Alcohol-induced neurodegeneration and the consequent dementia are important therapeutic targets in alcoholism. However, because alcohol-induced neurotoxicity has different mechanisms during the presence of alcohol and during its withdrawal, these are difficult targets for pharmacotherapy. Based on preclinical research, two types of neuroprotective compound, potent anti-oxidants, and agonists at alpha7 nicotinic receptors for acetylcholine (nicAChRs) are agents which seem particularly well-suited to this therapeutic challenge. As part of a minor specific aim in the original phase 2 STTR project (""""""""Anti-relapse agents, a plant genomics approach"""""""") , we have discovered a novel natural product from the native plant, Solidago nemoralis, which has both of these characteristics, and which is highly protective against alcohol-induced toxicity in simple cell culture models. This is tentatively identified as a methyl quercetagetin, and there are no previous reports of compounds from this plant species, or with similar quercetin-like structures, being active at alpha7-nicAChRs, or against this type of neurotoxicity. The original project (which focused on anti-relapse properties) was not designed to investigate neuroprotective activity. Under the program NOT-OD-09-058, """"""""NIH announces the availability of Recovery Act funds for competitive revision applications"""""""" we now propose to pharmacologically characterize this compound further, and to evaluate its therapeutic potential against the neurotoxic effects of alcohol, both in in vitro models, and in a developmental rodent model in vivo. In addition to this conventional approach, we also propose to use a selection procedure, based on the cytoprotective anti-oxidant properties of this compound, to generate mutant plant cell cultures which overproduce this activity. This was not a part of the original proposal because we had no idea that we would discover a structure which combined these properties! This supplement will enable us to employ two postdoctoral researchers to cover the additional research, and will enable us to accelerate the investigation of this novel neuroprotective agent in alcoholism. The development of novel medications for alcoholism is a stated priority for NIAAA and for NIH.
Notice Number (NOT-OD-09-058) and Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications The dementia associated with alcoholism is a major, but largely unrecognized, clinical problem, probably rivaling Alzheimer's Dementia in incidence in the USA. There are no recognized treatments, and this probably impacts the low rate of diagnosis of the condition. Basic research suggests that two types of pharmacological activity are of most potential therapeutic value and, somewhat serendipitously, we have discovered a natural product molecule which appears to have both of these properties. This proposal is to characterize this molecule more fully, and to begin to evaluate its potential as a neuroprotective drug in alcoholism. Since ultimately the best treatment for alcoholism is a marked reduction in consumption, we envisage this product being used as a part of a pharmacotherapeutic and behavioral program aimed at abstinence, or at a reduction of alcohol consumption from pathological levels.
| Lutz, Joseph A; Carter, Megan; Fields, Logan et al. (2015) The Dietary Flavonoid Rhamnetin Inhibits Both Inflammation and Excitotoxicity During Ethanol Withdrawal in Rat Organotypic Hippocampal Slice Cultures. Alcohol Clin Exp Res 39:2345-53 |
| Lutz, Joseph A; Carter, Megan; Fields, Logan et al. (2015) Altered relation between lipopolysaccharide-induced inflammatory response and excitotoxicity in rat organotypic hippocampal slice cultures during ethanol withdrawal. Alcohol Clin Exp Res 39:827-35 |
| Lutz, Joseph A; Kulshrestha, Manish; Rogers, Dennis T et al. (2014) A nicotinic receptor-mediated anti-inflammatory effect of the flavonoid rhamnetin in BV2 microglia. Fitoterapia 98:11-21 |
