Table 2.
Targeting Gs-coupled prostanoid receptors for experimental brain ischemia.
| Receptor | Animal model | Major therapeutic outcomes | Reference |
|---|---|---|---|
| DP1 | Transient MCAO (90 min) induced in adult male C57BL/6 mice | Genetic ablation of the DP1 receptor enhanced ischemic brain injury and neurological dysfunction after transient ischemia 4 days after MCAO without affecting the mean arterial blood pressure, cerebral blood flow, or core body temperature. | Saleem et al., 2007 |
| Hypoxic ischemia (30 min) induced in C57BL/6 neonatal mice (P7) | The ischemic lesion was increased in H-PGDS/L-PGDS double knock-out mice or DP1 knock-out mice, but not in L-PGDS knock-out mice 24 hr and 7 days after hypoxic ischemia; the infarct size was in inverse relation to the amount of PGD2 production in L-PGDS, H-PGDS, and H-PGDS/L-PGDS knock-out mice. | Taniguchi et al., 2007 | |
| EP2 | Transient MCAO (90 min) induced in adult male C57BL/6 mice | Global deletion of the EP2 receptor exacerbated the infarct volume and neurological deficit 24 hr after MCAO without affecting the cerebral arterial vasculature or cerebral blood flow. | McCullough et al., 2004 |
| Permanent MCAO induced in adult male C57BL/6 mice | Global EP2 deficiency increased the infarct volume 24 hr after MCAO without altering the cerebral blood flow. | Liu et al., 2005 | |
| Transient MCAO (90 min) induced in adult male C57BL/6 mice | Global ablation of the EP2 receptor or pre-treatment with agonist ONO-AE1-259-01 (1 or 2 nmol, i.c.v.) 45-50 min before MCAO exacerbated the infarct volume and neurological deficit 4 days after MCAO without affecting the gross vascular anatomy of the brain, cerebral blood flow, body temperature, or mean arterial blood pressure. | Ahmad et al., 2010 | |
| Permanent MCAO induced in adult male C57BL/6 mice | Global EP2 deficiency increased the infarct volume and neurological deficit 7 days after MCAO. | Ahmad et al., 2010 | |
| Transient MCAO (45 min) induced in adult male C57BL/6 mice | Tamoxifen-induced postnatal deletion of the EP2 receptor reduced the infarct volume, neurological deficit, and neuroinflammation 2 days after MCAO without altering the peripheral immune mobilization in the spleen; treatment with EP2 antagonist benzoxazepine 52 (10 mg/kg, p.o., 2 dose at 4.5 and 24 hr after MCAO onset) reduced the infarct volume, neurological deficit, and post-stroke weight loss 3 days after MCAO. | Liu et al., 2019 | |
| Transient MCAO (45 min) induced in adult male and female C57BL/6 mice | EP2 deletion in neurons but not in myeloid or endothelial cells reduced the infarct volume in male and female mice in a gene dose dependent manner 2 days after MCAO. | Liu et al., 2019 | |
| Transient MCAO (45 min) induced in adult male C57BL/6 mice | Treatment with EP2 antagonist TG6-10-1 (5 or 10 mg/kg, p.o., 3 doses at 4.5, 12 and 24 hr after MCAO onset) reduced the infarct volume, neurological deficit, and cytokine induction 3 days after MCAO. | Li et al., 2020 | |
| EP4 | Transient MCAO (60 min) induced in adult male C57BL/6 mice | Treatment with EP4 selective agonist ONO-AE1-329 (0.03 or 0.3 mg/kg, s.c., once at 3 hr after MCAO) reduced the infarct volume in a dose-dependent manner 24 hr after MCAO; treatment with ONO-AE1-329 (0.3 mg/kg, s.c., twice at 2 and 8 hr after MCAO) reduced the infarct volume and neurological deficit 24 hr after MCAO. | Liang et al., 2011 |
| Transient MCAO (60 min) induced in adult male F1 hybrid B6D2F1/J mice | Treatment with ONO-AE1-329 (0.03 mg/kg, s.c., once at 3 hr after MCAO) improved the rotarod performance at both 2 day and 7 days after MCAO. | Liang et al., 2011 | |
| Transient MCAO (45 or 60 min) induced in adult male and female C57BL/6 mice | Neuronal EP4 ablation increased the infarct volume 24 hr after MCAO, which was reversed by treatment with ONO-AE1-329 (0.3 mg/kg, s.c., once at 3 hr after MCAO). | Liang et al., 2011 | |
| Transient MCAO (30, 45, or 60 min) induced in adult male C57BL/6 mice | Tamoxifen-induced EP4 deletion in endothelial cells increased the infarct volume 24 hr after MCAO, which was reversed by treatment with ONO-AE1-329 (0.3 mg/kg, s.c., once at 3 hr after MCAO); endothelial EP4 deletion did not affect the cerebral blood flow or mean arterial pressure. | Liang et al., 2011 | |
| Transient MCAO (60 min) induced in adult male and female C57BL/6 mice | Treatment with EP4 selective agonist L-902688 (0.75 μg/kg, i.p., 2 doses at 1 and 24 hr after MCAO) decreased the infarct volume and neurological deficit 2 days after MCAO without affecting the post-stroke weight loss, survival, or the cerebral blood flow | Akram et al., 2013 | |
| Transient MCAO (90 min) induced in adult male Sprague-Dawley rats | Treatment with L-902688 (0.3 or 1.0 mg/kg, i.v., once at 1.5 hr after MCAO) reduced the infarct volume, blood-brain barrier breakdown, the induction of IL-1β, IL-6, MMP-3/9, and preserved the tight junction proteins 24 hr after MCAO; treatment with L-902688 (1.0 mg/kg, i.v., once at 1.5 hr after MCAO) reduced the long-term neurological deficit for up to 3 weeks after MCAO. | DeMars et al., 2018 | |
| IP | Transient MCAO (60 min) induced in adult male Long-Evans rats | Overexpression of PGIS by adenovirus-mediated gene delivery into the lateral ventricle 3 days before but not after ischemia reduced infarct volume 24 hr after MCAO. | Fang et al., 2006 |
| Transient MCAO (90 min) and permanent MCAO induced in adult male C57BL/6 mice | Genetic deletion of IP receptor exacerbated the infarct volume and neurological deficit 4 days after transient MCAO and 7 days after permanent MCAO without altering cerebral blood flow, body temperature, or arterial blood pressure; pre- or post-treatment with IP selective agonist beraprost (50 or 100 μg/ml, p.o.) decreased infarct volume and neurological deficit in wild-type mice but not in IP knock-out mice 4 days after transient ischemia; treatment with beraprost (100 μg/ml, p.o.) 4.5 hr after MCAO onset decreased the neurological deficit and infarct volume in wild-type mice 7 days after permanent MCAO began. | Saleem et al., 2010 | |
| Transient global brain ischemia (12 min) induced in adult young and old male C57BL/6 mice | Genetic ablation of IP receptor increased the cognitive deficit, hippocampal CA1 pyramidal neuronal death, microglial activation, and myeloperoxidase activity, and decreased the phosphorylation of CREB in both young and old adult mice. | Shakil and Saleem, 2013 | |
| Transient global brain ischemia (12 min) induced in adult young and old male C57BL/6 mice | Post-treatment with IP agonist beraprost (25, 50, or 100 μg/ml, p.o.) attenuated neuronal death, astrogliosis, microbial invasion, and myeloperoxidase activity, and increased the phosphorylation of CREB in both young and old adult mice in a dose-dependent manner. | Shakil and Saleem, 2014 |