Nitric oxide mimetic NSAIDs for treatment of Alzheimer's Disease

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DESCRIPTION (provided by applicant): 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.