Clostridial Neurotoxins

Tetanus has been known from the very beginning of medical literature since it was first described by Hyppocrates of Cos in the fifth century B.C. For 24 centuries it was considered a neuro logical disease until the breakthrough of CARLE and RATIONE (1884) who demonstrated its infectious etiology. Following the establishment of purified cultures of Clostridium tetani(KITASATO 1889), FABER (1890), and TIZZONI and CATIANI (1890) demon strated that the disease is actually an intoxication caused by a proteic neurotoxin. This toxin was shown by BRUSHCHETIINI (1892) to move retroaxonally and to act at the spinal cord level. Soon thereafter VAN ERMENGEN (1897) demonstrated that botu lism is also due to intoxication with a protein toxin produced by bacteria of the genus Clostridium. These bacteria and their spores and ubiquitous, and the majority of them do not produce neurotoxins. The selective advantage of producing such potent toxin is still a matter of speculation (see Popoff, this volume). The next major advance was the discovery that tetanus neurotoxin 1 can be converted by formaldehyde treatment to a nonpathogenic but still fully immunogenic form, and that this can be used successfully as a vaccine to prevent tetanus (RAMON and DESCOMBEY 1925). Similar vaccines (toxoids) can be prepared with botulism neurotoxins (see MiDDLEBROOK and BROWN, this volume). The prevention oftetanus by vaccination (see Galatzka and Gasse, this volume) is one of the great successes of basic research coupled with an efficient public medicine service.

As little as two decades ago, deliberately injecting botulinum toxin into patients would have seemed foolhardy at best and criminal at worst. The increased clinical use of botulinum toxins has expanded the body of knowledge available on the structure and function of these proteins. This knowledge can be applied to topics as varied as therapies based on the endopeptidase activity of the toxins, vaccine development, protection against botulism, and vectors for neuronal drug delivery. Based on recent scientific and clinical information from top international authorities, Treatments from Toxins: The Therapeutic Potential of Clostridial Neurotoxins reviews the status of current research and development and identifies significant developments. Drawing on their vast experience in this field, the editors present the basic background of the bacteriology and genetics of the neurotoxigenic clostridia, a history of the discovery of the neurotoxins, and an overview of the tetanus and botulism diseases. The chapters detailing common medical applications of the toxins cover side effects and novel uses, including neuronal drug delivery strategies, and provide a fresh look at what can still be achieved. They also explore the toxins as potential threat agents and the advent of the therapeutic use of botulinum toxins. Highlighting the pitfalls, successes, and challenges that exist when engineering complex proteins, the book brings together the clinical and theoretical worlds. It presents a broad overview of the current status of botulinum research and its clinical applications.

Botulinum Neurotoxin and Tetanus Toxin covers the mechanism of action, pathogenesis, and treatment of clostridial neurotoxins. The book is organized into four parts encompassing 18 chapters that discuss the origin, structure, pharmacology, toxicology, immunology, assays, and clinical issues of botulinum and tetanus neurotoxins. The introductory part of the book discusses the discovery and production of neurotoxins in various strains of Clostridium bacteria. This text also describes how specific bacteriophages and plasmids mediate the pathogenicity of some types of Clostridium botulinum and Clostridium tetani. The subsequent part provides an overview of issues related to toxin binding, including toxins that may serve as models for botulinum and tetanus neurotoxins. Discussions on the peripheral and central aspects of poisoning transport in the central nervous system and on the antagonistic drugs for clostridial neurotoxins are provided. The third part of the book addresses the antibodies against botulinum neurotoxin. Bioassay in mice and highly sensitive immunoassays, such as reversed passive hemagglutination, reversed passive latex agglutination, radioimmunoassay, and enzyme-linked immunosorbent assay, are presented. The concluding part covers the animal models for these toxins and discusses the diagnosis and treatment of botulism and tetanus in human. The clinical use of Clostridium botulinum toxin type A in ocular and neuromuscular disease is also examined. This book will be of value to protein chemists, microbiologists, virologists, pharmacologists, immunologists, and clinicians.

Three days in Madison have thoroughly modified my view on clostridial neurotoxins. While still realizing the numerous activating, modifying and protective inputs, I cannot judge the meaningfulness of the meeting impartially. Neither may the reader expect a complete summary of all presentations. Collected in this volume, they speak for themselves without requiring an arbiter. Instead I shall write down my very personal opinions as a researcher who has studied clostridial neurotoxins for nearly 25 years. Comparable conferences have been rare during this time. A comprehensive symposium 4 on C. botulinum neurotoxins has been organized at Ft. Detrick. International conferences on tetanus have been held regularly under the auspices of the Wodd Health Organization. One or maximally two days of these meetings have been devoted to tetanus toxin and its actions whereas the sponsor and the majority of the participants have been interested mainly in epidemiology, prevention and treatment of tetanus as a disease (see refs. 5,6). Some aspects of clostridial neurotoxins have been addressed in the context of bacterial toxins, in particular in the biennial European workshops. 1-3,7,8 The Madison meeting differed from the previous ones in three aspects. First, it covered both tetanus and botulinum neurotoxins. The fusion was justified because of their huge similarities in primary structure, in their mode of action and in their cellular targets. Second, the meeting was not limited to toxins but drew some lines on which modern neurobiology might proceed.

The extremely potent substance botulinum neurotoxin (BoNT) has attracted much interest in diverse fields. Originally identified as cause for the rare but deadly disease botulism, military and terrorist intended to misuse this sophisticated molecule as biological weapon. This caused its classification as select agent category A by the Centers for Diseases Control and Prevention and the listing in the Biological and Toxin Weapons Convention. Later, the civilian use of BoNT as long acting peripheral muscle relaxant has turned this molecule into an indispensable pharmaceutical world wide with annual revenues >$1.5 billion. Also basic scientists value the botulinum neurotoxin as molecular tool for dissecting mechanisms of exocytosis. This book will cover the most recent molecular details of botulinum neurotoxin, its mechanism of action as well as its detection and application.

Clostridial Diseases of Animals is the first book to focus on clostridial diseases in domestic and wild animals, offering a comprehensive reference on these common diseases. Provides a single resource for all aspects of clostridial diseases Presents current, comprehensive information with a focus on clinical relevance Covers each disease in depth, including etiology, epidemiology, clinics, gross pathology, histopathology, diagnostics, diagnostic criteria, prophylaxis, control, and treatment Written by the world-leading experts in the field of clostridial diseases in animals Offers photographs and summary tables to support the concepts discussed in the text and aid in recognition

Neurotoxicology is a broad and burgeoning field of research. Its growth in recent years can be related, in part, to increased interest in and concern with the fact that a growing number of anthropogenic agents with neurotoxic potential, including pesticides, lead, mercury, and the polytypic bypro ducts of combustion and industrial production, continue to be spewed into and accumulate in the environment. In addition, there is great interest in natural products, including toxins, as sources of therapeutic agents. Indeed, it is well known that many natural toxins of broadly differing structure, produced or accumulated for predatory or defensive purposes, and toxic agents, accumulated incidentally by numerous species, function to perturb nervous tissue. Components of some of these toxins have been shown to be useful therapeutic agents and/or research reagents. Unfor tunately, the environmental accumulation of some neurotoxic ants of anthropogenic ori gin, especially pesticides and metals, has resulted in incidents of human poisoning, some of epidemic proportion, and high levels of morbidity and mortality. Furthermore, an increasing incidence of neurobehavioral disorders, some with baffling symptoms, is confronting clinicians. It is not clear whether this is merely the result of increased vigi lance and/or improved diagnostics or a consequence of improved health care. In any case, the role of exposure to environmental and occupational neurotoxic ants in the etiology of these phenomena, as well as neurodegenerative diseases, is coming under increasing scrutiny and investigation.

Currently, there are tremendous advances being made in understanding the basic science of both the structure and function of botulinum neurotoxins. This knowledge is opening up opportunities in regard to both therapeutic uses and treatment and protection options for civil and bio-defense applications. This volume fully evaluates the status of neurotoxin research and exploitation with a focus on clinical application. The book is a multi-authored collection of chapters written by the leading authorities responsible for the current scientific and clinical research that is advancing the understanding and exploitation of the neurotoxins and is both up to date and authoritative.