Hatfield, Richard H.; (1991) Neuroprotection with the N-methyl-D-aspartate antagonist dizocilpine (MK-801) in a model of focal ischaemia. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Ischaemic brain damage, due to cerebrovascular disease ("stroke"), head injury, cardiac arrest, surgery (cardiopulmonary bypass and intracranial) and perinatal hypoxia, is a major cause of death and disability in the western world. Stroke alone is the third most common cause of death after cancer and heart disease, accounting for some 10% of all deaths, approximately 60,000 per year in England and Wales. Recently there has been rapidly growing evidence supporting the "excitotoxic" theory of neuronal damage in ischaemia, in which excitatory amino acid neurotransmitters are implicated as agents of damage to ischaemic brain. Excitatory amino acid antagonists, in particular N-methyl-D-aspartate (NMDA) antagonists, have proved to be dramatically effective in the protection of brain parenchyma in experimental models of ischaemia, especially focal ischaemia. The role of excitatory amino acid neurotransm itters in ischaemia and the experimental evidence for amelioration of ischaemic brain damage by NMDA antagonists, is reviewed. A model of focal ischaemia in the rat is described, which can be used for assessing drugs that might be useful clinically. A method of volumetric analysis of infarct size using conventional histopathology is compared to a much cheaper and faster m ethod using the m itochondrial redox stain, 2,3,5,triphenyltetrazolium chloride (TTC). The later method can be used for the rapid screening of compounds, but it has limitations which are fully explored. The neuroprotective effects of the NMDA antagonist, dizocilpine (MK-801) in acute and chronic ischaemia are compared and the chronic model is used to establish a "dose response" and "therapeutic window" for dizocilpine. Hypertension is a major risk factor in stroke and the neuroprotective effects of dizocilpine are examined in both normotensive and spontaneously hypertensive strains of rat, with pure cortical and combined cortical and striatal lesions. Finally, release of neuron-specific enolase into the CSF is correlated with infarct size in dizocilpine treated and control animals with a view to the possible clinical use of NSE in the quantification of ischaemic damage.

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