α, β-DCP-LA Selectively Activates PKC-ε and Stimulates Neurotransmitter Release with the Highest Potency among 4 Diastereomers

Abstract

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 α α-, α, β-, β,α-, and β, β-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 α, β-DCP-LA selectively and directly activated PKC-ε, with the highest potency. α β-DCP-LA stimulated release of glutamate, dopamine, and serotonin from rat hippocampal, striatal, and hypothalamic slices, respectively, under the control of PKC, possibly PKC-ε, and α7 nicotinic ACh receptors, with the highest potency among 4 diastereomers. Conclusion: α, β-DCP-LA serves as a selective and direct activator of PKC-ε, to stimulate transmitter release by targeting α7 nicotinic ACh receptors. This suggests that α, β-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.

Apolipoprotein E3 (ApoE3) but Not ApoE4 Protects against Synaptic Loss through Increased Expression of Protein Kinase Cϵ

“…However, other mechanisms cannot be ruled out. DCPLA has also been reported to stimulate AMPA receptor exocytosis by inhibiting protein phosphatase-1 (40) and to enhance synaptic vesicle stability and stimulate neurotransmitter release (55).…”

Linoleic Acid Derivative DCP-LA Prevents Tau Phosphorylation by Targeting GSK-3β

“…DCP-LA-induced increase in 7 ACh receptor on the plasma membrane at presynaptic terminals stimulates presynaptic glutamate release [52,54]. DCP-LA, alternatively, promotes exocytosis of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, a major postsynaptic excitatory receptor, through CaMKII activation due to PP-1 inhibition [55].…”

PTP1B Inhibition Causes Rac1 Activation by Enhancing Receptor Tyrosine Kinase Signaling

“…8-[2-(2-Pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), a synthesized linoleic acid derivative, serves as a selective activator of protein kinase Cε (PKCε) [1,2]. DCP-LA-induced PKCε activation causes an enhancement in the activity of presynaptic α7 acetylcholine (ACh) receptors, to stimulate presynaptic glutamate release and facilitate hippocampal synaptic transmission [3,4].…”