Neurotoxic Factors in Parkinson's Disease and Related Disorders Kluwer Academic / Plenum, 2000, 340 pages A. Storch and M. A. Collins, ed.

Many scientists suspect that an environmental factor may be responsible for Parkinson's disease because its geographical distribution is not uniform. Parkinson's disease is slightly more common in rural areas than cities. There is also a very high prevalence of amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) among Japanese residents of the Kii peninsula in Japan and in Guam. This appears to be caused by ingestion of cycad, a natural plant that contains methylazoxymethanol, a naturally-occurring molecule that attacks the DNA of its victims to produce a syndrome closely resembling Parkinson's disease.

Another important clue about Parkinson's disease is MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a synthetic molecule produced as an accidental byproduct by people attempting to manufacture pethidine (meperidine), a mu-receptor opioid agonist, in their bathtub. MPTP produces an irreversible, incapacitating paralysis in its victims that closely resembles advanced Parkinson's disease. MPTP is oxidized to MPDP+ in astrocytes by the enzyme monoamine oxidase type B, and then spontaneously oxidizes to MPP+ (1-methyl-4-phenylpyridine) which then kills dopaminergic neurons in the substantia nigra pars compacta. The mechanism of MPP+ toxicity has not been definitively established, but may be production of superoxide which reacts with nitric oxide in the cell. After a single exposure to MPTP, the victims are permanently paralyzed. Even with L-dopa treatment, many are unable to move normally for the rest of their lives. The main difference between MPTP poisoning and true Parkinson's disease is the absence of Lewy bodies, which are eosinophilic inclusions in the neurons of Parkinson's disease patients.

A third interesting molecule is 6-hydroxydopamine (6-OHDA). Although 6-hydroxydopamine cannot cross the blood-brain barrier, it can be formed spontaneously in the brain by reaction of dopamine with iron and hydrogen peroxide. This is consistent with the association of Parkinson's disease with physical brain trauma, which exposes neurons to iron from blood that is released during injury. However, the molecular sites affected during 6-OHDA poisoning are not exactly the same as those affected in Parkinson's disease.

Many other substances, including haloperidol, can induce parkinson-like syndromes, while smoking appears to protect against it. Much research has focused on searching for molecules in Parkinson's disease brains that are absent in normal brains. The holy grail is to find something in food or in the environment that not only selectively kills dopaminergic cells, but also produces Lewy bodies.

This book is a collection of scientific articles on these and other toxins including beta-carbolines, 1,2,3,4-tetrahydroisoquinoline and salsolinol, as possible causes of Parkinson's disease. Isoquinolines can be produced from phenylethylamine or dopamine itself by condensation with acetaldehyde produced from ethyl alcohol. This is interesting in view of the recent findings of mutations in the enzyme alcohol dehydrogenase in some Parkinsons patients. Beta-carbolines are nitrogen-containing molecules, sometimes found in food, that are structurally similar to MPTP. Some of the articles are review papers, and others are short BBRC-style research papers. The intended audience is researchers and graduate students familiar with neuroanatomy, biochemistry, and the pathology of Parkinson's disease. The writing style is typical scientific writing--precise and functional technical prose full of abbreviations.

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