Amyotrophic lateral sclerosis peroxynitrite

The pathological characteristic of Parkinson s disease is the selective degeneration of dopamine neurons in the pars compacta of the substantia nigra. The mechanism for the loss of neurons remains to be elucidated, and recently apoptosis has been proposed as a death process in Parkinson s disease. For example, the level of a product of the oxidative stress, 4-hydroxy-2-nonenal protein adduct, was found to increase in the nigral neurons of parkinsonian brains. Peroxynitrite (see Figure 13.6) has been proposed to be involved in the neuronal cell death in some neurodegenerative diseases, such as amyotrophic lateral sclerosis. 

The cadmium(II) complex corresponding to 9 (M = Cd n = 2) was the first texaphyrin made [6], This aromatic expanded porphyrin was found to differ substantially from various porphyrin complexes and it was noted that its spectral and photophysical properties were such that it might prove useful as a PDT agent. However, it was also appreciated that the poor aqueous solubility and inherent toxicity of this particular metal complex would likely preclude its use in vivo [29-31], Nonetheless, the coordination chemistry of texaphyrins such as 9 was soon generalized to allow for the coordination of late first row transition metal (Mn(II), Co(II), Ni(II), Zn (II), Fe(III)) and trivalent lanthanide cations [26], This, in turn, opened up several possibilities for rational drag development. For instance, the Mn(II) texaphyrin complex was found to act as a peroxynitrite decomposition catalyst [32] and is being studied currently for possible use in treating amyotrophic lateral sclerosis. This work, which is outside the scope of this review, has recently been summarized by Crow [33],... 

Because of the instability of peroxynitrite under physiological conditions, the detection of 3-nitrotyrosine (NC>2-Tyr) has become a biochemical marker for the presence of peroxynitrite in pathophysiological processes. The biological significance of tyrosine nitration is a subject of great interest, because extensive evidence supports the formation of nitrotyrosine in vivo in diverse pathological conditions such as heart diseases, chronic inflammation and autoimmune diseases, cancer, Parkinson s disease, Alzheimer s disease, multiple sclerosis, amyotrophic lateral sclerosis, and ischemia-reperfusion injury [11]. 

C19. Crow, J. P., Sampson, J. B., Zhuang, Y., Thompson, J. A., and Beckman, J. S., Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. J. Neurochem. 69, 1936-1944 (1997). 

Amyotrophic lateral sclerosis is an adult onset neurodegenerative disease. The motomeurons in the brainstem and in the spinal cord are selectively damaged. 15-20% of the patients have a mutation in the gene for the cytosolic superoxide dismutase (SOD I). It is thought that superoxide is not detoxified, side reactions of this enzyme form oxidants including peroxynitrite and the formation of nitrated proteins, is one of the reasons for cellular death [5]. 

The peroxynitrite ion is a reactive oxygen species that damages proteins, DNA, and hpids, possibly leading to heart disease, amyotrophic lateral sclerosis (Lou Gehrig s disease), Alzheimer s disease, and multiple sclerosis. We note that the structure of the ion is consistent with the bonding scheme of Fig. 10.35 because the unpaired electron in NO is slightly more localized on the N atom, we expect that atom to form a bond with an O atom from the O2 ion. 

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