Neuroprotection mediated by the EP₄ receptor avoids the detrimental side effects of COX-2 inhibitors following ischaemic injury

Although COX-2 inhibition in animal models of ischaemia has shown neuroprotection, clinical trials revealed long term side effects with COX-2 inhibitors. A more focussed approach is necessary to retain the therapeutic effects of prostaglandins. This study investigated the role of the PGE ₂ EP₄ receptor using both in vitro and in vivo models of ischaemia. To demonstrate whether targeting the EP₄ receptor is as neuroprotective as COX-2 inhibition, simultaneous experiments were carried out using a selective COX-2 inhibitor. Organotypic hippocampal sliced cultures, exposed to 2 h of oxygen glucose deprivation, were treated with; DMSO only, COX-2 inhibitor (NS-398), EP₄ agonist (L-902688) or EP₄ antagonist (GW627368X) and cell death was assessed. The EP₄ agonist and the COX-2 inhibitor significantly reduced cell death following in vitro ischaemia, whereas treatment with the EP₄ antagonist significantly increased cell death in hippocampal cultures. Following a 1 h occlusion of middle cerebral artery, mice were treated with the COX-2 inhibitor (10 mg kg, I.P), EP₄ agonist (0.75 μg/kg, I.P) or vehicle (I.P), at the onset of reperfusion and again at 24 h post stroke. The COX-2 inhibitor and EP ₄ agonist treated animals showed a significant reduction in infarct volume (P < .05) at 48 h post stroke compared to the vehicle treated group. These results show that selective activation of the EP₄ receptor following acute ischaemic damage is neuroprotective, and support the concept of targeting protective prostaglandin receptor signalling as a potential therapeutic target for cerebral stroke.