Laboratory for Molecular Neuropathogenesis and Remediation
Principle Investigator: Richard M. LoPachin, Ph.D.
Cellular oxidative stress is strongly implicated in the pathogenesis of numerous human diseases and tissue injuries; e.g., Alzheimer’s disease, stroke, atherosclerosis, diabetes, traumatic spinal cord injury and certain cancers. The associated cell damage is mediated by the sequential involvement of electron deficient species or electrophiles; e.g. hydroxyl radicals, transition metal ions and toxic a,b-unsaturated aldehydes such as acrolein and 4-hydroxy-2-nonenal (HNE). The unsaturated aldehydes are soft electrophiles and our research has shown that these type-2 alkenes cause toxicity by forming adducts with soft nucleophilic sulfhydryl thiolates groups on cysteine residues of functionally critical proteins. In addition to being important mediators of oxidative stress, acrolein and other type-2 alkenes are pervasive environmental toxicants (e.g., methylvinyl ketone, acrylonitrile) and dietary contaminants (e.g., acrylamide). Because the type-2 alkenes produce cytotoxicity via a common mechanism, we have proposed that environmental exposure to these chemicals might accelerate ongoing oxidative disease/injury process by additively (or multiplicatively) interacting with endogenously generated acrolein and other type-2 alkenes. This possibility is supported by the recent epidemiological findings that exposure to cigarette smoke and air pollution, which contain high type-2 alkene levels, can increase the risk of Alzheimer’s disease (AD). We are currently conducting NIH-supported research to determine whether environmental type-2 alkene exposure can accelerate the onset and development of certain diseases in animal models.
We are also interested in developing pharmacotherapeutic approaches to managing diseases that might be influenced by environmental type-2 alkene exposure. Thus, we have discovered a series of 1,3-dicarbonyl enols; e.g., 2-acetylcyclopentanone (2-ACP), acetylacetone (AcAc) that provide substantial cytoprotection in several cell culture and animal models of oxidative stress (LoPachin et al., J. Neurochemistry 116(1): 132-143, 2011). Whereas enol-based prevention has not been considered previously, it is based on the recognition that the well-documented cytoprotective properties of curcumin and other plant-derived polyphenols involves electrophile scavenging by ionized (enolate) nucleophilic forms of resident phenolic or 1,3-dicarbonyl substructures. However, unlike their phytopolyphenols counterparts, 2-ACP and other 1,3-dicarbonyl analogs are readily bioavailable, chemically stable and non-toxic. Our research has shown that these compounds are not free radical scavengers, rather the cytoprotective ability of the 1,3-dicarbonyls is related to: 1) conformational flexibility, which determines the ability to chelate metal ions, 2) the inherent pKa of the parent b-diketone, which determines the relative enolate concentration at physiological pH, and 3) the nucleophilicity of the enolate, which determines the ability of the 1,3-dicarbonyls to form covalent adducts with toxic electrophilic aldehydes. We are currently synthesizing new, structurally flexible 1,3-dicarbonyl analogs with lower pKa values and higher nucleophilicities. These de novo compounds are being tested in several rodent models of oxidative stress; i.e., acetaminophen (Tylenol) hepatotoxicity, liver ischemia/reperfusion (I/R) injury, and neurodegeneration in a transgenic mouse model (Tg2576) of Alzheimer’s disease. This generation of “designer” compounds could lead to the development of new and effective pharmacotherapeutic approaches to many diseases that have a common molecular etiology of cellular oxidative stress.
- Terrence Gavin, Ph.D. (Co-PI): Department of Chemistry, Iona College
- Brian Geohagen BS (Research Assistant): Department of Anesthesiology, Montefiore Medical Center
- Lihai Zhang, Ph.D. (Senior Fellow): Department of Anesthesiology, Montefiore Medical Center
- Diana Casper, Ph.D. (Investigator): Department of Neurosurgery, Montefiore Medical Center
Montefiore Medical Center
Department of Anesthesiology
Moses Research Tower – 701
111 E. 210th St.