Edaravone attenuates hippocampal damage in an infant mouse model of pneumococcal meningitis by reducing HMGB1 and iNOS expression via the Nrf2/HO-1 pathway.

AIM: Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger that has shown potent antioxidant, anti-inflammatory and neuroprotective effects in variety of disease models. In this study, we investigated whether edaravone produced neuroprotective actions in an infant mouse model of pneumococcal meningitis. METHODS: C57BL/6 mice were infected on postnatal d 11 by intracisternal injection of a certain inoculum of Streptococcus pneumoniae. The mice received intracisternal injection of 10 µL of saline containing edaravone (3 mg/kg) once a day for 7 d. The severity of pneumococcal meningitis was assessed with a clinical score. In mice with severe meningitis, the survival rate from the time of infection to d 8 after infection was analyzed using Kaplan-Meier curves. In mice with mild meningitis, the CSF inflammation and cytokine levels in the hippocampus were analyzed d 7 after infection, and the clinical neurological deficit score was evaluated using a neurological scoring system d 14 after infection. The nuclear factor (erythroid-derived 2)-like 2 knockout (Nrf2 KO) mice and heme oxygenase-1 knockout (HO-1 KO) mice were used to confirm the involvement of Nrf2/HO-1 pathway in the neuroprotective actions of edaravone. RESULTS: In mice with severe meningitis, edaravone treatment significantly increased the survival rate (76.4%) compared with the meningitis model group (32.2%). In mice with mild meningitis, edaravone treatment significantly decreased the number of leukocytes and TNF- levels in CSF, as well as the neuronal apoptosis and protein levels of HMGB1 and iNOS in the hippocampus, but did not affect the high levels of IL-10 and IL-6 in the hippocampus. Moreover, edaravone treatment significantly improved the neurological function of mice with mild meningitis. In Nrf2 KO or HO-1 KO mice with the meningitis, edaravone treatment was no longer effective in improving the survival rate of the mice with severe meningitis (20.2% and 53.6%, respectively), nor it affected the protein levels of HMGB1 and iNOS in the hippocampus of the mice with mild meningitis. CONCLUSION: Edaravone produces neuroprotective actions in a mouse model of pneumococcal meningitis by reducing neuronal apoptosis and HMGB1 and iNOS expression in the hippocampus via the Nrf2/HO-1 pathway. Thus, edaravone may be a promising agent for the treatment of bacterial meningitis.

Lipopolysaccharides shapes the human Wharton's jelly-derived mesenchymal stem cells in vitro.

BACKGROUND: Although the expression of toll-like receptors (TLRs) on different types of human mesenchymal stem cells (hMSCs) has recently been reported, controversy remains regarding the presence of TLR4 as well as its engagement and impact on human Wharton's jelly-derived MSCs (hWJ-MSCs). METHODS: In the present study, the expression and role of TLR4 in hWJ-MSCs was investigated using a model of lipopolysaccharide (LPS). Proliferation, apoptosis, and the expression of paracrine factors in hWJ-MSCs primed with LPS were analysed. RESULTS: The expression of TLR4 was high at the RNA level but very low at the protein level. hWJ-MSCs responded to LPS stimulation and initiated a marked up-regulation of inflammatory cytokine (IL-1α, IL-1ß, IL-6, and IL-8) production. Moreover, hWJ-MSCs LPS stimulation resulted in the up-regulation of indoleamine 2,3-dioxygenase [IDO]-1, Cox2, interferon [IFN]-ß, and matrix metalloproteinase (MMP)-2 but a down-regulation of MMP-9, which affect the immunosuppressive potential of hWJ-MSCs. CONCLUSIONS: These data suggest that LPS engagement shapes hWJ-MSCs and results in the production of pro-inflammatory cytokines and inhibitory immune mediators, showing TLR4 agonist induces the hWJ-MSCs polarization to a pro-inflammatory and immunosuppressive state, which may be beneficial for the exploration of the clinical potential of hWJ-MSCs.

Neonatal outcomes of very preterm infants from a neonatal intensive care center.

BACKGROUND: Information about clinical outcomes of very preterm (VPT) infants in tertiary neonatal intensive care unit (NICU) setting is scant in China. This study aimed to investigate the mortality and morbidity of VPT infants admitted to BaYi Children's Hospital, which serves as a NICU referral center for the city of Beijing, China. METHODS: Retrospectively collected perinatal/neonatal data on all admissions of infants born at <32 weeks of gestational age and subsequently admitted to the VPTNICU from clinical records between October 2010 and September 2011. RESULTS: Totally 729 infants were identified. 90% of VPT infants were outborn. The overall survival of the infants to discharge was 92%, which increased with increasing gestational age (range from 69% at <28 weeks to 99% at 31 weeks). The incidence of bronchopulmonary dysplasia was 4%, retinopathy of prematurity requiring treatment 2%, intraventricular hemorrhage III-IV 6%, and periventricular leukomalacia 2%. 10% of the VPT infants had a major morbidity at discharge. CONCLUSIONS: The outcomes of the VTP infants at this referral NICU were comparable to those in tertiary centers in developed countries. The most common complications were lower than those in other cohorts. Accordingly, high-volume NICU may minimize the adverse effects of VPT infants' transport.

Neuroprotective effects of icariin on memory impairment and neurochemical deficits in senescence-accelerated mouse prone 8 (SAMP8) mice.

The senescence-accelerated mouse prone 8 (SAMP8) is a novel aging model characterized by early onset and rapid advancement of senescence. In the present study, 6-month-old male SAMP8 mice were orally administered icariin (75, 150mg/kg) for 15weeks. Mice were submitted to passageway water maze test and step-down passive avoidance test for evaluating cognitive impairments. The HPLC-EC technique was used to determine the monoamine contents in the brain. The effects of icariin on oxidative stress and the acetylcholinesterase (AChE) activity of SAMP8 mice were also investigated. We found that icariin treatment significantly prevented learning and memory impairments of SAMP8 mice in passageway water maze test and step-down test. Icariin could partly reverse alterations of monoamines and metabolites levels in the cortex and hippocampus of SAMP8 mice. Furthermore, icariin-treated SAMP8 mice had significantly decreased malondialdehyde (MDA), nitric oxide (NO) contents, lowered nitric oxide synthase (NOS) activity and higher glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities in the brain homogenates and serum. Meanwhile, the acetylcholinesterase activity was markedly inhibited after icariin administration. However, the positive control piracetam did not show significant beneficial effects. In conclusion, the present findings demonstrated that the improvement of icariin on cognitive impairments in SAMP8 mice may be due to increasing monoamines levels, inhibiting oxidative damage and decreasing acetylcholinesterase activity.