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Title: The development of a novel model of focal cerebral ischaemia using endothelin isopeptides
Author: Henshall, David C.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1997
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Several animal models of focal cerebral ischaemia have been developed to gain insight into the pathophysiology and possible therapeutic treatment of stroke. This thesis aimed to optimise & characterise a model of focal cerebral ischaemia that utilises perivascular microinjection of endothelin-1 (ET-1) to occlude the middle cerebral artery (MCA) of the rat, and to develop a novel model of endothelin-induced MCA occlusion with controlled reperfusion. The MCA of the anaesthetised rat was occluded by the intracerebral microinjection of ET-1 into the outer layers of cortex adjacent to the MCA. Elistopathological analysis of ischaemic brain damage three days following injection, determined that ET-1 produced a large volume of ischaemic brain damage confined to the vascular territory of the MCA within the dose range 33-300 pmols, whilst a 10 pmol injection was ineffective. The optimal injection volume was found to be in the range 1-3pi. The isopeptide ET-3 was found to be equipotent with ET-1 in the ischaemic insult it produced, having the same minimal effective dose, and being effective over the same dose range. This is the first demonstration that ET-3 is capable of producing ischaemic damage by constricting a major cerebral artery. The equipotency of ET-1 and ET-3 in terms of histopathological outcome in this experimental model of stroke, was supported by laser Doppler flowmetry (LDF) recordings of perfusion velocity from the parietal cortex, in which the severity and duration of ischaemia was found to be the same between isopeptides. These isopeptides are only equipotent at the ET0 receptor, however, ETB receptor involvement was excluded by the ineffectiveness of the selective ETB receptor agonists BQ3020 and IRL1620 in producing MCA occlusion. Furthermore, whilst intracerebral injection of the specific ETA receptor antagonist FR139317 (3 nmols in 3 pi) 10 minutes before ET-3, blocked MCA occlusion, this dose of FR13 9317 was ineffective against ET-1 -induced MCA occlusion. This suggests the involvement of an atypical receptor in the contractile response of the rat MCA to endothelin isopeptdies. Intracerebral probes determined that striatal temperature remained unchanged following ET-1-induced MCA occlusion. By contrast, striatal oxygen tension, measured by intracerebral oxygen electrodes, and cortical tissue perfusion velocity, measured by laser Doppler flowmetry (LDF) fell rapidly following ET-1 injection. Oxygen tension did not recover for 3 hours following ET-1 injection, whilst the LDF signal showed some recovery but still remained below 50% of baseline levels after 2 hours. [l4C]iodoantipyrine autoradiography determined that local cerebral blood flow (CBF) was profoundly reduced throughout much of the vascular territory of the MCA three hours after injection of ET-1. This pathophysiological profile suggests that ET-1-induced MCA occlusion represents a model of permanent focal cerebral ischaemia in which reperfusion is limited. A 17mer sequence of the secreted form of (β-amyloid precusor protein (βAPP), which has previously been shown to possess trophic and neuroprotective properties, was evaluated using this experimental model of stroke. The 17mer peptide was found to confer neuroprotection to both cortex and striatum, when delivered intracerebroventricularly for three days before inducing ET-1-induced MCA occlusion. However, the 17mer peptide did not improve functional recovery following ET-1-induced MCA occlusion as assessed by a model of skilled motor control.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available