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2015 Grants - Schiefer
PK/PD Study of a Prototype Attenuated NO Mimetic Furoxan
Isaac Thomas Schiefer, Ph.D.
University of Toledo
2015 New Investigator Research Grant
Can a novel compound that boosts brain levels of molecules important for nerve cell function help prevent memory loss in Alzheimer’s disease?
CAMP response element binding protein, or CREB, is a molecule that binds to specific regions of DNA to promote the generation of proteins. CREB activity also boosts the production of brain derived neurotrophic factor (BDNF), a protein essential for maintaining the health and survival of nerve cells. In Alzheimer’s disease, dysfunctional CREB and reduced levels of BDNF may contribute to nerve cell damage and lead to memory loss and other cognitive problems. Thus, researchers are looking for ways to restore CREB and BDNF function as a potential treatment for Alzheimer’s and other dementias.
One group of molecules shown to promote CREB and BDNF activity are called nitric oxide (NO) mimetics. Such compounds mimic the activities of nitric oxide, a type of “neurotransmitter” or chemical messenger in the brain. However, the earliest NO mimetics produced excessive chemical activity in the brain, leading to toxic side effects.
Isaac Thomas Schiefer, Ph.D., and colleagues have developed a novel compound that belongs to a group of NO mimetics known as furoxans. In their initial studies in mice, the researchers have shown that this furoxan can produce just enough chemical activity to promote CREB/BDNF function without the harmful side effects. In addition, this compound helped improve learning and memory in mice engineered to develop Alzheimer’s-like brain changes.
For their current studies, Dr. Schiefer and colleagues plan to conduct a series of experiments using nerve cells grown in laboratory dishes and Alzheimer’s-like mice to verify and extend their earlier results. This effort will assess the compound’s “pharmacokinetic (PK) profile,” or how it is absorbed and eliminated from the body; as well as its “pharmacodynamic (PD) profile,” or the effect different doses have on the body. PK and PD studies are important steps in the development of a drug for human clinical trials. The researchers hope to learn more about how this novel compound promotes CREB/BDNF function in the brain and determine what doses might be optimal for use in future studies and clinical trials.
If successful, the results of this effort could lead to the future development of human clinical trials for this and other promising furoxans. Such compounds could provide an important therapeutic avenue for preventing Alzheimer’s disease or slowing its progression.