Examining the potential of PGE[subscript 2] receptor EP[subscript 4] as a neuroprotective target following ischaemic injury
thesisposted on 04.10.2013, 10:41 by Asha Akram
Ischaemic stroke instigates a series of pathological mechanisms which contribute to injury. Despite significant research in this field successful clinical treatment is limited. This highlights the need to identify novel therapeutic targets in order to assess whether clinical investigation is warranted. The enzyme cyclooxygenase-2 (COX-2) is a key contributor to inflammatory injury following stroke. Upregulation of this enzyme results in increased prostanoid synthesis, which mediate many physiological and pathological functions. Prostaglandin E[subscript 2] (PGE[subscript 2) is a key mediator in inflammation and activation of its receptor subtypes is both neuroprotective and neurotoxic. COX-2 inhibition in animal models of stroke has demonstrated neuroprotection. However, long term arthritis trials have revealed detrimental effects of COX-2 inhibitors. This highlights the need to identify mediators of the detrimental effects of COX-2 and capitalise those that mediate the beneficial effects. The aim of this study was to investigate the role of the PGE[subscript 2] receptor EP[subscript 4] following in vitro and in vivo ischaemia. Organotypic hippocampal sliced cultures (OHSCs) were exposed to oxygen and glucose deprivation (OGD). Treatment with a selective EP[subscript 4] agonist following OGD significantly reduced cell death, whereas application of the EP[subscript 4] receptor antagonist exacerbated injury. C57/BL6 mice were subjected to focal cerebral ischaemia via middle cerebral artery occlusion (MCAO). Administration of the selective EP[subscript 4] agonist significantly reduced infarct volume and prevented the decline in neurological function. COX-2 inhibition and EP[subscript 4] receptor stimulation resulted in similar levels of protection both in vitro and in vivo ischaemia. EP[subscript 4] receptor expression was assessed using immunohistochemistry and real time-PCR. This study provides evidence that selective activation of the EP[subscript 4] receptor following ischaemic injury is as neuroprotective as COX-2 inhibition but possibly without the deleterious side effects of COX-2 inhibitors. This supports the concept of targeting protective prostaglandin receptor signalling as a potential therapeutic target for stroke.