Abstract
Germinal matrix hemorrhage (GMH) is a detrimental form of neonatal CNS injury. Following GMH-mediated eNOS inhibition, inflammation arises, contributing to GMH-induced brain injury. We investigated the beneficial effects of Serelaxin, a clinical tested recombinant Relaxin-2 protein, on brain injury after GMH in rats. We investigated whether effects of Serelaxin are mediated by its ability to activate the GMH-suppressed eNOS pathway resulting in attenuation of inflammatory marker overproduction. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U). Seven day old Sprague–Dawley rat pups (P7) were used (n = 63). GMH animals were divided in vehicle or serelaxin treated (3 µg once, 30 µg once, 30 µg multiple, i.p., starting 30 after GMH and then daily). Sham operated animals were used. We monitored the developmental profile working memory and spatial function (T-maze and open field test respectively). At day 28, all rats underwent MRI-scans for assessment of changes in cortical thickness and white matter loss. Effects of Serelaxin on eNOS pathway activation and post-GMH inflammation were evaluated. We demonstrated that Serelaxin dose-dependently attenuated GMH-induced developmental delay, protected brain and improved cognitive functions of rats after GMH. That was associated with the decreased post-GMH inflammation, mediated at least partly by amelioration of GMH-induced eNOS inhibition.
Highlights
Germinal matrix hemorrhage (GMH) is a detrimental form of neonatal CNS injury
It has been demonstrated before that compared to relaxin 1 and relaxin 3, relaxin 2 (Serelaxin is an analog of relaxin 2) most effectively produces endothelium relaxation and that this effect is mediated via eNOS pathway[11]
In this project we evaluate whether a therapy with the clinically tested medication Serelaxin can attenuate post-GMH inflammation, protecting the brain, attenuating developmental delay and improving cognitive function of rats after GMH
Summary
Germinal matrix hemorrhage (GMH) is a detrimental form of neonatal CNS injury. Following GMHmediated eNOS inhibition, inflammation arises, contributing to GMH-induced brain injury. We investigated the beneficial effects of Serelaxin, a clinical tested recombinant Relaxin-2 protein, on brain injury after GMH in rats. We investigated whether effects of Serelaxin are mediated by its ability to activate the GMH-suppressed eNOS pathway resulting in attenuation of inflammatory marker overproduction. Authors demonstrated that bleeding induced in the germinal matrix of 7 day old rat pups results in sequelae similar to those observed in human infants post GMH. There are the indications that serelaxin can attenuate cigarette smoke induced apoptosis and cell death and that this effects are mediated by ability of serelaxin to stimulate the eNOS pathway It has been demonstrated on the other side, that GMH results in significant inhibition of eNOS pathway, resulting decrease of eNOS phosphorylation[13]. It has not decrease the importance of their interested study, has decrease the clinical relevance of it
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