alpha,beta-DCP-LA Selectively Activates PKC-epsilon and Stimulates Neurotransmitter Release with the Highest Potency among 4 Diastereomers

Background/Aims: We have been probing bioactivities of 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), a linoleic acid derivative with cyclopropane rings instead of cis-double bonds, using a racemic modification. Racemic DCP-LA contains possible 4 diastereomers. We, therefore, separately synthesized DCP-LA diastereomers such as alpha,alpha-, alpha,beta-, beta,alpha-, and beta,beta-DCP-LA and assessed the effects of each diastereomer on protein kinase C (PKC) activity and transmitter release. Methods: PKC activity under the cell-free conditions and in PC-12 cells, and glutamate, dopamine, and serotonin released from rat brain slices were assayed with a high performance liquid chromatography (HPLC) system. Results: Of 4 diastereomers alpha,beta-DCP-LA selectively and directly activated PKC-epsilon, with the highest potency. alpha,beta-DCP-LA stimulated release of glutamate, dopamine, and serotonin from rat hippocampal, striatal, and hypothalamic slices, respectively, under the control of PKC, possibly PKC-epsilon, and alpha 7 nicotinic ACh receptors, with the highest potency among 4 diastereomers. Conclusion: alpha,beta-DCP-LA serves as a selective and direct activator of PKC-epsilon, to stimulate transmitter release by targeting alpha 7 nicotinic ACh receptors. This suggests that alpha,beta-DCP-LA could be developed as a promising drug for treatment of not only dementia but neurodegenerative diseases and psychiatric disorders due to reduction/deficiency of neurotransmitters. Copyright (C) 2011 S. Karger AG, Basel