PGE2 receptor agonist misoprostol protects brain against intracerebral hemorrhage in mice

Abstract

Intracerebral hemorrhage (ICH) is a devastating form of stroke. Misoprostol, a synthetic PGE1 analog and PGE2 receptor agonist, has shown protection against cerebral ischemia. In this study, we tested the efficacy of misoprostol in 12-month-old mice subjected to one of two complementary ICH models, the collagenase model (primary study) and blood model (secondary study, performed in an independent laboratory). We also investigated its potential mechanism of action. Misoprostol post-treatment decreased brain lesion volume, edema, and brain atrophy and improved long-term functional outcomes. In the collagenase-induced ICH model, misoprostol decreased cellular inflammatory response; attenuated oxidative brain damage and gelatinolytic activity; and decreased HMGB1 expression, Src kinase activity, and interleukin-1β expression without affecting cyclooxygenase-2 expression. Further, HMGB1 inhibition with glycyrrhizin decreased Src kinase activity, gelatinolytic activity, neuronal death, and brain lesion volume. Src kinase inhibition with PP2 decreased gelatinolytic activity and brain edema and improved neurologic function, but did not decrease HMGB1 protein level. These results indicate that misoprostol protects brain against ICH injury through mechanisms that may involve the HMGB1, Src kinase, and MMP-2/9 pathway.

Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice

“…7,23,25,26 Mice positioned on a stereotaxic frame (Stoelting Co., Wood Dale, IL, USA) were anesthetized by isoflurane (3.0% for induction and 1.0% for maintenance) and ventilated with oxygen-enriched air (20%:80%) via a nose cone. We injected collagenase into the left striatum of mice at the following stereotactic coordinates: 0.8 mm anterior and 2.0 mm lateral of the bregma, and 2.9 mm in depth.…”

“…7,23 Relative values of protein carbonylation were obtained by a Luminescent Image Analyzer LAS-4000 system as for Western blotting.…”

“…23 The toxic role of HMGB1 in the acute stage of ICH was further confirmed by using the nonspecific HMGB1 inhibitor glycyrrhizin. 23 In this study, the marked increase or decrease in IL-1b and HMGB1 conferred by EP2 deletion and activation, respectively, suggest that neuronal EP2 signaling can also modulate molecular inflammatory responses. Microglia/macrophages and leukocytes are major sources of ROS, which can activate MMP-2/9 and damage the blood-brain barrier and neurovascular unit.…”

“…23 In the present study, we used genetic and pharmacologic approaches to selectively target the EP2 receptor in order to determine its contribution to ICH pathology in these same two mouse models. We used middle-aged mice to enhance the clinical relevance of the study, as ICH occurs more frequently in the middle-aged population than in younger individuals.…”

Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury

“…2,3 For many years, investigators have been researching ways to either reduce PGE 2 production or regulate the four receptors to minimize progressive brain damage. [4][5][6] PGE 2 receptor EP3 (EP3R) is expressed mainly by neurons and activated glial cells in brain 7,8 and is associated with neuronal death. 8,9 Of the four G-proteincoupled PGE 2 receptors, EP3R is unique in its ability to bind to multiple G-proteins based on different spliced carboxy-terminal tail isoforms.…”