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RvD1binding with FPR2 attenuates inflammation via Rac1/NOX2 pathway after neonatal hypoxic-ischemic injury in rats.

ABSTRACT: Neuroinflammation plays a crucial role in the pathological development after neonatal hypoxia-ischemia (HI). Resolvin D1 (RvD1), an agonist of formyl peptide receptor 2 (FPR2), has been shown to exert anti-inflammatory effects in many diseases. The objective of this study was to explore the protective role of RvD1 through reducing inflammation after HI and to study the contribution of Ras-related C3 botulinum toxin substrate 1 (Rac1)/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) pathways in RvD1-mediated protection. Rat pups (10-day old) were subjected to HI or sham surgery. RvD1 was administrated by intraperitoneal injection 1?h after HI. FPR2 small interfering ribonucleic acid (siRNA) and Rac1 activation CRISPR were administered prior to RvD1 treatment to elucidate the possible mechanisms. Time course expression of FPR2 by Western blot and RvD1 by ELISA were conducted at 6?h, 12?h, 24?h, 48?h and 72?h post HI. Infarction area, short-term neurological deficits, immunofluorescent staining and Western blot were conducted at 24?h post HI. Long-term neurological behaviors were evaluated at 4?weeks post HI. Endogenous expression levels of RvD1 decreased in time dependent manner while the expression of FPR2 increased after HI, peaking at 24?h post HI. Activation of FPR2, with RvD1, reduced percent infarction area, and alleviated short- and long-term neurological deficits. Administration of RvD1 attenuated inflammation after HI, while, either inhibition of FPR2 with siRNA or activation of Rac1 with CRISPR reversed those effects. Our results showed that RvD1 attenuated neuroinflammation through FPR2, which then interacted with Rac1/NOX2 signaling pathway, thereby reducing infarction area and alleviating neurological deficits after HI in neonatal rat pups. RvD1 may be a potential therapeutic approach to reduce inflammation after HI.

SUBMITTER: Liu W

PROVIDER: S-EPMC6708447 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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RvD1binding with FPR2 attenuates inflammation via Rac1/NOX2 pathway after neonatal hypoxic-ischemic injury in rats.

Liu Wei W Huang Juan J Doycheva Desislava D Gamdzyk Marcin M Tang Jiping J Zhang John H JH

Experimental neurology 20190624

Neuroinflammation plays a crucial role in the pathological development after neonatal hypoxia-ischemia (HI). Resolvin D1 (RvD1), an agonist of formyl peptide receptor 2 (FPR2), has been shown to exert anti-inflammatory effects in many diseases. The objective of this study was to explore the protective role of RvD1 through reducing inflammation after HI and to study the contribution of Ras-related C3 botulinum toxin substrate 1 (Rac1)/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 ...[more]

PMID: 31247196

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Project description:Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of death in neonates with no effective treatments. Recent advancements in hydrogen (H2) gas offer a promising therapeutic approach for ischemia reperfusion injury; however, the impact of this approach for HIE remains a subject of debate. We assessed the therapeutic effects of H2 gas on HIE and the underlying molecular mechanisms in a rat model of neonatal hypoxic-ischemic brain injury (HIBI). H2 inhalation significantly attenuated neuronal injury and effectively improved early neurological outcomes in neonatal HIBI rats as well as learning and memory in adults. This protective effect was associated with initiation time and duration of sustained H2 inhalation. Furthermore, H2 inhalation reduced the expression of Bcl-2-associated X protein (BAX) and caspase-3 while promoting the expression of Bcl-2, nuclear factor erythroid-2-related factor 2, and heme oxygenase-1 (HO-1). H2 activated extracellular signal-regulated kinase and c-Jun N-terminal protein kinase and dephosphorylated p38 mitogen-activated protein kinase (MAPK) in oxygen-glucose deprivation/reperfusion (OGD/R) nerve growth factor-differentiated PC12 cells. Inhibitors of MAPKs blocked H2-induced HO-1 expression. HO-1 small interfering RNA decreased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1?) and sirtuin 1 (SIRT1) and reversed the protectivity of H2 against OGD/R-induced cell death. These findings suggest that H2 augments cellular antioxidant defense capacity through activation of MAPK signaling pathways, leading to HO-1 expression and subsequent upregulation of PGC-1? and SIRT-1 expression. Thus, upregulation protects NGF-differentiated PC12 cells from OGD/R-induced oxidative cytotoxicity. In conclusion, H2 inhalation exerted protective effects on neonatal rats with HIBI. Early initiation and prolonged H2 inhalation had better protective effects on HIBI. These effects of H2 may be related to antioxidant, antiapoptotic, and anti-inflammatory responses. HO-1 plays an important role in H2-mediated protection through the MAPK/HO-1/PGC-1? pathway. Our results support further assessment of H2 as a potential therapeutic for neurological conditions in which oxidative stress and apoptosis are implicated.

Project description:BackgroundMicroglia-mediated neuroinflammation plays a crucial role in the pathogenesis of hypoxic-ischemic (HI)-induced brain injury. Activation of melanocortin-1 receptor (MC1R) has been shown to exert anti-inflammatory and neuroprotective effects in several neurological diseases. In the present study, we have explored the role of MC1R activation on neuroinflammation and the potential underlying mechanisms after neonatal hypoxic-ischemic brain injury in rats.MethodsA total of 169 post-natal day 10 unsexed rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. BMS-470539, a specific selective MC1R agonist, was administered intranasally at 1 h after HI induction. To elucidate the potential underlying mechanism, MC1R CRISPR KO plasmid or Nurr1 CRISPR KO plasmid was administered via intracerebroventricular injection at 48 h before HI induction. Percent brain infarct area, short- and long-term neurobehavioral tests, Nissl staining, immunofluorescence staining, and Western blot were conducted.ResultsThe expression levels of MC1R and Nurr1 increased over time post-HI. MC1R and Nurr1 were expressed on microglia at 48 h post-HI. Activation of MC1R with BMS-470539 significantly reduced the percent infarct area, brain atrophy, and inflammation, and improved short- and long-term neurological deficits at 48 h and 28 days post-HI. MC1R activation increased the expression of CD206 (a microglial M2 marker) and reduced the expression of MPO. Moreover, activation of MC1R with BMS-470539 significantly increased the expression levels of MC1R, cAMP, p-PKA, and Nurr1, while downregulating the expression of pro-inflammatory cytokines (TNFα, IL-6, and IL-1β) at 48 h post-HI. However, knockout of MC1R or Nurr1 by specific CRISPR reversed the neuroprotective effects of MC1R activation post-HI.ConclusionsOur study demonstrated that activation of MC1R with BMS-470539 attenuated neuroinflammation, and improved neurological deficits after neonatal hypoxic-ischemic brain injury in rats. Such anti-inflammatory and neuroprotective effects were mediated, at least in part, via the cAMP/PKA/Nurr1 signaling pathway. Therefore, MC1R activation might be a promising therapeutic target for infants with hypoxic-ischemic encephalopathy (HIE).

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RvD1binding with FPR2 attenuates inflammation via Rac1/NOX2 pathway after neonatal hypoxic-ischemic injury in rats.

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RvD1binding with FPR2 attenuates inflammation via Rac1/NOX2 pathway after neonatal hypoxic-ischemic injury in rats.

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