Prostaglandin FP receptor inhibitor reduces ischemic brain damage and neurotoxicity

Abstract

Bioactive lipids such as the prostaglandins have been reported to have various cytoprotective or toxic properties in acute and chronic neurological conditions. The roles of PGF2α and its receptor (FP) are not clear in the pathogenesis of ischemic brain injury. Considering that this G-protein coupled receptor has been linked to intracellular calcium regulation, we hypothesized that its blockade would be protective. We used FP antagonist (AL-8810) and FP receptor knockout (FP−/−) mice in in vivo and in vitro stroke models. Mice that were treated with AL-8810 had 35.7 ± 6.3% less neurologic dysfunction and 36.4 ± 6.0% smaller infarct volumes than did vehicle-treated mice after 48 hours of permanent middle cerebral artery occlusion (pMCAO); FP−/− mice also had improved outcomes after pMCAO. Blockade of the FP receptor also protected against oxygen-glucose deprivation (OGD)-induced cell death and reactive oxygen species formation in slice cultures. Finally, we found that an FP receptor agonist dose dependently increased intracellular Ca2+ levels in cultured neurons and established that FP-related Ca2+ signaling is related to ryanodine receptor signaling. These results indicate that the FP receptor is involved in cerebral ischemia-induced damage and could promote development of drugs for treatment of stroke and acute neurodegenerative disorders.

Prostaglandin F2α FP receptor antagonist improves outcomes after experimental traumatic brain injury

“…To evaluate the FP receptor as a novel target, selective FP receptor antagonist AL-8810 was administered intraperitoneally within ten minutes after CCI, as we previously did in ischemic stroke models [21,22]. …”

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

“…Nonetheless, these preclinical studies suggest that PGE 2 signaling pathways via EP1 and EP2 receptors are critically involved in neuroinflammation and neurodegeneration after seizures, and point to EP1 and/or EP2 antagonism as a possible adjunctive therapeutics – for the well-documented neuroprotection – to treat SE, along with the current first-line AED therapies [11]. Other prostaglandin receptors such as EP3, EP4 and FP also contribute to inflammation in both the periphery and the brain (Figure 2A) [64–66]. Whether the activation of these receptors is proconvulsant as well remains unknown.…”

Lipoxygenase: An Emerging Target for Stroke Therapy

“…Here, especially the Prostaglandin E2 receptors EP1 – EP4 are seen as promising targets, as well as the microsomal Prostaglandin E synthase[113]. Receptors of the D and F series have also been targeted[114, 115]. …”