Mitochondrial Inhibitors and Neurodegenerative Disorders

The mitochondrion is an important constituent of the eukaryotic cell. Its inner membrane is the site of cellular respiration, which provides the cell with adenosine triphosphate (ATP) via the Krebs cycle and the electron transport chain. When mitochondrial dysfunction occurs, the effects may be widespread, affecting the central and peripheral nervous system, the visual system, the auditory system, and muscle. The discovery of toxins, both natural and synthetic, that disrupt mitochondrial function has allowed for the development of experimental models of mitochondrial disease. Mitochondrial Inhibitors and Neurodegenerative Disorders details one such toxin, 3-nitropropionic acid (3-NPA), an irreversible inhibitor of succinate dehydrogenase, and its use in experimental models of central nervous system neurotoxicity and neurodegenerative diseases like Huntington's disease (HD).

This is a multi-authored text. Most of its contributors are basic researchers in the area of mitochondrial function, as are its three editors. The book contains 20 chapters divided among three subject areas: mitochondrial toxins, models of neurodegeneration secondary to mitochondrial dysfunction, and treatment strategies for mitochondrial-induced neurotoxicity.

The opening chapter, by Mohammad I. Sabri, Peter S. Spencer, Safia Baagia, and Albert C. Ludolph, provides an overview of both the clinical symptomatology and the mechanisms of actions of several mitochondrial toxins, including 3-NPA, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and cyanide. The second chapter, by Bradley F. Hamilton, Daniel H. Gould, and David L. Gustine, focuses on the clinical manifestations of 3-NPA intoxication in both animals and humans, while the third chapter, by Norman C. Reynolds and Wen Lin, details the biochemistry and neurochemistry of 3-NPA.

Animal intoxication with 3-NPA usually occurs when livestock in the western United States or Canada ingest a member of the Astragalus species of plant. Intoxication may be either acute or chronic. In the acute form in cattle, generalized weakness and incoordination develop, which may progress to respiratory distress, coma, and death, depending on the amount of toxin ingested. The chronic form in cattle consists of both respiratory dysfunction and incoordination.

Outbreaks of 3-NPA toxicity in humans have been described in China. Generalized and neurologic symptoms have been reported in children after they ingested moldy sugarcane contaminated with the fungal species Arthrinium. A spectrum of clinical manifestations develops within a few hours of ingestion of moldy sugarcane, varying from gastrointestinal symptoms and headache to coma, seizures, and death. For those who survive the initial manifestations, dystonia will develop in up to one-half within 7 to 40 days after ingestion. The dystonia tends to be persistent and nonprogressive. CT scans of those affected demonstrate hypodense lesions in the basal ganglia.

The second section of the book describes animal models of 3-NPA–induced neurodegeneration. Each chapter in this section opens with a brief introduction and statement of the authors' particular hypotheses (including models of cognitive dysfunction, gender-based differences in neurotoxicity, and a model of neuronal death in HD), followed by a presentation of the authors' own data and their conclusions. Although this section is clearly and uniformly written, one wonders how a peer reviewer would respond to the experimental methodology, the data, and the conclusions as they are currently presented. This section does point out that the striatum appears to be selectively vulnerable to the affects of 3-NPA but that it is unclear whether the mechanism of such vulnerability is excitotoxicity, apoptosis, or oxidative stress.

The final section of the book discusses experimental mechanisms for prevention of mitochondrial toxin–induced neurotoxicity. The first chapter, “Neuroprotective Strategies Against Cellular Hypoxia,” by Matthias W. Riepe, both describes the basic mechanisms of hypoxic damage to neurons and reviews the agents-to-date that have been used in studies of neuroprotection. The theme of this chapter, that 3-NPA-induced chemical hypoxia may be used as a neuroprotective strategy, is then presented and possible mechanisms are discussed. The three remaining chapters are similarly organized. Data concerning the protective effect of perinatal ischemic-hypoxic injury on subsequent 3-NPA neurotoxicity in rats, the therapeutic effect of fetal transplant into rat striatum to reverse 3-NPA–induced akinesia, and other therapeutic strategies to combat MPTP and 3-NPA neurodegeneration are reviewed and the results discussed.

The majority of the black-and-white figures in the book, while simple, clearly illustrate the authors' points. Some, however, appear to be personal computer–generated presentation slides that the authors simply pasted into the text. Tables and graphs, also presented in a black-and-white format, adequately illustrate the data on which the authors base their conclusions.

This is a technically oriented book whose main audience will be basic researchers with a specific interest in both mitochondrial function and the use of mitochondrial toxins as a method of creating animal models of neurodegeneration. Although the authors speculate on the use of such models to delineate the pathologic mechanisms of Alzheimer's disease, Parkinson's disease, and Huntington's disease, this speculation appears a bit premature; further work will be necessary to delineate the pathophysiologic mechanisms responsible for these disorders. This is not a book for the practicing neuropsychiatrist, since the experimental methodologies described are works in progress and as yet have limited clinical relevance. Instead, Mitochondrial Inhibitors and Neurodegenerative Disorders is a concise summary of the present state of research in the area of mitochondrial toxins and their role in animal models of neurodegenerative disease.

Dr. Musser is a neurologist and a psychiatrist. He is a Clinical Neurophysiology Fellow in the Department of Neurology and an Associate in the Department of Psychiatry at the University of Rochester School of Medicine, Rochester, NY.