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Mechanisms of actions of neurotoxic substances
93
TIPS - February 1983
This book suffers from trying to be all things to all men. Very basic information on the bodily functions are not necessary and neither are many of the illustrations. The main interest in this single volume is that it can act as a rapid source of information on medicinal and toxic plants. Regrettably it does not go into sufficient detail on these aspects and thus falls between being a useful scientific reference book and a coffee table publication.
urogenital system, skin and deterrents (e.g. antibiotics)- in that order! Again the text is liberally sprinkled'with illustrations, many consisting of either ancient herbal drawings or else simple drawings depicting basic anatomy, e.g. page 175 is devoted to a schematic diagram of the circulatory system followed by half a page on the heart which is suitable for secondary school and contrasting with the chemical structures on p. 134 of some naturally occurring chemotherapeutic agents such as vinblastine (incorrectly presented). The third section (pp. 377-448) on
'psychoactive' plants is divided into chapters on stimulants, hallucinogens and depressants, the latter containing information on alcohol and barbiturates. Taking one example, ergot, which has been and continues to be a source of valuable therapeutic agents, the text is located mainly in the third section on hallucinogens and basically this covers a potted history with two gruesome illustrations of gangrene produced in 1782 and 1892. For a description of the plant, we have to tum to p. 321 in the chapter on the urogenital system.
Just GABA
amount of circumstantial evidence to sug- though GABAphiles may fred much of the gest that GABA may have a direct influence information dated. Nevertheless, the overon peripheral organs. However, while a all quality of the presentations ensures some great deal of information is contained in new insights for the careful reader. In this these research papers, a better service may regard the editors have achieved their goal have been rendered with a comprehensive, of providing a text that, while not encyclopedic, may serve to stimulate further and critical, review of this subject. Overall, this text contains several inter- work in the field. S. J. ENNA esting manuscripts on selected topics in GABA research. Because of the paucity of The author Is Professor of Pharmacology and of review articles, the book will be of most Neuroblology at the Umversity of Texas Medical value to those actively working in the area, School at Houston, Houston, TX, U.S.A.
Problems in GABA Research
edited by Yasuhiro Okada and Eugene Roberts, Excerpta Medica 1982. Dfl. 260.00 (xx + 443 pages) ISBN 90 219 0510 8 This volume summarizes the proceedings of an International Symposium on GABA held in Japan during the summer of 1981. The text contains 40 manuscripts, most of which are biochemically oriented, with little emphasis on electrophysiological, behavioral, or anatomical studies. A journal format (introduction, Methods, Results, Discussion) is used, with the majority of authors describing their most recent experiments, The contributors are recognized as leaders in the field, and, dis,. counting the typographical errors characteristic of 'camera-ready' works, the presentations are generally clear, concise and complete. Three areas of GABA research are covered. Thirty chapters deal with some aspect of GABA as a central neurotransmitter; five consider the possible role of GABA in the peripheral nervous system, with emphasis on the autonomic control of cardiovascular, respiratory and gastrointestinal activity; and five articles are devoted to discussing the presence, and possible function, of GABA in non-neural tissue (pancreas). GABA synthesis, uptake, storage, receptor binding and the role of this amino acid in extrapyramidal function and seizure threshold are the topics covered relating to the central nervous system, Perhaps most useful are the reviews by Lloyd, Gale, Hassler, Schousboe and Schrier. The latter two are especially worthwhile as they cover an area (tissue culture) not dealt with extensively in other texts.
The collection of studies dealing with the possible roles of GABA outside the central nervous system make this monograph particularly useful. Although far from conclusive, these studies provide a compelling
Neurotoxicity news Mechanisms of Actions of Neurotoxic Substances
edited by Kedar Prasad and Antonia Vernadakis, Raven Press (1982): $36.04 (ix + 225 pages) ISBN 0 89004 638 7 The admirable objectives of this volume are to provide a platform for discussion of the effect of selected toxic agents on nervous tissue at the molecular, cellular and organism levels. While such principles espoused fervently and repetitively proclaimed at the outset are seldom adhered to, such is not the case in the present work. Although at times there is repetition of data which have been previously recorded in a voluminous literature (e.g. on mercury and lead), by and large the initial goals set by the authors have been met. The result is a compendium of important data on several critical neurotoxic agents. Some with the capability of exerting neurobehavioral and neurologic insult via expression of an especially insidious neurotoxic profile. On cursory appraisal the inclusion of DDT seemed somewhat redundant, particularly since this agent has been banned as an environmental hazard in the U.S.A. since 1972. However, careful perusal of the neurotoxicity of this agent indicates that it can serve as a useful experimental animal model for understanding the underlying
J DAVID PHILLIPSON
The author ts Reader m pharmacognosy at the School of pharmacy, London, U K.
mechanisms of myoelonic movements in humans. The continuing quest for elucidation of the CNS site of action of DDT is ably reviewed by Woolley. In discussing the neurochemical mechanisms underlying the neurotoxic effects of DDT, less stress is now given to involvement of the cholinergic neuronal system, and more is given instead to recent evidence indicating the involvement of brain 5-HT in the symptomatology of neurotoxicity. In an accompanying chapter Van Woert and his colleagues continue to expand their studies on the neurochemistry of myoclonic movements. Abnormal movements produced by DDT are similar to stimulus- sensitive interv ion myocionus which occurs in man. Clinical studies have suggested that this particular variant of abnormal movement disorders may be causally related to a deficiency of brain 5-HT since CSF 5HIAA (5-hydroxy indoleacetic acid) is decreased in such patients. Evidence for this concept, it is noted, arises especially from the observation that the precursor of 5-HT, L. 5-hydroxytryptophan along with carbidopa is effective treatment in these patients. Silbergeld reviews the neuroehemical mechanisms of lead neurotoxicity and summarises current clinical and experimental studies. While conceding that the precise mechanism(s) for the toxic insult of lead on nervous tissue are still unknown, a number of hypotheses of lead intoxication principally relating to cho'lmergic, catechol-
TIPS - February 1983
94 aminergic, and GABA-ergic pathways are discussed, albeit somewhat less than adequately. This chapter suffers from considerable compression resulting in inadequate treatment of subjects which in themselves would require almost an entire volume. There is one particular chapter the inclusion of which in the bias of this reviewer would have rendered purchase of the book a bargain even if it had been the sole topic! The use of neurotransmitter receptorbinding interactions as a pharmacological screen for detecting neurotoxic action. This topic has been eagerly awaited by those neurotoxicologists currently enmeshed in the complexities of setting up their own neurotransmitter receptor assay. In an all too brief exposition of the intricacies of this novel technique, Bondy (NIEHS) discusses the advantages of the receptor-binding approach as an aid in uncovering or generating clues towards solution of the enigma of action mechanisms surrounding important neurotoxins. The devastating consequences occurring following poisoning with an insidious neurotoxin like alkyl mercury was tragically demonstrated in the crippling neurological and neurobehavioral disorders that followed contamination at Minimata Bay in Japan. Though less publicised, an equally crippling incapacitation occurred among native people eating mercury contaminated fish from Northern rivers of Canada. Parenthetically, it is always a matter of grave discontent to scientists that solution of many problems of environmental toxicology actually lie in the political realm and could be relatively easily solved by legislative protective guidelines rather than the sometimes draconian measures required following a disaster. In this connection, the pathogenetic mechanisms of the neurotoxicity of methylmercury and Minimata disease as well as experimental changes in the brain of mercury intoxicated animals are discussed by Chang. Unfortunately, as noted for lead neurotoxicity, this chapter attempts to compress the voluminous data on methylmercury neurotoxicity into a few short pages and suffers accordingly. The feasibility of using monolayer cultures of neuroblastoma and glioma cells as a screen to detect neurotoxicity of metals and other agents is a timely chapter and does provide convincing data of the potentiality of tissue culture as a supplementary detection technique for neurotoxins. The effects of psychotropic agents on cell proliferation, and the use of both biochemical and morphological parameters of cultured cells to predict potential neurotoxicity to the developing CNS in the fetus of pregnant women receiving medication for psychiatric or epileptic disorders is very ably dis-
cussed by Patel and Lewis. This is a complex problem and has received only cursory scrutiny in the past. The data presented in this chapter argue slxongly for increased caution in the administration to pregnant or lactating women of drugs that act on the nervous system. The authors are to be complimented on their contribution towards a critical and insidious problem of maternal therapeutics; that of predicting behavioral teratogenicity. One particular defect of this book is that little information is given on metals other than lead and mercury. It would have added considerably to the originality of this book to also have included data on other metal neurotoxins such as vanadium, manganese, zinc, etc. and perhaps also to have included
Side effects summarized Side Effects of Drugs Annual 6
edited by M. N. G. Dukes, Excerpta Medica 1982. $69.75/Dfl. 150 (xviii + 478pages) ISBN 90 219 3060 9 I doubt if many would quibble with the claim that 'Metiers Side Effects of Drugs' is one of the best (some might argue the • best) sources of information about adverse drug reactions. These annual volumes with their year-by-year analysis of the latest information supplement the parent volume and ensure that the data are readily and widely available. Volume 6 is the most recent annual, covering the period from August 1980 to July 1981, and summarizes the most recent information on the adverse reactions and interactions of old and new drugs. In addition these annuals contain a considerable number of special reviews of variable length which survey and interpret both old and new data on particular topics or individual drugs. As before, this is a multi-author publication. Each of these volumes can stand independently, but they are best read in conjunction with the parent book and, in the case of Annual 6, with the two previous annuals because the indices carry crossreferences to all of these volumes. As usual there are four separate indices, synonyms, drugs, side effects and interactions which ensure that the information in the book can be approached from different angles. This annual continues the extremely useful practice of coding the references, so that if one wishes to pursue a detailed line of enquiry and read the original literature, it is possible to distinguish papers which are reviews (R) from those containing only a brief reference
a chapter on the implications of free radical pathology in relation to neurotoxicity. However, these are relatively minor criticisms which can be easily rectified in other editions, and there is little doubt that the volume not only deserves a place on the neurotoxicologist's shelf, but also is of value to the general neuroscientist concerned with the elucidation of underlying mechanisms of neurotoxic insult, as well as to the practising clinical neurologist. JOHN DONALDSON
The author is Assistant Professor in the Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Mamtoba, Winmpeg, Canada.
(r), or those which carry a little (c) or a lot (C) of clinical evidence. Among the special reviews which are dealt with this year and which I found of particular interest were those concerned with cimetidine and gastric cancer, theophylline intoxication, the digitalis-quinidine interaction, and benzodiazepine dependence. There are many others of equal merit as well as a handful dealing with drugs which have been marketed relatively recently (captopril) and others which have been with us for years (nitrofurantoin). One of the most valuable features of these annuals is that they not only give the latest information on new drugs, but they continue to survey old and well-tried drugs so that the entire field of drugs continues to be under review. Like its predecessors, Annual 6 is not only an excellent and up-to-date source of information, but also makes extraordinarily interesting reading, and my enthusiasm for this series of publications continues unabated. I have only two small criticisms to offer. Firstly, when I came to use the indices I found one or two omissions. For example the isoniazid-halothane interaction can be found by looking up isoniazid but not halothane, and there are other examples where a drug is mentioned in the text but not, as far as I could find, in an index. My other, quite different comment, is that as these books are so good and should be readily available to everyone who is concerned with the safe administration of drugs, it is regrettable that their price almost certainly excludes them from the shelves of the majority of individual users. Is there no practical solution to this problem? IVAN STOCKLEY
The author is Lecturer in Pharmacology in the Department of Pharmacy, University of Notangham, Nottingham, U.K.
TIPS - February 1983
This book suffers from trying to be all things to all men. Very basic information on the bodily functions are not necessary and neither are many of the illustrations. The main interest in this single volume is that it can act as a rapid source of information on medicinal and toxic plants. Regrettably it does not go into sufficient detail on these aspects and thus falls between being a useful scientific reference book and a coffee table publication.
urogenital system, skin and deterrents (e.g. antibiotics)- in that order! Again the text is liberally sprinkled'with illustrations, many consisting of either ancient herbal drawings or else simple drawings depicting basic anatomy, e.g. page 175 is devoted to a schematic diagram of the circulatory system followed by half a page on the heart which is suitable for secondary school and contrasting with the chemical structures on p. 134 of some naturally occurring chemotherapeutic agents such as vinblastine (incorrectly presented). The third section (pp. 377-448) on
'psychoactive' plants is divided into chapters on stimulants, hallucinogens and depressants, the latter containing information on alcohol and barbiturates. Taking one example, ergot, which has been and continues to be a source of valuable therapeutic agents, the text is located mainly in the third section on hallucinogens and basically this covers a potted history with two gruesome illustrations of gangrene produced in 1782 and 1892. For a description of the plant, we have to tum to p. 321 in the chapter on the urogenital system.
Just GABA
amount of circumstantial evidence to sug- though GABAphiles may fred much of the gest that GABA may have a direct influence information dated. Nevertheless, the overon peripheral organs. However, while a all quality of the presentations ensures some great deal of information is contained in new insights for the careful reader. In this these research papers, a better service may regard the editors have achieved their goal have been rendered with a comprehensive, of providing a text that, while not encyclopedic, may serve to stimulate further and critical, review of this subject. Overall, this text contains several inter- work in the field. S. J. ENNA esting manuscripts on selected topics in GABA research. Because of the paucity of The author Is Professor of Pharmacology and of review articles, the book will be of most Neuroblology at the Umversity of Texas Medical value to those actively working in the area, School at Houston, Houston, TX, U.S.A.
Problems in GABA Research
edited by Yasuhiro Okada and Eugene Roberts, Excerpta Medica 1982. Dfl. 260.00 (xx + 443 pages) ISBN 90 219 0510 8 This volume summarizes the proceedings of an International Symposium on GABA held in Japan during the summer of 1981. The text contains 40 manuscripts, most of which are biochemically oriented, with little emphasis on electrophysiological, behavioral, or anatomical studies. A journal format (introduction, Methods, Results, Discussion) is used, with the majority of authors describing their most recent experiments, The contributors are recognized as leaders in the field, and, dis,. counting the typographical errors characteristic of 'camera-ready' works, the presentations are generally clear, concise and complete. Three areas of GABA research are covered. Thirty chapters deal with some aspect of GABA as a central neurotransmitter; five consider the possible role of GABA in the peripheral nervous system, with emphasis on the autonomic control of cardiovascular, respiratory and gastrointestinal activity; and five articles are devoted to discussing the presence, and possible function, of GABA in non-neural tissue (pancreas). GABA synthesis, uptake, storage, receptor binding and the role of this amino acid in extrapyramidal function and seizure threshold are the topics covered relating to the central nervous system, Perhaps most useful are the reviews by Lloyd, Gale, Hassler, Schousboe and Schrier. The latter two are especially worthwhile as they cover an area (tissue culture) not dealt with extensively in other texts.
The collection of studies dealing with the possible roles of GABA outside the central nervous system make this monograph particularly useful. Although far from conclusive, these studies provide a compelling
Neurotoxicity news Mechanisms of Actions of Neurotoxic Substances
edited by Kedar Prasad and Antonia Vernadakis, Raven Press (1982): $36.04 (ix + 225 pages) ISBN 0 89004 638 7 The admirable objectives of this volume are to provide a platform for discussion of the effect of selected toxic agents on nervous tissue at the molecular, cellular and organism levels. While such principles espoused fervently and repetitively proclaimed at the outset are seldom adhered to, such is not the case in the present work. Although at times there is repetition of data which have been previously recorded in a voluminous literature (e.g. on mercury and lead), by and large the initial goals set by the authors have been met. The result is a compendium of important data on several critical neurotoxic agents. Some with the capability of exerting neurobehavioral and neurologic insult via expression of an especially insidious neurotoxic profile. On cursory appraisal the inclusion of DDT seemed somewhat redundant, particularly since this agent has been banned as an environmental hazard in the U.S.A. since 1972. However, careful perusal of the neurotoxicity of this agent indicates that it can serve as a useful experimental animal model for understanding the underlying
J DAVID PHILLIPSON
The author ts Reader m pharmacognosy at the School of pharmacy, London, U K.
mechanisms of myoelonic movements in humans. The continuing quest for elucidation of the CNS site of action of DDT is ably reviewed by Woolley. In discussing the neurochemical mechanisms underlying the neurotoxic effects of DDT, less stress is now given to involvement of the cholinergic neuronal system, and more is given instead to recent evidence indicating the involvement of brain 5-HT in the symptomatology of neurotoxicity. In an accompanying chapter Van Woert and his colleagues continue to expand their studies on the neurochemistry of myoclonic movements. Abnormal movements produced by DDT are similar to stimulus- sensitive interv ion myocionus which occurs in man. Clinical studies have suggested that this particular variant of abnormal movement disorders may be causally related to a deficiency of brain 5-HT since CSF 5HIAA (5-hydroxy indoleacetic acid) is decreased in such patients. Evidence for this concept, it is noted, arises especially from the observation that the precursor of 5-HT, L. 5-hydroxytryptophan along with carbidopa is effective treatment in these patients. Silbergeld reviews the neuroehemical mechanisms of lead neurotoxicity and summarises current clinical and experimental studies. While conceding that the precise mechanism(s) for the toxic insult of lead on nervous tissue are still unknown, a number of hypotheses of lead intoxication principally relating to cho'lmergic, catechol-
TIPS - February 1983
94 aminergic, and GABA-ergic pathways are discussed, albeit somewhat less than adequately. This chapter suffers from considerable compression resulting in inadequate treatment of subjects which in themselves would require almost an entire volume. There is one particular chapter the inclusion of which in the bias of this reviewer would have rendered purchase of the book a bargain even if it had been the sole topic! The use of neurotransmitter receptorbinding interactions as a pharmacological screen for detecting neurotoxic action. This topic has been eagerly awaited by those neurotoxicologists currently enmeshed in the complexities of setting up their own neurotransmitter receptor assay. In an all too brief exposition of the intricacies of this novel technique, Bondy (NIEHS) discusses the advantages of the receptor-binding approach as an aid in uncovering or generating clues towards solution of the enigma of action mechanisms surrounding important neurotoxins. The devastating consequences occurring following poisoning with an insidious neurotoxin like alkyl mercury was tragically demonstrated in the crippling neurological and neurobehavioral disorders that followed contamination at Minimata Bay in Japan. Though less publicised, an equally crippling incapacitation occurred among native people eating mercury contaminated fish from Northern rivers of Canada. Parenthetically, it is always a matter of grave discontent to scientists that solution of many problems of environmental toxicology actually lie in the political realm and could be relatively easily solved by legislative protective guidelines rather than the sometimes draconian measures required following a disaster. In this connection, the pathogenetic mechanisms of the neurotoxicity of methylmercury and Minimata disease as well as experimental changes in the brain of mercury intoxicated animals are discussed by Chang. Unfortunately, as noted for lead neurotoxicity, this chapter attempts to compress the voluminous data on methylmercury neurotoxicity into a few short pages and suffers accordingly. The feasibility of using monolayer cultures of neuroblastoma and glioma cells as a screen to detect neurotoxicity of metals and other agents is a timely chapter and does provide convincing data of the potentiality of tissue culture as a supplementary detection technique for neurotoxins. The effects of psychotropic agents on cell proliferation, and the use of both biochemical and morphological parameters of cultured cells to predict potential neurotoxicity to the developing CNS in the fetus of pregnant women receiving medication for psychiatric or epileptic disorders is very ably dis-
cussed by Patel and Lewis. This is a complex problem and has received only cursory scrutiny in the past. The data presented in this chapter argue slxongly for increased caution in the administration to pregnant or lactating women of drugs that act on the nervous system. The authors are to be complimented on their contribution towards a critical and insidious problem of maternal therapeutics; that of predicting behavioral teratogenicity. One particular defect of this book is that little information is given on metals other than lead and mercury. It would have added considerably to the originality of this book to also have included data on other metal neurotoxins such as vanadium, manganese, zinc, etc. and perhaps also to have included
Side effects summarized Side Effects of Drugs Annual 6
edited by M. N. G. Dukes, Excerpta Medica 1982. $69.75/Dfl. 150 (xviii + 478pages) ISBN 90 219 3060 9 I doubt if many would quibble with the claim that 'Metiers Side Effects of Drugs' is one of the best (some might argue the • best) sources of information about adverse drug reactions. These annual volumes with their year-by-year analysis of the latest information supplement the parent volume and ensure that the data are readily and widely available. Volume 6 is the most recent annual, covering the period from August 1980 to July 1981, and summarizes the most recent information on the adverse reactions and interactions of old and new drugs. In addition these annuals contain a considerable number of special reviews of variable length which survey and interpret both old and new data on particular topics or individual drugs. As before, this is a multi-author publication. Each of these volumes can stand independently, but they are best read in conjunction with the parent book and, in the case of Annual 6, with the two previous annuals because the indices carry crossreferences to all of these volumes. As usual there are four separate indices, synonyms, drugs, side effects and interactions which ensure that the information in the book can be approached from different angles. This annual continues the extremely useful practice of coding the references, so that if one wishes to pursue a detailed line of enquiry and read the original literature, it is possible to distinguish papers which are reviews (R) from those containing only a brief reference
a chapter on the implications of free radical pathology in relation to neurotoxicity. However, these are relatively minor criticisms which can be easily rectified in other editions, and there is little doubt that the volume not only deserves a place on the neurotoxicologist's shelf, but also is of value to the general neuroscientist concerned with the elucidation of underlying mechanisms of neurotoxic insult, as well as to the practising clinical neurologist. JOHN DONALDSON
The author is Assistant Professor in the Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Mamtoba, Winmpeg, Canada.
(r), or those which carry a little (c) or a lot (C) of clinical evidence. Among the special reviews which are dealt with this year and which I found of particular interest were those concerned with cimetidine and gastric cancer, theophylline intoxication, the digitalis-quinidine interaction, and benzodiazepine dependence. There are many others of equal merit as well as a handful dealing with drugs which have been marketed relatively recently (captopril) and others which have been with us for years (nitrofurantoin). One of the most valuable features of these annuals is that they not only give the latest information on new drugs, but they continue to survey old and well-tried drugs so that the entire field of drugs continues to be under review. Like its predecessors, Annual 6 is not only an excellent and up-to-date source of information, but also makes extraordinarily interesting reading, and my enthusiasm for this series of publications continues unabated. I have only two small criticisms to offer. Firstly, when I came to use the indices I found one or two omissions. For example the isoniazid-halothane interaction can be found by looking up isoniazid but not halothane, and there are other examples where a drug is mentioned in the text but not, as far as I could find, in an index. My other, quite different comment, is that as these books are so good and should be readily available to everyone who is concerned with the safe administration of drugs, it is regrettable that their price almost certainly excludes them from the shelves of the majority of individual users. Is there no practical solution to this problem? IVAN STOCKLEY
The author is Lecturer in Pharmacology in the Department of Pharmacy, University of Notangham, Nottingham, U.K.