Cholinesterase

The Fifth International Meeting on Cholinesterases convened in Madras, India, in September of 1994. The long and rich history and culture of India provided an excellent setting for the meeting. More than 120 delegates from Asia, Australia, Europe and North America heard 54 oral presentations and viewed 54 posters on current research on enzymes of the cholinesterase family. The aim of this book is to compile the presentations of the Fifth International Meeting on Cholinesterases into a volume that describes recent investigations on the structure and catalytic function of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and related enzymes, as well as studies on the molecular and cellular biology of these enzymes and the genes which encode them. Cholinesterases enjoy a long and storied history in diverse areas. In basic biochemical research, AChE is one of the best studied, though yet enigmatic, of enzymes. The efficient catalytic function of this enzyme presents the biochemist with a fundamental challenge in understanding the relationship between structure and function. AChE and BuChE belong to a family of proteins, the alB hydrolase fold family, whose constituents evolutionarily diverged from a common ancestor. Proteins in this family have a wide range of physiological functions. In commerce, AChE is a prime target for agricultural insect control, and for the development of therapeutic agents for Alzheimer's disease.

Acetylcholinesterase plays a key role in cholinergic transnnSSlOn. By rapid hydrolysis of the neurotransmitter acetylcholine the enzyme terminates the chemical impluse, thereby allowing rapid repetitive responses. Inhibitors of cholinesterases have important applications in agriculture - pest control, and in medicine - treatment of various disorders such as myasthenia gravis, glaucoma and management of Alzheimer's disease. These are some of the reasons for the special attraction of scientists from multiple disciplines such as neurobiology, pharmacology, chemistry, biochemistry, molecular biology and biotechnology to cholinesterase research. We have been fortunate to organize the 36th OHOLO conference on Multidisciplinary Approaches to Cholinesterase Functions at a time when this field of research is bursting with new concepts and ideas, brought about by the recent structural resolution of the catalytic subunit of acetylcholinesterase and by application of methodologies related to molecular genetics and protein engineering. This volume summarizes most of the important advances resulting from these developments as reflected in the OHOLO meeting.

Although the anticholinesterase (anti-ChE) agents have only limited applica tions in therapy, and from the viewpoint of practical significance they are more appropriately classified as toxic compounds or insecticides than as drugs, in their capacity of pharmacological tools they have few equals. The concept of neuro humoral transmission was originally established largely from experiments in which physostigmine, or eserine, was employed to protect acetylcholine (ACh), the trans mitter of the cholinergic nerves, from rapid hydrolytic destruction by acetyl cholinesterase (AChE) and other cholinesterases (ChE's). Since then, a great num ber of additional reversible and irreversible anti-ChE agents also have been indis pensable in studies of synaptic and neuroeffector transmission, and of other physiological processes. At the same time, there is practically no other class of compounds for which a mechanism of pharmacological action can be described in such concrete biochemical and physiological terms. Consequently, it is not sur prising that a huge literature has developed on these several closely interdependent topics. The assembling anrl proper correlation of this material for the present volume has taken the collaborative efforts of over two dozen . investigators. It iR believed that their contributions to this end will prove invaluable to future in vestigators in providing a ready, inclusive source of established information, in defining areas where further studies are indicated, and in preventing unnecessary duplication of past work. How well these aims have been accomplished will be for time and the reader to judge.

Epidemiological studies, modern clinical, neuroimaging, neuropsychological, molecular biological, and genetic studies have considerably enhanced our knowledge about ageing processes of the human brain, its sequelae, diagnostic, and therapeutic possibilities and limits. In addition to Alzheimer's disease and other degenerative dementias, the impact of cerebrovascular lesions and their risk factors in the pathogenesis of cognitive disorders of the aged are increasingly acknowledged, and the recognition of mild cognitive impairment as a frequent initial stage of developing dementia is becoming an increasingly important diagnostic and therapeutic problem. The included papers were presented at the 7th International Symposium in Graz, Sept. 2001 and give a timely overview of the current and future concepts of pathogenesis, diagnosis, and treatment strategies of pathological brain ageing and dementias, early recognition of mild cognitive impairment and future possiblities of prevention of dementing processes.

With the collaboration of the most distinguished scholars in this field Professor Giacobini has put together a publication which will convey present knowledge in the field of molecular biology and genetics, biochemistry, cell biology, pharmacology and toxicology as well of clinical applications (particularly in the field of Alzheimer's disease therapy) of cholinesterase inhibitors. In a concise but precise manner it condenses our present knowledge of these enzymes and their inhibitors and helps those who want to understand them as well as to utilize them for therapeutic purposes.

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