Brain, Vol. 123, No. 4, 847-848,
April 2000
© 2000 Oxford University Press
Book Reviews |
CEREBRAL ISCHEMIA: MOLECULAR AND CELLULAR PATHOPHYSIOLOGY.
.
Department of Histopathology, Imperial College School of Medicine, London, UK
The book aims to deal with the mechanisms underlying the neuronal dysfunction which results from loss of cerebral blood/oxygen supply. The book is divided into three parts and is a series of review articles by different authors with expertise in their specific fields.
Part I is an overview of the subject. As such it is a rapid but helpful review of the mechanisms underlying cerebral ischaemic damage. The chapter starts with a look at the haemodynamic changes occurring in a focal cerebral infarct which result in a central ischaemic core and a less severely injured penumbra. There is then a brief section describing the effects on the various cellular elements of the brain—neural, astroglial, microglial and vascular—and the inflammatory response following ischaemia, with a useful table putting the events in their temporal context.
Next follows a discussion of the molecular events in cerebral ischaemia with brief details of immediate early genes, heat shock proteins, inflammation and apoptosis-related genes and growth factors that may be involved in repair. The relationship between the various mechanisms of ischaemic damage follows, and these are placed in temporal sequence. The chapter ends with a look at therapeutic strategies based on the preceding sections. This opening overview clearly introduces the topic of the book and lays the ground for what is to follow.
The second part, entitled `Factors in the brain microenvironment', comprises four chapters examining, largely, pathophysiological changes in the brain following ischaemia. Chapter 2 discusses the deleterious and cerebroprotective effects of spreading depression (SD) waves initiated after focal cerebral ischaemia. It describes the evidence that SD waves are an important factor in extending the area of cerebral infarction into the ischaemic penumbra surrounding the infarct and also that stimulation of astrocytes and microglia in normal brain by SD waves has a protective effect on undamaged brain. The following chapter is a review of the mechanisms of cell swelling after cerebral ischaemia. It is a detailed, if sometimes complicated, discussion of the physiology of cell swelling, the mechanisms used to measure cell swelling and its consequence. The chapter ends with a section on the different modes of release of excitatory amino acids—one of the mediators of cell swelling—following ischaemia.
Chapter 4 examines the role of calcium in cellular injury following ischaemia. The authors detail the changes in intercellular calcium concentrations observed in in vivo and in vitro models of ischaemia and describe the variations in calcium fluxes in different parts of the neuron. The role of mitochondria, endoplasmic reticulum and calcium-binding proteins in calcium homeostasis is examined, and the response of these to ischaemia is described. This is followed by a short section on the cellular processes, such as enzyme activation, free radical production and immediate early gene responses, consequent upon an elevation of intracellular calcium. The chapter is concluded by a detailed look at the role of the voltage-sensitive calcium channels, ionotropic glutamate receptors and intracellular calcium stores in producing the elevation of intracellular calcium after ischaemia based on studies using the various specific and less specific inhibitors of these pathways. Finally, there is a description of the various, mainly unsuccessful attempts at pharmacological attempts in the clinical situation to interrupt the calcium response to ischaemia and modify outcome.
The next subject for review is the role of free radicals in post-ischaemic brain injury. After a useful brief review of the chemistry of free radical production, and the antioxidant superoxide dismutase (SOD) enzymes, there is a discussion of the evidence from transgenic mouse models—SOD overexpression and knockout and nitric oxide synthetase knockouts—that free radicals are important in cerebral ischaemia.
The final chapter in Section 2 looks at the role of tumour necrosis factor (TNF) and transforming growth factor ß (TGFß) in post-ischaemic neuroprotection. The authors describe how the cells of the central nervous system express these two inflammatory cytokines following ischaemic injury and the signalling pathways that may be activated. Some useful and detailed cartoons help greatly in the understanding of these complex interconnected and still incompletely characterized pathways.
Section 3, `Cellular changes', commences with an extensive review of the alterations in gene expression that follow ischaemic brain injury. The changes in expression of mRNA and protein of a wide range of genes is considered, from heat shock proteins and cellular immediate early genes particularly members of the fos and jun families of transcription factors to genes of the apoptosis pathway, trophic factors, cytokines and neurotransmitters.
The immediate early genes are the main focus of the chapter and the regulation of these transcription factors and the reported changes following both global and focal ischaemia are discussed and an attempt is made to link this to upstream and downstream events.
Conditioning of the brain produces tolerance to subsequent insults, and changes in gene expression associated with this phenomenon are described, with a dissection of those that are likely to be causative, particularly `jun' expression, and those that are not. The identification of depolarization thresholds for expression of different genes, as an approach to recognizing those genes whose induction correlates with development of ischaemic tolerance, is a fascinating approach to linking electrical events to genetic changes.
The final three chapters deal with the changes in the various cell types of the brain. Firstly, there is a brief discussion of the routes to cell death of neurons—apoptosis and necrosis. The conclusion is that the processes are not mutually exclusive, but are ends of a spectrum, and the way a cell dies depends on the cell type and the injury it receives.
This is followed by a review of the mechanisms leading to astrocytic gliosis and the effects on neuronal survival through the extracellular matrix and production of neurotrophic factors.
The last chapter describes the changes in the brain's resident histiocytes, the microglia. A significant part of the chapter is taken up with methods for demonstrating microglia. The sequence of morphological changes which microglia undergo after ischaemia is laid out and a few of the antigenic and cytokine responses are detailed.
The book will be useful for new entrants to the field of cerebral ischaemia and will also be of value to workers in the field who wish to get up to speed in aspects in which they are not primarily active. The reviews are, on the whole, well written and extensively referenced, and personally, I found the chapters on gene expression and cytokines most interesting. In the round, this book helps to emphasize how far research has come but also how far we still are from a clear understanding of which processes, pathways and gene products are the key mediators in cell death and cell survival after ischaemia and how much further there is to go to identify effective treatments to minimize the effects of cerebral ischaemia.
Notes
Edited by Wolfgang Walz Totowa.
1999. New Jersey: The Humana Press.
Price $125.00. Pp. 288. ISBN 0-896-03540-9.
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