title: α, β-DCP-LA selectively activates PKC-ε and stimulates neurotransmitter release with the highest potency among 4 diastereomers.
abstract: OBJECTIVE
  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-e, 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-e, and α7 nicotinic ACh receptors, with the highest potency among 4 diastereomers.
  
  
  CONCLUSIONS
  α, β-DCP-LA serves as a selective and direct activator of PKC-e, 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.
authors.affiliation: Laboratory of Chemical Biology, Advanced Medicinal Research Center, Hyogo University of Health Sciences, Kobe, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanno
authors.forename: Akito
authors.initials: A
authors.lastname: Tanaka
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishizaki
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002210:Caprylates / Q000737:chemistry / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D016716:PC12 Cells; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013237:Stereoisomerism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C506022:8-(2-(2-pentyl-cyclopropylmethyl)cyclopropyl)octanoic acid; D002210:Caprylates; C579165:Chrna7 protein, rat; D034741:RNA, Small Interfering; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D012701:Serotonin; D018698:Glutamic Acid; D051744:Protein Kinase C-epsilon; D004298:Dopamine