Neuroprotective effect of linagliptin against cuprizone-induced demyelination and behavioural dysfunction in mice: A pivotal role of AMPK/SIRT1 and JAK2/STAT3/NF-κB signalling pathway modulation

Elbaz, Eman M.; Senousy, Mahmoud A.; El-Tanbouly, Dalia M.; Sayed, Rabab H.

doi:10.1016/j.taap.2018.05.035

Cited by 81 publications

(48 citation statements)

References 57 publications

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“…The P65 pathway has been found to mediate the process of ischemic brain injury, hence a promising therapeutic target for ischemic stroke, and ikB as the master inhibitor of the P65 pathway, to have a degrading function during pathway activation (Hayden et al, 2008;Tu et al, 2014;Wang et al, 2017). A recent study has shown that linagliptin could suppress the expression of phosphorylated J A K 2 , p h o s p h o r y l a t e d S T A T 3 a n d P 6 5 t o c o n f e r neuroprotection (Marotta et al, 2011;Chang et al, 2018;Elbaz Eman et al, 2018). These results are similar to those which were found in the current study, which suggests the effects of inflammation reduction and neuroprotection.…”

Section: Discussionsupporting

confidence: 91%

Protective Effect of Stachydrine Against Cerebral Ischemia-Reperfusion Injury by Reducing Inflammation and Apoptosis Through P65 and JAK2/STAT3 Signaling Pathway

Sun

Qiu

et al. 2020

Front. Pharmacol.

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Stachydrine, a constituent of Leonurus japonicus Houtt which also called Japanese motherwort has been shown to improve vascular microcirculation and ameliorate endothelial dysfunction. This study investigated the neuroprotective effect of stachydrine. Male Sprague-Dawley (SD) rats were randomly divided into sham, control, and stachydrine groups. The neurological deficit score was evaluated and the infarct size of the brain was measured using 2,3,5-triphenyltetra-zolium (TTC) chloride staining assay, and the pathological changes in the brain tissues were examined by HE staining. Nissl and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) staining were performed to assess the numbers of Nissl bodies and the levels of apoptosis in the neurons. The activities of superoxide dismutase (SOD) and the levels of malondialdehyde (MDA) were also measured. The release of inflammatory factors IL-1b and TNF-a were detected by Enzyme-linked immunosorbent assay (ELISA). Compared with the control group, the stachydrine group showed a significant prevention of neurological deficit, as indicated by the reduced infarct volume in the brain. Moreover, the stachydrine treatment reduced the activities of SOD, the levels of MDA and decreased the amount of IL-1b, and TNF-a, indicating that it could function to decrease the level of inflammation, thus reducing brain damage. The ischemic stroke model of PC12 cells was prepared via oxygen-glucose deprivation (OGD) protocol for 6 h. The expression of P65 and JAK2/STAT3 signaling pathway related proteins was measured by western blot. The treatment group was found to have the survival rate of PC12 cells improved and the release of inflammatory factors reduced when compared with the OGD group. This study demonstrated that stachydrine could improve nerve function by inhibiting the phosphorylation of P65/JAK2 and STAT3. FIGURE 1 | The chemical structure of stachydrine. Stachydrine (purity> 97%) purchased from Dalian Meilun Biology Technology Co. (Dalian, China). Li et al. Stachydrine Protects Against Cerebral Ischemia-Reperfusion InjuryFrontiers in Pharmacology | www.frontiersin.org February 2020 | Volume 11 | Article 64 absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Section: Discussionsupporting

confidence: 91%

Protective Effect of Stachydrine Against Cerebral Ischemia-Reperfusion Injury by Reducing Inflammation and Apoptosis Through P65 and JAK2/STAT3 Signaling Pathway

Sun

Qiu

et al. 2020

Front. Pharmacol.

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“…WM lesions are inherent characteristics of MS from the early phase, and both quantitative and qualitative changes in the WM can be observed as the disease progresses: microglia activation in the NAWM [20], increasing number of chronic active lesions, and decreasing number of remyelinating lesions [17, 66]. B cells are also present in active WM lesions in progressive MS, and the number of plasma cells is higher in lesions from progressive MS compared to acute MS [22, 53].…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Unique RNA signature of different lesion types in the brain white matter in progressive multiple sclerosis

Elkjaer

Frisch

Reynolds

et al. 2019

acta neuropathol commun

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The heterogeneity of multiple sclerosis is reflected by dynamic changes of different lesion types in the brain white matter (WM). To identify potential drivers of this process, we RNA-sequenced 73 WM areas from patients with progressive MS (PMS) and 25 control WM. Lesion endophenotypes were described by a computational systems medicine analysis combined with RNAscope, immunohistochemistry, and immunofluorescence. The signature of the normal-appearing WM (NAWM) was more similar to control WM than to lesions: one of the six upregulated genes in NAWM was CD26/DPP4 expressed by microglia. Chronic active lesions that become prominent in PMS had a signature that were different from all other lesion types, and were differentiated from them by two clusters of 62 differentially expressed genes (DEGs). An upcoming MS biomarker, CHI3L1 was among the top ten upregulated genes in chronic active lesions expressed by astrocytes in the rim. TGFβ-R2 was the central hub in a remyelination-related protein interaction network, and was expressed there by astrocytes. We used de novo networks enriched by unique DEGs to determine lesion-specific pathway regulation, i.e. cellular trafficking and activation in active lesions; healing and immune responses in remyelinating lesions characterized by the most heterogeneous immunoglobulin gene expression; coagulation and ion balance in inactive lesions; and metabolic changes in chronic active lesions. Because we found inverse differential regulation of particular genes among different lesion types, our data emphasize that omics related to MS lesions should be interpreted in the context of lesion pathology. Our data indicate that the impact of molecular pathways is substantially changing as different lesions develop. This was also reflected by the high number of unique DEGs that were more common than shared signatures. A special microglia subset characterized by CD26 may play a role in early lesion development, while astrocyte-derived TGFβ-R2 and TGFβ pathways may be drivers of repair in contrast to chronic tissue damage. The highly specific mechanistic signature of chronic active lesions indicates that as these lesions develop in PMS, the molecular changes are substantially skewed: the unique mitochondrial/metabolic changes and specific downregulation of molecules involved in tissue repair may reflect a stage of exhaustion. Electronic supplementary material The online version of this article (10.1186/s40478-019-0709-3) contains supplementary material, which is available to authorized users.

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“…Liu et al demonstrated that JAK2 inhibitors have clinical efficacy in multiple preclinical models of MS by suppressing downstream activation of STAT, particularly STAT3 [46]. Modulation of the JAK/STAT pathway is thought to mediate the beneficial effect of neuroprotective compound linagliptin in cuprizone-induced demyelination [47]. Studies have suggested that JAK/STAT signaling occurs upstream of NF-kappaB activation [48].…”

Section: Discussionmentioning

confidence: 99%

Dense module searching for gene networks associated with multiple sclerosis

et al. 2020

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Background: Multiple sclerosis (MS) is a complex disease in which the immune system attacks the central nervous system. The molecular mechanisms contributing to the etiology of MS remain poorly understood. Genome-wide association studies (GWAS) of MS have identified a small number of genetic loci significant at the genome level, but they are mainly non-coding variants. Network-assisted analysis may help better interpret the functional roles of the variants with association signals and potential translational medicine application. The Dense Module Searching of GWAS tool (dmGWAS version 2.4) developed in our team is applied to 2 MS GWAS datasets (GeneMSA and IMSGC GWAS) using the human protein interactome as the reference network. A dual evaluation strategy is used to generate results with reproducibility. Results: Approximately 7500 significant network modules were identified for each independent GWAS dataset, and 20 significant modules were identified from the dual evaluation. The top modules included GRB2, HDAC1, JAK2, MAPK1, and STAT3 as central genes. Top module genes were enriched with functional terms such as "regulation of glial cell differentiation" (adjusted p-value = 2.58 × 10 − 3), "T-cell costimulation" (adjusted p-value = 2.11 × 10 − 6) and "virus receptor activity" (adjusted p-value = 1.67 × 10 − 3). Interestingly, top gene networks included several MS FDA approved drug target genes HDAC1, IL2RA, KEAP1, and RELA, Conclusions: Our dmGWAS network analyses highlighted several genes (GRB2, HDAC1, IL2RA, JAK2, KEAP1, MAPK1, RELA and STAT3) in top modules that are promising to interpret GWAS signals and link to MS drug targets. The genes enriched with glial cell differentiation are important for understanding neurodegenerative processes in MS and for remyelination therapy investigation. Importantly, our identified genetic signals enriched in T cell costimulation and viral receptor activity supported the viral infection onset hypothesis for MS.

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Neuroprotective effect of linagliptin against cuprizone-induced demyelination and behavioural dysfunction in mice: A pivotal role of AMPK/SIRT1 and JAK2/STAT3/NF-κB signalling pathway modulation

Cited by 81 publications

References 57 publications

Protective Effect of Stachydrine Against Cerebral Ischemia-Reperfusion Injury by Reducing Inflammation and Apoptosis Through P65 and JAK2/STAT3 Signaling Pathway

Protective Effect of Stachydrine Against Cerebral Ischemia-Reperfusion Injury by Reducing Inflammation and Apoptosis Through P65 and JAK2/STAT3 Signaling Pathway

RETRACTED ARTICLE: Unique RNA signature of different lesion types in the brain white matter in progressive multiple sclerosis

Dense module searching for gene networks associated with multiple sclerosis

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