Protein kinase C-mediated protection of motoneurons from excitotoxicity.
Amyotrophic lateral sclerosis (ALS) is a progressive motoneuron disease, whose pathogenesis remains unclear. Phorbol 12-myristate 13-acetate (PMA) has been shown to be neurotrophic and neuroprotective in several types of neurons in culture. However, the survival effect of PMA on motoneurons has not been reported. Therefore, we investigated this using purified rat motoneurons. PMA showed a small but significant neurotrophic activity, which was inhibited by GF109203X, a protein kinase C (PKC) inhibitor. Under the conditions in which the survival of motoneurons is supported by brain-derived neurotrophic factor (BDNF), excitotoxicity was induced by glutamate. PMA markedly protected motoneurons against excitotoxicity. The up-regulation of PKC in the spinal cord of ALS patients was previously reported, therefore, the present results indicate that PKC activation might be involved in neuroprotection.
Clinical Research Center, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan.
Naoko
N
Tomimatsu
Yoshihiro
Y
Arakawa
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000633:toxicity*; D018698:Glutamic Acid / Q000633:toxicity*; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D013116:Spinal Cord / Q000166:cytology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018846:Excitatory Amino Acids; D007211:Indoles; D008301:Maleimides; D018696:Neuroprotective Agents; D018698:Glutamic Acid; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate