Protease-Activated Receptor 1 and 4 Signal Inhibition Reduces Preterm Neonatal Hemorrhagic Brain Injury

Abstract

Background and Purpose— This study examines the role of thrombin’s protease-activated receptor (PAR)-1, PAR-4 in mediating cyclooxygenase-2 and mammalian target of rapamycin after germinal matrix hemorrhage. Methods— Germinal matrix hemorrhage was induced by intraparenchymal infusion of bacterial collagenase into the right ganglionic eminence of P7 rat pups. Animals were treated with PAR-1, PAR-4, cyclooxygenase-2, or mammalian target of rapamycin inhibitors by 1 hour, and ≤5 days. Results— We found increased thrombin activity 6 to 24 hours after germinal matrix hemorrhage, and PAR-1, PAR-4, inhibition normalized cyclooxygenase-2, and mammalian target of rapamycin by 72 hours. Early treatment with NS398 or rapamycin substantially improved long-term outcomes in juvenile animals. Conclusions— Suppressing early PAR signal transduction, and postnatal NS398 or rapamycin treatment, may help reduce germinal matrix hemorrhage severity in susceptible preterm infants.

Dabigatran ameliorates post-haemorrhagic hydrocephalus development after germinal matrix haemorrhage in neonatal rat pups

“…Yet, neither mTOR inhibition, PAR-1,-4 inhibition, nor ECM protein proliferation have been evaluated for long-term outcomes after GMH. 13 Herein, p-mTOR expression was increased immediately following GMH and remained elevated for seven days, and a similar trend was observed for p-p70s6k (Figure 4(a) and (b)). Additionally, increased activated mTOR was observed in neurons, astrocytes, and fibroblasts of GMH brains compared to sham at three days post-ictus ( Figure 4(c)), indicating that GMH-induced mTOR activation is complex with a diverse range of potential effects.…”

“…Additionally, mTOR inhibition by rapamycin treatment improved long-term neurofunctional and brain morphological outcomes after GMH. 13 Thus, this pathway warrants further investigation. Dabigatran is a novel direct thrombin inhibitor clinically approved for treating deep vein thrombosis and preventing stroke from atrial fibrillation.…”

Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats

“…siRNA sestrin2 (300 pmol/1μl, mixed by three different rat-derived siRNA with siRNA ID: SASI_Rn02_00247651, SASI_Rn02_00247652, SASI_Rn02_00247645, Sigma-Aldrich, USA), and scramble RNA (300 pmol/1μl) were delivered by intracerebroventricular injection, 2μl drug per pup injected slowly in 5min (Chen et al, 2015), at 1.5 mm posterior, 1.5mm lateral to the bregma and 1.7mm deep on the ipsilateral hemisphere at 24h pre HI. DMOG (HIF1α activator) (40 mg/kg, Sigma-Aldrich, USA)(Nagel et al, 2011) and FM19G11 (HIF1α inhibitor) (10 mg/kg, Sigma-Aldrich, USA) (El Assar et al, 2015) were injected intraperitoneally at 60min, and 30min after HI respectively (Lekic et al, 2015). …”

Major remodeling of brain microvessels during neonatal period in the mouse: A proteomic and transcriptomic study

“…21,22 Gelatinases target collagens and BBB proteins, 23,24 while thrombin activates protease-activated receptors. 25 Complex interplay of serine proteases and MMPs also contributes to ECM degradation either by mutual cross-activation or through receptor-mediated inductions. [26][27][28] In neonate mice invalidated on t-PA inhibitor-1 gene, age-dependent SEH/IVH/IPH could be mimicked up to five days after birth (P5) concomitantly with gelatinase activation within microvessels.…”