Microglia-derived IL-1ß contributes to axon development disorders and synaptic deficit through p38-MAPK signal pathway in septic neonatal rats.

BACKGROUND: Axon development plays a pivotal role in the formation of synapse, nodes of Ranvier, and myelin sheath. Interleukin-1ß (IL-1ß) produced by microglia may cause myelination disturbances through suppression of oligodendrocyte progenitor cell maturation in the septic neonatal rats. Here, we explored if a microglia-derived IL-1ß would disturb axon development in the corpus callosum (CC) following lipopolysaccharide (LPS) administration, and if so, whether it is associated with disorder of synapse formation in the cerebral cortex and node of Ranvier. METHODS: Sprague-Dawley rats (1-day old) in the septic model group were intraperitoneally administrated with lipopolysaccharide (1 mg/kg) and then sacrificed for detection of IL-1ß, interleukin-1 receptor (IL-1R1), neurofilament-68, neurofilament-160, and neurofilament-200, proteolipid, synaptophysin, and postsynaptic density 95 (PSD95) expression by western blotting and immunofluorescence. Electron microscopy was conducted to observe alterations of axonal myelin sheath and synapses in the cortex, and proteolipid expression was assessed using in situ hybridization. The effect of IL-1ß on neurofilament and synaptophysin expression in primary neuron cultures was determined by western blotting and immunofluorescence. P38-MAPK signaling pathway was investigated to determine whether it was involved in the inhibition of IL-1ß on neurofilament and synaptophysin expression. RESULTS: In 1-day old septic rats, IL-1ß expression was increased in microglia coupled with upregulated expression of IL-1R1 on the axons. The expression of neurofilament-68, neurofilament-160, and neurofilament-200 (NFL, NFM, NFH) and proteolipid (PLP) was markedly reduced in the CC at 7, 14, and 28 days after LPS administration. Simultaneously, cortical synapses and mature oligodendrocytes were significantly reduced. By electron microscopy, some axons showed smaller diameter and thinner myelin sheath with damaged ultrastructure of node of Ranvier compared with the control rats. In the cerebral cortex of LPS-injected rats, some axo-dendritic synapses appeared abnormal looking as manifested by the presence of swollen and clumping of synaptic vesicles near the presynaptic membrane. In primary cultured neurons incubated with IL-1ß, expression of NFL, NFM, and synaptophysin was significantly downregulated. Furthermore, p38-MAPK signaling pathway was implicated in disorder of axon development and synaptic deficit caused by IL-1ß treatment. CONCLUSIONS: The present results suggest that microglia-derived IL-1ß might suppress axon development through activation of p38-MAPK signaling pathway that would contribute to formation disorder of cortical synapses and node of Ranvier following LPS exposure.

Melatonin Reduces Neuroinflammation and Improves Axonal Hypomyelination by Modulating M1/M2 Microglia Polarization via JAK2-STAT3-Telomerase Pathway in Postnatal Rats Exposed to Lipopolysaccharide.

Microglia activation and associated inflammation are implicated in the periventricular white matter damage (PWMD) in septic postnatal rats. This study investigated whether melatonin would mitigate inflammation and alleviate the axonal hypomyelination in the corpus callosum in septic postnatal rats. We further explored if this might be related to the modulation of microglial polarization from M1 phenotype to M2 through the JAK2/STAT3/telomerase pathway. We reported here that indeed melatonin not only can it reduce the neurobehavioral disturbances in LPS-injected rats, but it can also dampen microglia-mediated inflammation. Thus, in LPS + melatonin group, the expression of proinflammatory mediators in M1 phenotype microglia was downregulated. As opposed to this, M2 microglia were increased which was accompanied by upregulated expression of anti-inflammatory mediators along with telomerase reverse transcriptase or melatonin receptor 1(MT1). In parallel to this was decreased NG2 expression but increased expression of myelin and neurofilament proteins. Melatonin can improve hypomyelination which was confirmed by electron microscopy. In vitro in primary microglia stimulated by LPS, melatonin decreased the expression of proinflammatory mediators significantly; but it increased the expression of anti-inflammatory mediators. Additionally, the expression levels of p-JAK2 and p-STAT3 were significantly elevated in microglia after melatonin treatment. Remarkably, the effect of melatonin on LPS-treated microglia was blocked by melatonin receptor, JAK2, STAT3 and telomerase reverse transcriptase inhibitors, respectively. Taken together, it is concluded that melatonin can attenuate PWMD through shifting M1 microglia towards M2 via MT1/JAK2/STAT3/telomerase pathway. The results suggest a new therapeutic strategy whereby melatonin may be adopted to convert microglial polarization from M1 to M2 phenotype that would ultimately contribute to the attenuation of PWMD.

An NT-3-releasing bioscaffold supports the formation of TrkC-modified neural stem cell-derived neural network tissue with efficacy in repairing spinal cord injury.

The mechanism underlying neurogenesis during embryonic spinal cord development involves a specific ligand/receptor interaction, which may be help guide neuroengineering to boost stem cell-based neural regeneration for the structural and functional repair of spinal cord injury. Herein, we hypothesized that supplying spinal cord defects with an exogenous neural network in the NT-3/fibroin-coated gelatin sponge (NF-GS) scaffold might improve tissue repair efficacy. To test this, we engineered tropomyosin receptor kinase C (TrkC)-modified neural stem cell (NSC)-derived neural network tissue with robust viability within an NF-GS scaffold. When NSCs were genetically modified to overexpress TrkC, the NT-3 receptor, a functional neuronal population dominated the neural network tissue. The pro-regenerative niche allowed the long-term survival and phenotypic maintenance of the donor neural network tissue for up to 8 weeks in the injured spinal cord. Additionally, host nerve fibers regenerated into the graft, making synaptic connections with the donor neurons. Accordingly, motor function recovery was significantly improved in rats with spinal cord injury (SCI) that received TrkC-modified NSC-derived neural network tissue transplantation. Together, the results suggested that transplantation of the neural network tissue formed in the 3D bioactive scaffold may represent a valuable approach to study and develop therapies for SCI.

Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/ß-catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide.

Neuroinflammation is thought to play a pivotal role in the pathogenesis of periventricular white matter (PWM) damage (PWMD) induced by neonatal sepsis. Because the complement cascade is implicated in inflammatory response, this study was carried out to determine whether C3a is involved in PWMD, and, if so, whether it would induce axonal hypomyelination. Furthermore, we explored if C3a would act through its C3a receptor (C3aR) and thence inhibit maturation of oligodendrocyte precursor cells (OPCs) via the WNT/ß-catenin signal pathway. Sprague Dawley (SD) rats aged 1 day were intraperitoneally injected with lipopolysaccharide (LPS) (1 mg/kg). C3a was upregulated in activated microglia and astrocytes in the PWM up to 7 days after LPS injection. Concomitantly, enhanced C3aR expression was observed in NG2+ oligodendrocytes (OLs). Myelin proteins including CNPase, PLP, MBP and MAG were significantly reduced in the PWM of 28-day septic rats. The number of PLP+ and MBP+ cells was markedly decreased. By electron microscopy, myelin sheath thickness was thinner and the average g-ratios were higher. This was coupled with an increase in number of NG2+ cells and decreased number of CC1+ cells. Olig1, Olig2 and SOX10 protein expression was significantly reduced in the PWM after LPS injection. Very strikingly, C3aRa administration for the first 7 days could reverse the above-mentioned pathological alterations in the PWM of septic rats. When incubated with C3a, expression of MBP, CNPase, PLP, MAG, Olig1, Olig2, SOX10 and CC1 in primary cultured OPCs was significantly downregulated as opposed to increased NG2. Moreover, WNT/ß-catenin signaling pathway was found to be implicated in inhibition of OPCs maturation and differentiation induced by C3a in vitro. As a corollary, it is speculated that C3a in the PWM of septic rats is closely associated with the disorder of OPCs differentiation and maturation through WNT/ß-catenin signaling pathway, which would contribute ultimately to axonal hypomyelination.

Interleukin-1ß Disturbs the Proliferation and Differentiation of Neural Precursor Cells in the Hippocampus via Activation of Notch Signaling in Postnatal Rats Exposed to Lipopolysaccharide.

Infectious exposure during the perinatal period may predispose to permanent neurological disorders in later life. Here we investigated whether changes in interleukin-1ß (IL-1ß) are associated with cognitive dysfunction in later life of septic neonatal rats through suppression of neurogenesis in the hippocampus. Sprague-Dawley rats (1-day old) administered lipopolysaccharide (LPS) showed upregulated expression of IL-1ß and IL-1 receptors in the hippocampus. At 28 days of age, rats showed longer escape latencies and decreased numbers of crossings after LPS administration. This was coupled with increased numbers of glial fibrillary acidic protein positive (GFAP+) astrocytes and decreased numbers of neuronal nuclei positive (NeuN+) cells. The numbers of sex-determining region Y-box 2 positive (SOX2+) and doublecortin positive (DCX+) cells were decreased at 1 and 3 days but was increased at 7 and 14 days. The proliferation of SOX2+ cells was inhibited at 1 and 3 days but increased at 7 and 14 days. In vitro IL-1ß administration suppressed the proliferation of neural progenitor cells (NPCs) in neurospheres derived from the hippocampus. GFAP expression was upregulated in differentiated NPCs treated with IL-1ß for 4 days, but expression of DCX and microtubule associated protein-2 (MAP2) was decreased. Remarkably, the Notch signaling pathway involved in antineurogenic and progliogenic differentiation of NPCs was activated after IL-1ß administration. The results show that following LPS injection in neonatal rats, microglia were activated and generated excess amounts of IL-1ß in the hippocampus. It is suggested that this might have contributed to inhibiting neurogenesis but promoting gliogenesis of NPCs via activation of the Notch signaling pathway and maybe one of the causes for cognitive dysfunction in septic neonatal rats in later life.

Novel ß-lactam/ß-lactamase inhibitors versus alternative antibiotics for the treatment of complicated intra-abdominal infection and complicated urinary tract infection: a meta-analysis of randomized controlled trials.

INTRODUCTION: The aim of this study is to compare the efficacy and safety of novelBL/BLIs with alternative antibiotics for the treatment of cIAI and cUTI. Area covered: We performed a systematic review and meta-analysis of all randomized controlled trials comparing novel BL/BLIs with other antibiotics for the treatment of cIAI and cUTI. The primary outcome included clinical and microbiological treatment success. Expert commentary: We found that novel BL/BLIs obtained a similar clinical outcome with other antibiotics in CE population (OR = 1.07, 95%CI = (0.80, 1.44), P = 0.64). However, novel BL/BLIs had better clinical treatment success in the cUTI subgroup (OR = 2.14, 95%CI = (1.06, 4.31), P = 0.03). Furthermore, novel BL/BLIs achieved significant microbiological treatment success in patie nts with cUTI (OR = 1.70, 95%CI = (1.29, 2.25), P  =  0.0002) and had higher eradication rates for Gram-negative pathogens (OR = 1.82, 95%CI = (1.26, 2.64), P = 0.001) including E.coli and K.pneumoniae. No difference was observed concerning the incidence of mortality and adverse events between the two groups. Therefore, we concluded that novel BL/BLIs are not inferior to other available antibiotics for the treatment of cIAI, and they have advantages in patients with cUTI. Simultaneously, they are sensitive to Gram-negative pathogens, especially for E.coli and K.pneumoniae.