Alzheimer disease (AD) is the most common form of dementia and primarily affects older individuals. Currently approximately 4 million people in the United States (US) are affected with AD, and that number is expected to grow as the US population ages. Almost half of the population over age 85 have Alzheimer's disease. Recent evidence has implicated oxidative stress as playing a primary role in the etiology of AD and has suggested that AD neurons are more prone to the resultant damage. Severe oxidative damage may result in cellular loss of function and ultimately cell death. Anti-oxidative stress therapy may prevent or slow the progression of AD. The clinical studies using vitamin E in AD therapy only show limited and moderate effects due to its poor penetration into the brain and that it can be metabolized to "pro-oxidants" in the body. New and more effective anti-oxidative stress compounds are in great need for AD therapy. We have identified a class of compounds, including a lead candidate PAN-811 (MW195Da), which is neuroavailable and has exhibited potent anti-oxidative stress activity at low micro molar levels. In our in vitro models, comparison studies with vitamin E and lipoic acid, PAN-811 provided much better neuroprotection and a more favorable therapeutic index. In addition, we have established a novel cellular model for evaluating oxidative stress in AD employing olfactory neuroblasts (ONs) from AD patients and age-matched normal controls. Here, we propose to elucidate the mechanism of neuroprotection of PAN-811 and utilize the ON model to further evaluate, characterize and optimize the lead compound for future clinical drug development for AD.
Thesaurus Terms: Alzheimer's disease, antioxidant, brain disorder chemotherapy, cryoprotective agent, drug design /synthesis /production, neuroprotectant, pharmacokinetics amyloid protein, analog, chemical synthesis, enzyme activity, free radical oxygen, gene expression, glutathione peroxidase, glutathione reductase, heme oxygenase, neuron, respiratory epithelium, superoxide dismutase colorimetry, human tissue, tissue /cell culture
