GJ-4 ameliorates memory impairment in focal cerebral ischemia/reperfusion of rats via inhibiting JAK2/STAT1-mediated neuroinflammation

Liu, Hui; Zhang, Zihong; Zang, Caixia; Wang, Lu; Yang, Hanyu; Sheng, Chanjuan; Shang, Junmei; Zhao, Zhe; Yuan, Fang-Yu; Yu, Yang; Yao, Xin‐Sheng; Bao, Xiaoyong; Zhang, Dan

doi:10.1016/j.jep.2020.113491

Cited by 38 publications

(23 citation statements)

References 54 publications

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“…It plays a crucial role in the formation and fusion of synaptic vesicles, and the release of neurotransmitters from vesicles [12,31]. Previous studies have indicated that global cerebral ischemia produces a gradual decrease in SYP levels [32,33]. Consistent with these studies' results, cerebral ischemia decreased SYP expression in the rat hippocampus in our study, while the nicorandil significantly inhibited this change, suggesting that nicorandil exerts protective effects.…”

Section: Plos Onesupporting

confidence: 91%

The KATP channel opener, nicorandil, ameliorates brain damage by modulating synaptogenesis after ischemic stroke

Zhao

Yang

et al. 2021

PLoS ONE

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With population growth and aging, more and more patients with cerebral infarction have varying degrees of disability. ATP-sensitive potassium (KATP) channels regulate many cellular functions by coupling metabolic status with cell membrane electrical activity. Nicorandil (N-(2-hydroxyethyl)-nicotinamide nitrate) is the first KATP channel opener approved for clinical use. It has been reported that it might exert protective effects on the cerebral infarction by increasing cerebral blood flow and reducing inflammation. However, only a few studies explored its role in synaptogenesis. We made the rat model of middle cerebral artery occlusion (MCAO). Nicorandil was administered to rats via oral administration immediately after the surgery at a dose of 7.5 mg/kg and then daily for the next days. Infarct volume, cerebral edema, neurological deficits, cognitive impairment, and the level of Synaptophysin (SYP)、Growth associated protein-43 (GAP43) and neuronal nuclear antigen (NeuN) levels were measured to evaluate the effect of nicorandil. Our data showed that nicorandil treatment could decrease brain damage, improve learning and memory, and increase SYP、GAP43 and NeuN level. Taken together, we propose that nicorandil, as an opener of the KATP channel, provides a neuroprotective role in MCAO by promoting synaptic connections.

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Section: Plos Onesupporting

confidence: 91%

The KATP channel opener, nicorandil, ameliorates brain damage by modulating synaptogenesis after ischemic stroke

Zhao

Yang

et al. 2021

PLoS ONE

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“…GJ-4 (a natural extract from Gardenia jasminoides J. Ellis) improves memory impairment of stroke-induced vascular dementia rats by upregulating synaptophysin and PSD-95 expressions. The underlying mechanism is that GJ-4 suppresses microglia-mediated neuroinflammatory responses via inhibition of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) pathway ( Liu et al, 2021a ). Early inhibition of the Toll-like receptor (TLR)-4 pathway with TAK-242 (a TLR4-specific antagonist) administration improves the outcomes of neonatal hypoxic–ischemic brain damage though suppressing microglial activation and enhancing synaptic plasticity ( Tang et al, 2019 ).…”

Section: Microglia-based Treatment Targeting Post-stroke Neuroplasticitymentioning

confidence: 99%

New Insights Into the Roles of Microglial Regulation in Brain Plasticity-Dependent Stroke Recovery

Huang

Ran

et al. 2021

Front. Cell. Neurosci.

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Stroke remains the leading cause of long-term disability worldwide with significant long-term sequelae. However, there is no highly effective treatment to enhance post-stroke recovery despite extensive efforts in exploring rehabilitative therapies. Neurorehabilitation is recognized as the cornerstone of functional restoration therapy in stroke, where treatments are focused on neuroplastic regulation to reverse neural structural disruption and improve neurofunctional networks. Post-stroke neuroplasticity changes begin within hours of symptom onset and reaches a plateau by 3 to 4 weeks within the global brain in animal studies. It plays a determining role in spontaneous stroke recovery. Microglia are immediately activated following cerebral ischemia, which has been found both proximal to the primary ischemic injury and at the remote brain regions which have functional connections to the primary injury area. Microglia exhibit different activation profiles based on the microenvironment and adaptively switch their phenotypes in a spatiotemporal manner in response to brain injuries. Microglial activation coincides with neuroplasticity after stroke, which provides the fundamental base for the microglia-mediated inflammatory responses involved in the entire neural network rewiring and brain repair. Microglial activation exerts important effects on spontaneous recovery after stroke, including structural and functional reestablishment of neurovascular networks, neurogenesis, axonal remodeling, and blood vessel regeneration. In this review, we focus on the crosstalk between microglial activation and endogenous neuroplasticity, with a special focus on the plastic alterations in the whole brain network and their implications for structural and functional restoration after stroke. We then summarize recent advances in the impacts of microglial phenotype polarization on brain plasticity, trying to discuss the potential efficacy of microglia-based extrinsic restorative interventions in promoting post-stroke recovery.

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“…And compared with wild-type mice, STAT1-knockout mice had reduced numbers of TUNEL-positive neurons, smaller infarct volume, but higher neurological scores [31]. Inhibition of JAK2/STAT1-mediated neuroin ammation signaling pathway could ameliorate memory impairment in ischemia/reperfusion stroke rats [32], indicating the important role of JAK2/STAT1 pathway in VaD treatment.…”

Section: Discussionmentioning

confidence: 98%

Bioinformatics Approaches to Identify Novel Therapeutic Targets of Mixed Dementia

Zhang

Huang

Zhou

2022

Preprint

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Background Mixed dementia (MxD) refers to a patient's coexistence of Alzheimer's disease (AD) and vascular dementia (VaD). Until recently, pharmacological studies have generally focused on pure disease, AD or VaD, and have shed little light on the best therapeutic approaches to MxD. Therefore this study aimed to explore potential targets for MxD. Methods GSE36980 and GSE122063 datasets were downloaded from the Gene Expression Omnibus (GEO). GEO2R was utilized to identify the differentially expressed genes (DEGs) in GSE36980 between MxD and control groups. Then the genes in the top 50% of the median absolute deviation (MAD) with at least MAD greater than 0.01 and phenotypes of samples in GSE36980 were analyzed using R package “weighted gene co-expression network analysis” (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment were analyzed on the selected dark green module genes. Protein-protein interactions analyses were performed in the STRING database and key genes were screened based on the maximal clique centrality (MCC) and maximum neighborhood component (MNC) algorithm of Cytoscape software. Key genes were then verified in external dataset GSE122063. Results There were 162 DEGs identified, including 121 up-regulated and 41 down-regulated genes. And the dark green module was the mostly related to MxD, among which, 43 genes were also DEGs in GSE36980 datasets. The most significantly enriched biological processes were the type I interferon signaling pathway (GO:0060337, P = 1.79E-25) and defense response to virus (GO:0051607, P = 2.34E-22). Due to the highest scores received, STAT1, IFIT3, OAS2, and MX1 may play crucial roles in MxD. Finally, test in external dataset GSE122063, STAT1, and IFIT3 were significantly up-regulated in AD patients. Conclusions In conclusion, STAT1 and IFIT3 may serve as potential targets for the pathogenesis of MxD, which should be further explored in the future.

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GJ-4 ameliorates memory impairment in focal cerebral ischemia/reperfusion of rats via inhibiting JAK2/STAT1-mediated neuroinflammation

Cited by 38 publications

References 54 publications

The KATP channel opener, nicorandil, ameliorates brain damage by modulating synaptogenesis after ischemic stroke

The KATP channel opener, nicorandil, ameliorates brain damage by modulating synaptogenesis after ischemic stroke

New Insights Into the Roles of Microglial Regulation in Brain Plasticity-Dependent Stroke Recovery

Bioinformatics Approaches to Identify Novel Therapeutic Targets of Mixed Dementia

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