Previously we have reported that magnitude
Previously, we have reported that magnitude of the disruption of the blood–aqueous barrier after paracentesis was reduced by 82% in EP4 receptor knockout mice (Biswas et al., 2006). In the present study, we observed that pretreatment of EP1 receptor knockout mice with EP4 receptor antagonist, reduced the response to paracentesis by 83%. Furthermore, the response of the blood–aqueous barrier to paracentesis in wild type mice pretreated with EP1 receptor agonist was inhibited by 58% indicating that EP1 receptors has an inhibitory action on the disruption of the blood–aqueous barrier. These results strongly suggest that there is a cross-talk between EP1 and EP4 receptors but not between EP1 and EP2 receptors.
In our earlier study (Biswas et al., 2006); we demonstrated that leukocyte migration in response to LPS was enhanced in the EP4 knockout mice indicating that EP4 receptor are linked to extravascular migration. In the present study, LPS induced leukocyte infiltration and aqueous humor protein level was significantly increased in EP1 receptors knockout mice. To test whether these increases were due to EP4 receptors, eyes of EP1 receptor knock out mice were treated with EP4 antagonist, before and after LPS injection. The results showed that the EP4 receptor antagonist inhibited the increase in the leukocyte infiltration and protein level observed in the EP1 receptor knockout mice receiving LPS alone. These observations provide further support to our suggestion that there is a cross-talk between EP1 and EP4 receptors in an ocular inflammatory episode.
Introduction Spontaneous intracerebral hemorrhage (ICH) is a devastating type of stroke. It causes retinoic acid receptor damage through many mechanisms. Hematoma formation and expansion within the brain cause the primary, mechanical damage. Inflammatory cascades, including those mediated by certain prostaglandins, contribute to the progression of secondary injury (Keep et al., 2012, Wang, 2010, Wu et al., 2010), which causes severe neurologic deficits in patients. Interventions are needed that can limit detrimental effects of neuroinflammation on brain function and improve outcomes after ICH. Prostaglandin E2 (PGE2) is predominant in the brain. This bioactive lipid is synthesized from cyclooxygenases and PGE2 synthases. We and others have reported that the expression of cyclooxygenase-2 and microsomal PGE2 synthase-1 is increased after ICH (Gong et al., 2001, Wu et al., 2011). Consequently, PGE2 accumulates in the perihematomal region after ICH (Chu et al., 2004). Importantly, selective inhibition of cyclooxygenase-2 reduces ICH injury and improves outcomes (Chu et al., 2004). PGE2 acts through four G-protein-coupled receptor subtypes known as EP1–EP4. These receptors have divergent downstream signaling cascades and functional effects depending on the physiologic or pathologic context (Andreasson, 2010a, Andreasson, 2010b). Deletion or inhibition of the EP1 receptor (EP1R) was shown to reduce ischemic brain injury (Abe et al., 2009, Kawano et al., 2006). Based on these results, PGE2 signaling might also contribute to inflammation-mediated secondary ICH injury (Wang and Dore, 2007b). However, the role of EP1R in ICH remains to be determined because the pathogenesis of ICH is different from that of ischemic stroke. Mechanisms that underlie EP1R-mediated neurotoxicity are unknown, but one possibility is the Src pathway (Fukumoto et al., 2010). Two studies have shown that Src kinase activation mediates thrombin-induced blood–brain barrier disruption (Liu et al., 2010) and that inhibition of Src kinase activity reduces blood toxicity (Ardizzone et al., 2007). Matrix metalloproteinase (MMP)-9 mediates neuroinflammation and has been implicated in ICH pathology (Wang and Tsirka, 2005a, Xue et al., 2009b). Although Src kinases could phosphorylate and regulate MMP-9 (Liu and Sharp, 2011), a direct link between the two has not been established.