Xiaofeng Ma

Objective: Neuroinflammation is a central part of cerebral ischemia/reperfusion injury. The novel immune suppressant, fingolimod, is a promising candidate to ameliorate stroke-induced damage. Fingolimod is efficacious in experimental ischemic models, but a rigorous meta-analysis is lacking that considers how different experiment variables affect outcomes. Methods: We conducted a systematic literature review of fingolimod in stroke models, with the aim of rigorously evaluating fingolimod’s effects on reducing infarct volume improving neurological outcomes. Seventeen variables were evaluated as covariates for the source of heterogeneity, and effect sizes were combined by using normalized mean difference meta-analysis to evaluate efficacy. Study quality was evaluated by the CAMARADES ten-item checklist, and publication bias was evaluated by funnel plots and Egger’s tests. Results: About 123 unduplicated articles were identified in the literature research. Of these papers, 118 articles were excluded after reading titles and abstracts. Another 17 articles were selected in this study. Study quality was moderate (median = 6; interquartile range = 4), and publication bias was statistically insignificant. fingolimod reduced infarct volume by 30.4% (95% CI 22.4%−38.3%; n = 24; I² = 90.0%; p < 0.0001) and consistently enhanced neurobehavioral outcome by 34.2% (95% CI 23.1%−45.2%; n = 14; I² = 76.5%; p < 0.0001). No single factors accounted for heterogeneity. Conclusions: Our rigorous statistical evaluation confirmed the neuroprotective properties of fingolimod. New data can be used in designing future clinical trials.

Summary: Aims: Although converging evidence from experimental and epidemiological studies indicates Alzheimer's disease (AD) and ischemic stroke (IS) are related, the genetic basis underlying their links is less well characterized. Traditional SNP‐based genome‐wide association studies (GWAS) have failed to uncover shared susceptibility variants of AD and IS. Therefore, this study was designed to investigate whether pleiotropic genes existed between AD and IS to account for their phenotypic association, although this was not reported in previous studies.Methods: Taking advantage of large‐scale GWAS summary statistics of AD (17,008 AD cases and 37,154 controls) and IS (10,307 IS cases and 19,326 controls), we performed gene‐based analysis implemented in VEGAS2 and Fisher's meta‐analysis of the set of overlapped genes of nominal significance in both diseases. Subsequently, gene expression analysis in AD‐ or IS‐associated expression datasets was conducted to explore the transcriptional alterations of pleiotropic genes identified.Results: 16 AD‐IS pleiotropic genes surpassed the cutoff for Bonferroni‐corrected significance. Notably, MS4A4A and TREM2, two established AD‐susceptibility genes showed remarkable alterations in the spleens and brains afflicted by IS, respectively. Among the prioritized genes identified by virtue of literature‐based knowledge, most are immune‐relevant genes (EPHA1, MS4A4A, UBE2L3 and TREM2), implicating crucial roles of the immune system in the pathogenesis of AD and IS.Conclusions: The observation that AD and IS had shared disease‐associated genes offered mechanistic insights into their common pathogenesis, predominantly involving the immune system. More importantly, our findings have important implications for future research directions, which are encouraged to verify the involvement of these candidates in AD and IS and interpret the exact molecular mechanisms of action.

Summary: Acute ischaemic stroke can induce secondary brain injury by activating an inflammatory response that contributes to clinical impairment. As a specific inhibitor of the immunoproteasome subunit low molecular weight polypeptide 7 (LMP7), PR-957 may participate in regulating pathophysiological and inflammatory responses in multiple diseases of the central nervous system (CNS). We investigated the neuroprotective properties of PR-957 in a mouse model of stroke, induced by middle cerebral artery occlusion (MCAO). After MCAO and injections of PR-957 or vehicle, we evaluated mice behaviourally using modified Neurological Severity Scores (mNSS) and sensorimotor tests, including the adhesive-removal test, a foot-fault test and an inclined plane test. Infarct volume was measured 24 and 72 h after MCAO. Infiltration by different lymphocyte subpopulations was evaluated by flow cytometry and immunofluorescent staining of brain tissue from the penumbral area. Quantitative real-time polymerase chain reaction analysis and enzyme-linked immunosorbent assay were used to measure the expression of proinflammatory cytokines: interkeukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17A, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, granulocyte colony-stimulating factor (GCSF) and granulocyte–macrophage colony-stimulating factor (GM-CSF). Expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT-3) protein levels in brain was measured by immunoblot. MCAO mice treated with PR-957 showed a significant decrease in infarct volume and had mild neurological deficits compared to vehicle-treated mice. PR-957 administration also significantly decreased IL-1β, IL-6, IL-12, IL-17A and TNF-α. PR-957 provides neuroprotection via inhibiting T lymphocyte infiltration and decreasing T helper type 17 (Th17) cell differentiation in MCAO mice, which may result from the reduced expression of pSTAT-3. The neuroprotective effect of PR-957 indicates its potential utility as anti-inflammatory therapy for ischaemic stroke.

Immunity and inflammation play critical roles in the pathogenesis of acute ischemic stroke. Therefore, immune intervention, as a new therapeutic strategy, is worthy of exploration. Here, we tested the inflammation modulator, vinpocetine, for its effect on the outcomes of stroke. For this multi-center study, we recruited 60 patients with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h but lasted less than 48 h. These patients, after random division into two groups, received either standard management alone (controls) or standard management plus vinpocetine (30 mg per day intravenously for 14 consecutive days, Gedeon Richter Plc., Hungary). Vinpocetine treatment did not change the lymphocyte count; however, nuclear factor kappa-light-chain-enhancer of activated B cell activation was inhibited as seen not only by the increased transcription of IκBα mRNA but also by the impeded phosphorylation and degradation of IκBα and subsequent induction of pro-inflammatory mediators. These effects led to significantly reduced secondary lesion enlargement and an attenuated inflammation reaction. Compared to controls, patients treated with vinpocetine had a better recovery of neurological function and improved clinical outcomes during the acute phase and at 3-month follow-up. These findings identify vinpocetine as an inflammation modulator that could improve clinical outcomes after acute ischemic stroke. This study also indicated the important role of immunity and inflammation in the pathogenesis of acute ischemic stroke and the significance of immunomodulatory treatment. Clinical Trial Registration Information: www.clinicaltrials.gov . Identifier: NCT02878772

O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is involved in the regulation of many cellular cascades and neurological diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke. In the brain, the expression of O-GlcNAcylation is notably heightened, as is that of O-linked N-acetylglucosaminyltransferase (OGT) and β-N-acetylglucosaminidase (OGA), the presence of which is prominent in many regions of neurological importance. Most importantly, O-GlcNAcylation is believed to contribute to the normal functioning of neurons; conversely, its dysregulation participates in the pathogenesis of neurological disorders. In neurodegenerative diseases, O-GlcNAcylation of the brain’s key proteins, such as tau and amyloid-β, interacts with their phosphorylation, thereby triggering the formation of neurofibrillary tangles and amyloid plaques. An increase of O-GlcNAcylation by pharmacological intervention prevents neuronal loss. Additionally, O-GlcNAcylation is stress sensitive, and its elevation is cytoprotective. Increased O-GlcNAcylation ameliorated brain damage in victims of both trauma-hemorrhage and stroke. In this review, we summarize the current understanding of O-GlcNAcylation’s physiological and pathological roles in the nervous system and provide a foundation for development of a therapeutic strategy for neurological disorders.

IL-17–producing Th17 cells have gradually become considered as key factors in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS). Although the involvement of certain microRNAs in the development of MS has been reported, their role in Th17-driven autoimmunity is still poorly understood. In this study, we identified microRNA (miR)-15b as an important factor in Th17-associated effects and determined that the expression of miR-15b is significantly downregulated in MS patients and in mice with experimental autoimmune encephalomyelitis. Overexpression of miR-15b alleviated experimental autoimmune encephalomyelitis, whereas knockdown of miR-15b aggravated it. We demonstrated that miR-15b suppressed Th17 differentiation both in vivo and in vitro. We also found that O-linked N-acetylglucosamine transferase is a potential target of miR-15b, enabling it to affect the transcriptional regulation of retinoic acid–related orphan receptor γT through O-linked N-acetylglucosamine glycosylation of NF-κB. These results contribute to the importance of miR-15b in Th17 differentiation and the pathogenesis of MS.

For the epigenetic characterization of neuromyelitis optica (NMO), we determined whether messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) are expressed differentially in subjects with and without NMO. lncRNA and mRNA expression profiles of NMO patients and healthy controls were generated by using microarray analysis. For comparison, the differentially expressed mRNA functions were annotated by using gene ontology (GO) and pathway analyses. The microarray revealed that 1310 lncRNAs and 743 mRNAs differed in NMO patients from those in healthy controls. Pathway analysis then demonstrated that IL23-mediated signaling events, interferon gamma signaling, natural killer (NK)-κB signaling pathway, chemokine receptors that bind chemokines, GPCR ligand binding, and metabolic disorders of biological oxidation enzyme pathways play important roles in NMO. Several GO terms including cytokine stimulus, response to cytokine, immune response, cytokine-mediated signaling pathway, and response to chemical cytokine activity were enriched in gene lists, suggesting a potential correlation with NMO. Co-expression network analysis indicated that 183 lncRNAs and 458 mRNAs were included in the co-expression network. Our present study showed that these differentially expressed mRNAs and lncRNAs may play important roles in NMO and could provide basic information for new biomarkers or treatment targets to alleviate NMO.