Aron, B.R.; (2006) Neuroprotective effects of heat shock proteins in experimental ischaemia: an MRI study. Doctoral thesis , University of London.

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Abstract

Heat shock proteins (HSPs) are molecular chaperones with essential roles in cellular function such as modulating the proteolytic machinery and accelerating cell repair. HSP overexpression has been observed in vitro and in vivo under stresses including heat, nutrient deprivation and ischaemia. Experiments in in vivo models of stroke indicate that transgenically overexpressed or virally delivered HSPs can enhance cell survival but cannot always reduce lesion size. This study aims to assess the protective effects of HSPs in a rat model of reversible focal cerebral ischaemia using magnetic resonance imaging (MRI) techniques to measure cerebral blood flow and lesion size. The experiments described used three different herpes simplex virus (HSV) constructs: two potentially therapeutic vectors, HSV-HSP27 and HSV-HSP70, and an HSV-LacZ control vector. Initially, the localization and duration of expression from the viral vector used to deliver the HSP genes into the rat brain was assessed. Subsequently, the effect of pre-ischaemic intra-striatal microinjections of HSV-HSP27 and HSV-HSP70 was evaluated in a middle cerebral artery occlusion (MCAO) model of stroke. Finally, the effect of delivering the same HSPs 30 minutes after ischaemia was assessed. Behavioural tests were carried out in the latter study up to a month after MCAO in order to determine whether HSP treatment induced functional recovery as well as reduction in lesion size. Results suggest that intracerebral microinjections with HSV-HSP27 have a neuroprotective effect pre- and [?] ischaemia. Multislice T2-weighted images show that HSP27 treatment results in a significant reduction in lesion size after MCAO, whereas HSP70 treatment does not affect lesion size compared to controls. Western blots confirm that virally-induced overexpression of both HSP27 and HSP70 is achieved in treated animals. For the first time, non-invasive MRI techniques were used to demonstrate the neuroprotective effect of HSP27 and not HSP70 in a rat model of reversible focal cerebral ischaemia.

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