The role of mast cells in a mouse model of focal cerebral ischaemia

Treatments for ischaemic stroke are limited and have low efficacy despite many years of promising research uncovering many potential therapeutic targets. As a result, stroke ranks as the third leading cause of death and the leading cause of disability worldwide. Mast cells have been identified as contributors to ischaemic stroke pathology, and are therefore a novel candidate for targeted stroke therapy. Indeed, genetic mast cell deficiency prior to onset of transient middle cerebral artery occlusion (tMCAo) in rats resulted in a significant reduction in blood brain barrier (BBB) permeability, oedema and neutrophil recruitment. Therefore the hypothesis of this thesis was that mast cells are active in the acute phase of experimental focal cerebral ischaemia, and interact with the brain to potentiate ischaemic pathology by release of a plethora of pro-inflammatory, vasoactive and proteolytic mediators. These mediators could degrade the BBB leading to vasogenic oedema, and may also promote an inflammatory milieu within the brain. Using wild type C57BL6/J (WT) and, mast cell deficient, C57BL6/J Kit w-sh/w-sh (Kit) mice in the tMCAo model of focal cerebral ischaemia, we found a significant reduction of BBB permeability, oedema and neutrophil recruitment. Additionally, sodium cromoglycate (SCG) treatment prior to tMCAo had the added effect of reducing lesion volume in WT mice. Seventy two hours post-tMCAo, genetic mast cell deficiency did not result in reduction of any of the parameters analysed. Investigation of protein expression in brain homogenates, twenty minutes and forty-five minutes post-tMCAo, indicated that tumour necrosis factor-alpha (TNF-α) was not responsible for the pathology seen in the WT mice, as it was found at similar concentrations in both mouse strains. However, endothelin-1, endoglin and matrixmetaloproteinase-9 were highly expressed in the WT mice, but not in the Kit mice forty five minutes post tMCAo. Further studies are required to elucidate whether the absence of these mediators is responsible for the reduced pathology in the Kit mice. In conclusion, the present study has provided an insight into mast cell responses following tMCAo, and has highlighted potential mechanisms by which mast cells mediate their response.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral-pg

Grantor dc:publisher.institution

University of Strathclyde

Year dc:date.issued

2013

Author dc:creator

• McKittrick, Craig Martin

DOI

10.48730/b0tb-d963

Identifier

T13590

OAI identifier oai:identifier

oai:strathclyde:fb4948403