VOL. 1, No. 4, October 2004

Y. Nishida [2004] Med Hypotheses Res 1: 227-245.

Oxidative Stress and Neurodegeneration

Yuzo Nishida*

Chemical Institute for Neurodegeneration, Yamagata University, Yamagata 990-8560,

Abstract. We have investigated the chemical mechanisms underlying the
pathogenesis of neurodegenerative diseases based on our new concept for the so-called
“oxidative stress” induced by the metal ions. The following data were discussed in this
paper: (i) Reactivity of the metal-OOH, hydroperoxo-metal speices of Fe(III) or Cu(II), is
dependent on the interactions with peripheral groups and substrate, and is frequently
highly reactive to oxidation of cellular constituents, such as lipids, proteins, and DNA,
which leads to mutations and misfoldings of proteins. (ii) In some iron-containing
enzymes such as phenylalanine hydroxylase or tyrosine hydroxylase, Fe(II) can activate
O2 without change of its oxidation state, and in this case weak interaction between the
unpaired electrons of Fe(II) ion and O2 is necessary to activate the O2. The other metal
ions such as Al(III) or Mn(II) cannot activate O2 by the same mechanism, and thus the
accumulation of Al(III) or Mn(II) ions in brain will lead to the deficiency of dopamine
and other neurotransmitters, and also to the elevated iron levels in the brain. (iii) Elevated
iron levels in brains and abnormalities in brain iron metabolism (so-called iron-overload
syndrome) have been detected for Alzheimer’s and Parkinson’s diseases, and these iron
ions exist as a soluble polymeric species through chelate formation with amino acids or
small peptide. Soluble polynuclear metal chelates of Fe(III) or Cu(II) exhibit unique
reactivity toward O2, readily giving hydrogen peroxide in the presence of reducing agents.
Thus the hydrogen peroxide produced can be an intrinsic origin for the “oxidative stress”
in the presence of metal ions such as Fe(III) or Cu(II). Based on these results, we would
like to propose that one of the most risky factors for the neurodegenerative diseases is
accumulation of exogenous metal ions such as Al(III) or Mn(II) in brain, and thus, the
following points must be noted to protect the sporadic neurodegenerative diseases: (i) to
remove metallic aluminum from the instruments for storage of food and from the
manufactures for food productions (e.g., dry milk and beer, etc); (ii) to remove the risk
factors to induce “acid rain”; and (iii) to stop the use of methyl cyclopentadienyl
manganese tricarbonyl in gasoline.

*Address all correspondence to: Dr. Yuzo Nishida, Chemical Institute for
Neurodegeneration, Yamagata University, Yamagata 990-8560, Japan.

Full Text [PDF]