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Pharmacological advance in the treatment of acute brain injury
  1. Robert C Tasker
  1. Department of Paediatrics, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK
  1. Dr Tasker. email: rct31{at}hermes.cam.ac.uk

https://doi.org/10.1136/adc.81.1.90

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    This article discusses some of the issues related to advances in our understanding of the pharmacology of acute brain injury. My particular emphases are neuroprotective strategies, experimental models, and progress in clinical development. The primary aim is to provide a framework for assessing the literature of this important, clinically relevant field. The reader is also directed to recent reviews on the subject.

    Ischaemia induced ionic derangement

    The abrupt cessation of blood flow to brain tissue results in progressive pathophysiological changes which culminate in neurodegeneration. These acute, ischaemia induced processes can be divided into three important phases based on major movements in cellular ions (fig 1).1

    Figure 1

    Schematic illustration of cellular ionic changes occurring during the ischaemia induced periods of metabolic depression with bioenergetic stress (phase 1) and complete energy failure with anoxic depolarisation (phase 2). [ATP], concentration of adenosine triphosphate; [Ca++]i and [Na+]i, intracellular concentrations of calcium and sodium respectively; K+, potassium.

    First, there is a phase of metabolic depression, occurring within minutes of an insult, with a rapid decrease in electrical activity and suppression of neurotransmission (phase 1). At a cellular ionic level, there is a slow increase in extracellular potassium concentration ([K+]e) from ∼3 mM up to 8–10 mM. At least two types of potassium (K+) channel appear to be responsible for this change in K+ conductance, one activated by an increase in intracellular calcium (Ca++) concentration ([Ca++]i) and the other activated by a decrease in adenosine triphosphate (ATP), the ATP sensitive K+ channel (KATP).

    The second phase is characterised by almost complete energy failure and anoxic depolarisation (phase 2). It starts abruptly when a [K+]e of 8–10 mM triggers, within seconds, a rapid transition to an [K+] …

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