Highly potent, brain-penetrant EP₂ receptor antagonists for the treatment of permanent focal cerebral ischaemia in male and female mice.

Authors

Zhen Jin, Chenyao Jiang, Eun Bee Cho, M Dennis Leo, Jiukuan Hao, Jiawang Liu, Ying Yu, Jianxiong Jiang

Published in

British journal of pharmacology. Oct 13, 2026. Epub Oct 13, 2026.

Abstract

Cerebral ischaemia is a leading cause of death in older adults and imposes a substantial global economic burden. Recent studies indicate that inhibiting the Gα_s-coupled EP₂ receptor reduces ischaemic brain injury by modulating neuroinflammation. However, these findings derive from the transient middle cerebral artery occlusion (tMCAO) model, which represents only a small subset of large-vessel occlusion (LVO) cases with successful recanalisation.
We characterised the pharmacokinetic parameters of selective EP₂ antagonists CJ-18, CJ-19 and CJ-21 that we recently developed. We evaluated their therapeutic efficacy in mice subjected to permanent MCAO (pMCAO), a model that more accurately reflects the majority of LVO cases, and assessed the impact of EP₂ inhibition on brain injury and inflammation. Finally, we examined the effects of EP₂ inhibition in neuron-glia mixed cultures exposed to oxygen-glucose deprivation (OGD) without reoxygenation.
After systemic administration in mice, new compounds exhibited favourable plasma half-lives and brain penetration. In the pMCAO model, treatment with EP₂ antagonists significantly reduced brain infarction in both male and female mice, in a dose-dependent manner, whilst improving sensorimotor performance without affecting muscle strength. These benefits were accompanied by reduced neuronal death, lowered pro-inflammatory cytokines and attenuated reactive gliosis within the ischaemic penumbra. In addition, EP₂ inhibition by CJ-18 conferred marked neuroprotection in neuron-glia co-cultures exposed to prolonged OGD, preserving neurite integrity and postsynaptic density.
This proof-of-concept study supports our drug-like EP₂ receptor antagonists, particularly CJ-18, as potential treatments for permanent focal cerebral ischaemia.

PMID:
42865206
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.

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