Neuroprotective Agents and Cerebral Ischaemia

Abstract

edited by A.R. Green and A.J. Cross, Academic Press, 1997. £35.00 (xiii + 378 pages) ISBN 0 12 197880 XThis compact book (Vol. 40 in the International Review of Neurobiology series edited by R.J. Bradley, R.A. Harris and P. Jenner) brings together an impressive panel of experts to discuss emerging strategies for reducing the brain's vulnerability to ischemic injury. Such strategies are needed desperately, as stroke is a leading cause of death and disability around the world, and ischemic brain injury can complicate many clinical settings, such as cardiac arrest. Fortunately, a great deal has been learned over the past decade about the processes responsible for ischemic brain damage, and the development of effective counter measures seems truly imminent. At present, more than a dozen new drugs are moving through some stage of clinical testing towards possible use as acute interventional treatments for stroke. Roughly half of these drugs are aimed at improving or restoring lost blood flow; the other half are putative neuroprotectants, aimed at interdicting injury cascades within brain parenchyma.The book contains 373 pages organized into 15 chapters. The first four chapters lay a solid conceptual groundwork, summarizing major perturbations in ion homeostasis and cell degenerative changes that follow ischemic insults, as well as describing in some detail the experimental models, both culture based and animal based, that are used commonly to characterize the actions of candidate neuroprotective drugs. The next ten chapters discuss a set of prominent neuroprotective drug approaches, including calcium channel blockers, sodium channel blockers, N-methyl-d-aspartate (NMDA) antagonists, AMPA antagonists, adenosine agonists, gamma-aminobutyric acid (GABA) agonists, free radical scavengers, interleukin 1 receptor antagonists and nitric oxide synthase inhibitors. Each strategy is the focus of a single chapter, except for NMDA antagonists, which get two chapters, perhaps reflecting their historical precedence and the relative strength of the experimental data supporting their use in the treatment of stroke. Sadly, the main appeal of the second NMDA antagonist chapter, which specifically spotlights aptiganel (CNS 1102), has been relegated to historical interest by the very recent failure of interim analysis to demonstrate evidence of efficacy in a Phase III clinical trial, a setback which led the corporate sponsors, Cambridge NeuroScience and Boehringer Ingelheim, to suspend the trial. The closing chapter takes another cut through largely the same list of neuroprotectant drugs, reviewing clinical stroke studies that have been accomplished with these drugs over the past 15 years.This is not a comprehensive text. The short format used here does not permit coverage of many important topics such as ischemic glial cell death and white cell adhesion; in addition, there is no systematic coverage of anti-apoptotic approaches and many research-level controversies are not covered. But there is a still a lot for everyone here, clinician or bench researcher, generalist or specialist. Topics as a whole have been well chosen, and the chapters present pithy summaries of both underlying scientific rationale, and specific lead compounds in various stages of clinical testing. The discussions of rationale will probably be of most interest to clinicians, or research scientists seeking an overarching perspective of neuroprotective approaches as a whole. Researchers who actively follow or work in specific neuroprotection areas will probably find the chapters on in vitro and in vivo models, as well as the well-referenced (through 1995, with some 1996 citations) summaries of experimental or clinical studies, to be of greatest value. Apart from the useful review of clinical trials provided in the last chapter, the chapters on glutamate antagonists, or on nitrone-based free radical scavengers in particular contain superb tables compiling large amounts of experimental data. Reflecting the industry base or experience of many of the authors, the volume conveys a good sense of the neuroprotection drug development pipeline. In balance, I recommend this book as a superior volume, whose high `power-to-weight ratio', readability and availability in paperback make it attractive for personal acquisition.