Use this URL to cite or link to this record in EThOS:
Title: Investigating sex specific mechanisms of neuroprotection using mouse organotypic hippocampal slice cultures
Author: Altaee, Raeed A. K.
ISNI:       0000 0004 8498 2442
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2019
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Restricted access.
Access from Institution:
Ischaemic stroke initiates a pathological cascade resulting in brain injury and recombinant tissue plasminogen activator is the only available and approved drug, thus identification of novel therapeutic targets is essential. There is increasing evidence that men and women differ in incidence, mortality, and outcome following stroke yet the majority of preclinical stroke studies tend to focus on single sex, for in vivo studies, or mixed-sex if using in vitro approaches. The aim of this study was to establish a sex-specific in vitro model of ischaemia to then investigate if the effectiveness of neuroprotective steroids (i.e. oestrogens, progestin) were affected by biological sex. The aim was also to identify sex differences in the molecular processes activated under ischaemic conditions. Male and female-derived organotypic hippocampal sliced cultures (OHSCs) were exposed to oxygen and glucose deprivation (OGD) in order to model ischaemia. Treatment with sex steroid hormones (e.g. progesterone and oestrogens) did reduce the amount of cell death but some sex differences were observed. Administration of a caspase inhibitor, i.e. Q-VD-OPH, significantly reduced the amount of cell death only in female-derived OHSCs while poly (ADP) - ribose polymerase (PARP) inhibition, (via PJ-34 inhibition) significantly reduced the amount of cell death only in male-derived OHSCs. The ability of progesterone and oestrogens to induce neuroprotection were not affected, in both sexes, by the inhibition of caspase or PARP. Following the establishment of a sex-specific in vitro model of ischaemia we showed that caspase activation is a major contributor to cell death in female-derived cells only whereas, in contrast, PARP is a major contributor to cell death in males. This adds further evidence to sex differences in the specific elements of the cell death pathways activated following ischaemic stroke and highlights the need to consider sex effects when investigating novel therapeutic targets.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Thesis