory cytokines and neutralize the threat to the brain. This brain inflammation, or neuroinflammation, is generally beneficial and allows the brain to respond to changes in its environment and dispose of damaged tissue or undesirable substances. Unfortunately, this beneficial process sometimes gets out of balance and the neuroinflammatory process persists, even when the inflammation-provoking stimulus is eliminated. Uncontrolled chronic neuroinflammation is now known to play a key role in the progression of damage in a number of neurodegenerative diseases. Thus, overproduction of proinflammatory cytokines offers a pathophysiology progression mechanism that can be targeted in new therapeutic development for multiple neurodegenerative diseases. We summarize in this chapter the evidence supporting proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative disorders, with a focus on Alzheimer's disease. In addition, we discuss the drug discovery process and two approaches, function-driven and target-based, that show promise for development of neuroinflammation-targeted, disease-modifying therapeutics for multiple neurodegenerative disorders.

Hu W, Ranaivo HR, Roy SM, Behanna HA, Wing LK, Munoz L, Guo L, Van Eldik LJ, Watterson DM. · Center for Drug Discovery and Chemical Biology, Northwestern University, 303 E. Chicago Avenue, Mail Code W896, Chicago, IL 60611, USA. · Bioorg Med Chem Lett. · Pubmed #17079143 links to  free full text

Abstract: We report the development of a novel, aqueous-soluble, safe, small molecule, experimental therapeutic that suppresses injury-induced, proinflammatory cytokine increases in the brain, with resultant attenuation of synaptic protein biomarker loss and improvement in hippocampus-dependent behavioral deficits. A GMP production scheme for the active pharmaceutical ingredient, compound 17, is presented. The development and large-scale availability of this novel compound allow exploration of new, potentially disease-modifying, therapeutic approaches to CNS disorders.