title: Toxic effects of nicotinamide methylation on mouse brain striatum neuronal cells and its relation to manganese.
abstract: OBJECTIVE
  It is well known that manganese (Mn) exposure is involved in parkinsonism. The aim of our study was to test the hypotheses that Mn affects nicotinamide N-methyltransferase (NNMT) activity, increases the metabolism of nicotinamide (NA) to 1-methylnicotinamide (MNA), and leads to neurocytotoxicity.
  
  
  METHODS
  Following demonstration of the effects of Mn concentrations on the survival rate of Mouse CD1 brain striatum neuronal cells (MS cells), the effect of Mn on NNMT activity was investigated by comparing the difference in the amount of MNA produced after various Mn concentrations were added to mouse brain cytosol fractions as an enzyme solution. Toxicity induced by MNA and its precursor NA on MS cells was measured.
  
  
  RESULTS
  The survival rate of MS cells decreased significantly with increasing concentrations of Mn in the culture medium. With respect to the influence of Mn on NNMT activity, NNMT activity increased significantly at Mn concentrations of 1 μmol/mg protein. MNA and NA neurotoxicity were compared by comparing cell survival rate. Cell survival rate dropped significantly when the cells were cultivated with 10 mM of MNA. There was also a tendency for the survival rate to fall following the addition of 10 mM NA; however, the difference with the control was not significant.
  
  
  CONCLUSIONS
  Our study suggests the possibility that Mn causes increased NNMT activity, thereby increasing MNA levels in the brain and bringing about neuron death. Daily absorption of Mn and NA may thus contribute to idiopathic Parkinson's disease.
authors.affiliation: Department of Hygiene and Preventive Medicine, Fukushima Medical University School of Medicine, Japan. y-mori@fmu.ac.jp
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Mori
authors.forename: Akiko
authors.initials: A
authors.lastname: Sugawara
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Tsuji
authors.forename: Takeyasu
authors.initials: T
authors.lastname: Kakamu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tsuboi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kanda
authors.forename: Takehito
authors.initials: T
authors.lastname: Hayakawa
authors.forename: Tetsuhito
authors.initials: T
authors.lastname: Fukushima
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004229:Dithiothreitol / Q000633:toxicity*; D008345:Manganese / Q000633:toxicity*; D008745:Methylation; D051379:Mice; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism*; D050903:Nicotinamide N-Methyltransferase / Q000378:metabolism
chemical_list: D009536:Niacinamide; D008345:Manganese; D050903:Nicotinamide N-Methyltransferase; D004229:Dithiothreitol; C024058:N(1)-methylnicotinamide