Tomoyuki Nishizaki

α, β-DCP-LA Selectively Activates PKC-ε 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 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.

Resveratrol: A Candidate Drug for Treating Rheumatoid Arthritis

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of multiple joints, with disruption of joint cartilage. Accumulating evidence has pointed to inflammatory cytokines inducing hyperplasia of synovial cells in joints as an etiology for rheumatoid arthritis. High concentrations of cytokines such as tumor necrosis factor- (TNF-) and interleukin-1 (IL-1) are found in synovial fluid and plasma from patients with rheumatoid arthritis (Eastgate et al., 1988; Saxne et al., 1998) and those cytokines produce matrix metalloproteinases or activate osteoclasts, causing irreversible damage to soft tissues and bones (Olsen & Stein, 2004). Challenges for rheumatoid arthritis treatment, therefore, have been attempted using TNF- inhibitors, anti-TNF antibodies, a soluble TNF receptor-fusion protein, or an IL-1 receptor antagonist. A concern with these therapies, however, are side effects such as serious infections and inducible malignant tumors (den Broeder et al., 2002). Resveratrol (Fig. 8), a phytoalexin that is present in grape skin and red wine, exerts a variety of actions to reduce superoxides, suppress carcinogenesis and angiogenesis, prevent diabetes mellitus, inhibit inflammation, and prolong life span (Elliott & Jirousek, 2008). Furthermore, resveratrol decreases plaque formation relevant to neurodegenerative diseases such as Alzheimer’s disease and Huntington’s disease (Karuppagounder et al., 2009). Of particular interest is that resveratrol is a potent and specific inhibitor of NF-B activation induced by TNF- or IL-1, and therefore, resveratrol might be a potential therapy for rheumatoid arthritis (Elmali et al., 2007; Molnar & Garai, 2005; Penberthy, 2007).