Novel lipoxygenase inhibitors as neuroprotective reagents.
The lipid-metabolizing enzyme 12/15-lipoxygenase (12/15-LOX) mediates cell death resulting from oxidative stress in both neurons and oligodendrocytes. Specifically, it may contribute to the pathophysiology of stroke and Alzheimer's and Parkinson's diseases. We report here that two of three specific 12/15-LOX inhibitors, derived from a virtual screen by computer modeling and validated by inhibition of recombinant human 15-LOX in vitro, are able to rescue both neuronal as well as oligodendroglial cells from cell death induced by oxidative stress. Thus, in a fairly streamlined process, an initial virtual screen of 50,000 compounds in a library of drug-like molecules has led to the identification of two novel drug candidates for targeting LOX. Future studies of these novel neuroprotective inhibitors of 12/15-LOX may provide new therapeutic opportunities to combat stroke and other neurodegenerative diseases.
van Leyen
Klaus
K
Neuroprotection Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. klaus_vanleyen@hms.harvard.edu
Arai
Ken
K
Jin
Guang
G
Kenyon
Victor
V
Gerstner
Bettina
B
Rosenberg
Paul A
PA
Holman
Theodore R
TR
Lo
Eng H
EH
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001092:Arachidonate 12-Lipoxygenase / Q000187:drug effects*; D001093:Arachidonate 15-Lipoxygenase / Q000187:drug effects*; D002478:Cells, Cultured; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009836:Oligodendroglia / Q000187:drug effects*; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats
C475064:12-15-lipoxygenase; D000975:Antioxidants; D016859:Lipoxygenase Inhibitors; D018696:Neuroprotective Agents; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase