Genetic Deletion of PGF2α-FP Receptor Exacerbates Brain Injury Following Experimental Intracerebral Hemorrhage

Abstract

<b>Background:</b> The release of inflammatory molecules such as prostaglandins (e.g., PGF_2α) is associated with brain damage following an intracerebral hemorrhagic (ICH) stroke; however, the role of PGF_2α and its cognate FP receptor in ICH remains unclear. This study focused on investigating the role of the FP receptor as a target for novel neuroprotective drugs in a preclinical model of ICH, aiming to investigate the contribution of the PGF_2α-FP axis in modulating functional recovery and anatomical outcomes following ICH. <b>Results:</b> Neurological deficit scores in FP^-/- mice were significantly higher compared to WT mice 72 h after ICH (6.1 ± 0.7 vs. 3.1 ± 0.8; <i>P</i> < 0.05). Assessing motor skills, the total time mice stayed on the rotating rod was significantly less in FP^-/-mice compared to WT mice 24 h after ICH (27.0 ± 7.5 vs. 52.4 ± 11.2 s; <i>P</i> < 0.05). Using grip strength to quantify forepaw strength, results showed that the FP^-/- mice had significantly less strength compared to WT mice 72 h after ICH (96.4 ± 17.0 vs. 129.6 ± 5.9 g; <i>P</i> < 0.01). In addition to the behavioral outcomes, histopathological measurements were made. In Cresyl violet stained brain sections, the FP^-/- mice showed a significantly larger lesion volume compared to the WT (15.0 ± 2.2 vs. 3.2 ± 1.7 mm³; <i>P</i> < 0.05 mice.) To estimate the presence of ferric iron in the peri-hematoma area, Perls' staining was performed, which revealed that FP^-/- mice had significantly greater staining than the WT mice (186.3 ± 34.4% vs. 86.9 ± 13.0% total positive pixel counts, <i>P</i> < 0.05). Immunoreactivity experiments on brain sections from FP^-/- and WT mice post-ICH were performed to monitor changes in microgliosis and astrogliosis using antibodies against Iba1 and GFAP respectively. These experiments showed that FP^-/- mice had a trend toward greater astrogliosis than WT mice post-ICH. <b>Conclusion:</b> We showed that deletion of the PGF_2α FP receptor exacerbates behavioral impairments and increases lesion volumes following ICH compared to WT-matched controls.Detailed mechanisms responsible for these novel results are actively being pursued.