Characterization of novel neuroprotective lipid analogues for the treatment of stroke

Abstract

Epidemiological, clinical, and biochemical studies have shown that various types of dietary fatty acids can modify the risk of stroke suggesting that fatty acids might be a good starting point for the development of new neuroprotective compounds for the treatment of stroke. We took two distinct approaches to the modification of fatty acids for their use as neuroprotective compounds. In the first approach, we made simplified forms of the ganglioside GM1 that contain a saturated, unsaturated, or cyclic fatty acid linked via an amide bond to a hydrophilic moiety. In the second approach, we directly linked fatty acids to the carboxylic acid bioisostere 1,2,4-oxadiazolidine-3,5-dione. Bioisosteres act as biomimetics of the parent group with respect to key physicochemical properties but provide additional, potentially more beneficial properties. We tested these new compounds in two distinct models of nerve cell death that mimic several different aspects of ischemic injury and death. We found that only a small subset of the tested compounds were effective in both neuroprotection assays, suggesting that these may be the best leads for novel therapeutic compounds for stroke. Interestingly, their neuroprotective effects appear to be mediated by distinct mechanisms.