Brain-penetrant EP2 antagonists shrink infarcts in a permanent stroke model in male and female mice
- Three new selective antagonists (CJ-18, CJ-19, CJ-21) inhibit the Gαs-coupled EP2 receptor, a modulator of neuroinflammation in ischaemic brain injury.
- Systemic dosing in mice gave favourable plasma half-lives and brain penetration.
- In permanent MCAO, closer to most large-vessel occlusions, infarcts shrank dose-dependently in both sexes and sensorimotor performance improved, with muscle strength unchanged.
- Neuronal death, pro-inflammatory cytokines and reactive gliosis fell.
💡 Points
Permanent MCAO is a sensible model choice, but the verdict hinges on dosing window: if drug went in at or soon after occlusion in young, healthy mice, the infarct benefit says little about patients arriving hours later, aged and comorbid. Brain penetration is encouraging, but I'd want unbound brain exposure versus EP2 potency, and a safety margin for prostanoid-signalling side effects, before picking a lead.