Toxic effects of nicotinamide methylation on mouse brain striatum neuronal cells and its relation to manganese

Hideyuki Kanda,Masayoshi Tsuji,Akiko Sugawara,Takehito Hayakawa,Yayoi Mori,Satoshi Tsuboi,Takeyasu Kakamu,Tetsuhito Fukushima

doi:10.1007/s12199-011-0262-6

Abstract

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. 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. 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. 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.

Highlights

Parkinson’s disease (PD) is a neurogenerative disorder with a risk of onset that increases with age [1]
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 nicotinamide N-methyltransferase (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
Our study suggests the possibility that Mn causes increased NNMT activity, thereby increasing MNA

Summary

Introduction

Parkinson’s disease (PD) is a neurogenerative disorder with a risk of onset that increases with age [1]. The prevalence rate of PD among the general population of Japan has been reported to be about 150 per 100,000 people [2], while the prevalence rate in Western countries is about 300 per 100,000 people [3]. The search for the cause of PD is a critical social issue as the number of patients have been steadily increasing concurrently with the rapid aging of the Japanese population. One substance that has been associated to idiopathic Parkinson’s disease (IPD) is 1-methylnicotinamide (MNA), a metabolite of nicotinamide (NA) by methylation in vivo [8,9,10]. The toxicity of MNA in cultured neuroblastoma cells has been reported [11], and the ingestion of high quantities of NA, the precursor of MNA, has been suggested to play a role in PD pathogenesis in developed countries [12]

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Conclusion