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    • In the present study we investigated the role of

    2021-02-01

    In the present study, we investigated the role of EP1R after ICH and its mechanism of action. We hypothesized that EP1R activation aggravates ICH injury but that its blockade reduces injury through the Src kinases and the MMP-9 signaling pathway. To test this hypothesis, we examined the effects of selective EP1R agonist ONO-DI-004 (DI-004) and antagonist SC51089 (Abe et al., 2009, Jones et al., 2009, Kawano et al., 2006) on ICH outcomes in mice. We also measured inflammatory cells, reactive oxygen species (ROS) production, and Src kinase and MMP activity in the hemorrhagic brain. The role of Src kinases in EP1R-mediated ICH injury was confirmed by using the nonspecific Src family kinase inhibitor PP2. We conclude that EP1R activation elicits toxicity through the Src kinase and MMP-9 signaling pathways after ICH, and that inhibition of EP1R could be used therapeutically to protect against secondary neuraminidase inhibitors injury after ICH.
    Materials and methods
    Results
    Discussion This work presents several novel findings: (1) In the striatum of the ICH brain, EP1R is expressed primarily in neurons and axons, not in astrocytes or Cx3cr1+ microglia; (2) in middle-aged male mice subjected to the collagenase ICH model, EP1R activation exacerbates ICH-induced brain injury, cell death, neuronal degeneration, neuroinflammation, and neurobehavioral deficits. EP1R inhibition mitigates these negative effects and has a therapeutic window of 12h; (3) EP1R inhibition is also protective in middle-aged female mice and aged male mice and in the ICH models induced by blood or thrombin; (4) EP1R inhibition reduces oxidative stress, white matter injury, and brain atrophy and improves long-term functional outcomes; (5) EP1R activation increases, whereas its inhibition decreases, Src kinase phosphorylation and MMP-9 activity—EP1R regulates MMP-9 activity through Src kinase signaling; (6) Src kinase signaling mediates EP1R toxicity. Together, these findings suggest that EP1R activation promotes toxicity after ICH through mechanisms that involve the Src kinases and MMP-9 signaling pathway. PGE2 EP receptors mediate excitotoxicity and ischemic brain injury (Andreasson, 2010a, Andreasson, 2010b, Jones et al., 2009), but their role in ICH is unknown. Using middle-aged and aged mice subjected to three ICH-related models (collagenase, blood, and thrombin) to avoid translational pitfalls (Kirkman et al., 2011, Wang, 2010), we confirmed the toxic role of EP1R activation after ICH. Although sex differences and aging influence stroke outcomes and response to drug treatment (Fisher et al., 2009, Hurn et al., 2005), only a few ICH studies have been conducted in female and aged animals. We demonstrated here that the neuroprotective effect of EP1R inhibition after ICH is also present in middle-aged females and aged males. One limitation of ICH research is that most preclinical studies have focused only on mechanisms of gray matter injury. In contrast, our knowledge of white matter injury remains limited. White matter injury is often associated with a higher risk of death and poor functional outcome in stroke patients (Leys et al., 1999). Indeed, white matter injury was identified as a priority for both basic and clinical ICH research at the 2003 National Institute of Neurological Disorders and Stroke Intracerebral Hemorrhage workshop (2005). Since that time, only a few studies (Moxon-Emre and Schlichter, 2011, Wasserman and Schlichter, 2008), including our own (Wu et al., 2012), have investigated white matter injury in rodent ICH models, and only at early time points. No study has focused on white matter tracts during recovery after ICH. Although MRI has been used for ICH research in rats for years (Belayev et al., 2007, Brown et al., 1995, Del Bigio et al., 1996, MacLellan et al., 2008, Okauchi et al., 2010, Strbian et al., 2007), it is used mainly to determine the hematoma volume. MRI, especially DTI, can be used to monitor white matter damage (Mori and Zhang, 2006). DTI has been used to identify white matter injury and recovery after stroke, traumatic brain injury, and several other diseases in rodents (Jiang et al., 2011, Jiang et al., 2010, Zhang et al., 2012), but it has not been applied to ICH research in rodents. To our knowledge, this study is the first to investigate gray and white matter damage and recovery in mouse ICH models by three approaches: histology, immunohistochemistry, and MRI/DTI. Immunohistochemistry and histology showed that EP1R was expressed in the fiber tracts of the corpus callosum and that EP1R inhibition reduced demyelination and axonal loss. MRI/DTI confirmed histologic results and showed that EP1R inhibition reduced injury volume, white matter injury, and brain atrophy. The results also suggest that MRI/DTI can be used to evaluate gray and white matter damage and recovery in mouse ICH models.