The possible role of peroxynitrite in Alzheimer's disease: a simple hypothesis that could be tested more thoroughly.
Alzheimer's disease is characterized by the development of a degenerative condition in the elderly, associated with dementia. Upon pathological examination, cerebral amyloid plaques are found which contain denatured protein or peptide material. The process of denaturation of protein requires the presence of excessive heat, organic solvents, or oxidizing acids (OA). It seems that only OA could produce these effects since the other two are not present in the disease. Macrophages can produce the anion of an oxidizing acid known as peroxynitrite (OONO). This material is formed from two free radical gases, namely superoxide anion [.O2]- and nitric oxide (.N = O). Although (OONO)- is very reactive (1000 times more oxidizing than hydrogen peroxide), its half life in solution is only 1 to 2 seconds. Therefore, when it oxidizes a substance (such as protein) peroxynitrite disappears. The brain contains cells called microglia which are produced from monocytes in the same way as other types of macrophages from the lung and liver etc. The macrophages from the lung (alveolar) and liver (Kupfer cells) produce large amounts of peroxynitrite when activated by particles (silica) or infectious agents (lipopolysaccharide or interferon). Microglia produce highly oxidizing substances as well, but no one has ever measured production of peroxynitrite from these cells. Assuming that microglia produce peroxynitrite, or other similar oxidants, anti-oxidant and anti-inflammatory drugs should be helpful in treatment of early forms of the disease. In addition, large doses of anti-oxidant vitamin C and vitamin E might be helpful to people with Alzheimer's disease.
Van Dyke
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Department of Pharmacology & Toxicology, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown 26506, USA.
D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000209:etiology; D017628:Microglia / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism*; D011489:Protein Denaturation
D016564:Amyloid beta-Protein Precursor; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016328:NF-kappa B; D009566:Nitrates; C039642:peroxynitric acid