Arrowsmith, Joseph Edmund; (2001) The neuroprotective effects of remacemide hydrochloride in patients undergoing elective coronary artery bypass surgery. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Over the last forty years considerable evidence has been gathered in support of the hypothesis that amino acids are among the most important neurotransmitters within the central nervous system. The development of compounds that inhibit the actions of these recently described neurotransmitters led to the identification of several subtypes of amino acid receptor. Recognition of the neurotoxic effects mediated by excitatory amino acids (EAAs) has prompted investigation of the role of these naturally occurring substances in the processes that culminate in irreversible neuronal injury and death. The observation that EAA receptor antagonists protect neurons from the toxic effects of hypoxia and potent EAA receptor agonists has stimulated interest in the potential therapeutic use of this new class of drug in neurodegenerative disorders. These include stroke, head injury, epilepsy, Parkinson's and Alzheimer's diseases, motorneurone disease, Huntington's Chorea and the neurological sequelae of the acquired immunodeficiency syndrome (AIDS). Surgical procedures performed with the aid of cardiopulmonary bypass (CPB) represent a novel human model of diffuse neuronal injury. Advances in both technology and surgical technique have brought about a steady decline in the mortality and morbidity associated with such cardiac surgery. The fall in the incidence of major perioperative neurological sequelae (brain death, coma, stroke, seizures and altered conscious level) has paralleled that of other complications. Despite this apparent improvement in outcome, formal neuropsychological testing reveals that a significant proportion of patients sustain persistent deficits in cognitive function after otherwise successful surgery. Amongst the many factors implicated in the genesis of this phenomenon, the delivery of microemboli to the cerebral microcirculation during CPB, appears to be one of the most important. This thesis reviews some of the historical landmarks in the evolution of coronary artery bypass surgery (CABS); discusses the neurological consequences of cardiac surgery and reviews the evidence for a role for amino acids in neurotransmission and neurotoxicity. The hypothesis that the incidence and severity of neuropsychological deficits after CPB can be reduced by Remacemide, a selective inhibitor of excitotoxic amino acids, is examined in a detailed study of patients undergoing CABS. Evidence for pharmacological neuroprotection is presented in this first reported use of an EAA antagonist in this clinical setting.

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