GT 1061 is a novel therapeutic agent, developed in our labs, initially targeted at treatment of mild to moderate Alzheimer's Disease (AD) that was FDA approved for a phase I study in healthy aged volunteers in 2004. GT 1061 is 1 of a family of organic nitrates that have demonstrated neuroprotective as well as cognition-and memory-enhancing properties in a wide variety of animal behavioral models. In 1 model, GT 1061 reversed the cognition deficit produced by icv infusion of b-amyloid (Ab1-40) in rats. Nitrates are nitric oxide mimetics, since much of the biological activity mimics that of NO; and in some circumstances, nitrates may act as NO donors that produce very low levels of NO. So-called NO-NSAIDs (NO-donor non-steroidal anti-inflammatory drugs) are nitrates incorporating an NSAID drug such as flurbiprofen, but nitrates have demonstrated anti-inflammatory activity in their own right. We have observed cognition enhancement by an NSAID containing nitrate, GT 094, in a rat model of dementia, whereas others have reported that NO- flurbiprofen (but not flurbiprofen itself) reduces or clears amyloid and modulates microglial activity in APP transgenic mice. We have observed that GT 094 is also a chemopreventive anti-inflammatory agent in animal carcinogenesis models. It is the objective of this proposal to develop novel nitrates as anti-inflammatory therapeutics for AD, that provide cognition enhancement and neuroprotection.
Aim 1 : to design and synthesize novel anti-inflammatory nitrate drugs (NO mimetic NSAIDs) and to study limited markers of drug degradation, inflammation, and DNA damage in macrophage cell cultures.
Aim 2 : to assay drugs in hippocampal slice cultures, measuring by immunoblot, markers of cognition enhancement (pERK, pCREB) and inflammation (iNOS, MHC-II).
Aim 3 : to test drugs in a rat visual delayed matching to sample (DMTS) task using a cholinergic neuronal lesion to induce a cognitive deficit. This project will yield a drug candidate for which amyloid load will be measured in transgenic models in subsequent research, providing the impetus for moving this drug candidate from discovery to the clinic. ? ?
| Schiefer, Isaac T; Abdul-Hay, Samer; Wang, Huali et al. (2011) Inhibition of amyloidogenesis by nonsteroidal anti-inflammatory drugs and their hybrid nitrates. J Med Chem 54:2293-306 |
| Abdul-Hay, Samer O; Edirisinghe, Praneeth; Thatcher, Gregory R J (2009) Selective modulation of amyloid-beta peptide degradation by flurbiprofen, fenofibrate, and related compounds regulates Abeta levels. J Neurochem 111:683-95 |
| Abdul-Hay, Samer O; Luo, Jia; Ashghodom, Rezene T et al. (2009) NO-flurbiprofen reduces amyloid-beta, is neuroprotective in cell culture, and enhances cognition in response to cholinergic blockade. J Neurochem 111:766-76 |
