Dataset Information

Therapeutic Potential of Novel Twin Compounds Containing Tetramethylpyrazine and Carnitine Substructures in Experimental Ischemic Stroke.

ABSTRACT: Although studies have seen dramatic advances in the understanding of the pathogenesis of stroke such as oxidative stress, inflammation, excitotoxicity, calcium overload and apoptosis, the delivery of stroke therapies is still a great challenge. In this study, we designed and synthesized a series of novel twin compounds containing tetramethylpyrazine and carnitine substructures and explored their therapeutic potential and mechanism in stroke-related neuronal injury. We first screened the neuroprotective effects of candidate compounds and found that among the tested compounds, LR134 and LR143 exhibited significant neuroprotection as evidenced by reducing cerebral infarct and edema, improving neurological function as well as blood-brain barrier integrity in rats after cerebral ischemia/reperfusion injury. We further demonstrated that the neuroprotective effects of compounds LR134 and LR143 were associated with the reduced inflammatory responses and NADPH oxidase- (NOX2-) mediated oxidative stress and the protection of mitochondria accompanied by the improvement of energy supply. In summary, this study provides direct evidence showing that the novel twin compounds containing tetramethylpyrazine and carnitine substructures have neuroprotective effects with multiple therapeutic targets, suggesting that modulation of these chemical structures may be an innovative therapeutic strategy for treating patients with stroke.

SUBMITTER: Wang Z

PROVIDER: S-EPMC5745738 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Therapeutic Potential of Novel Twin Compounds Containing Tetramethylpyrazine and Carnitine Substructures in Experimental Ischemic Stroke.

Wang Ziying Z Zhou Zhuanli Z Wei Xinbing X Wang Mingwei M Wang Bi-Ou BO Zhang Yanan Y He Xiaoting X Sun Yu Y Wang Xiaojie X Sun Mingcheng M Zhang Yan Y Gong Xiaowei X Yi Fan F

Oxidative medicine and cellular longevity 20171213

Although studies have seen dramatic advances in the understanding of the pathogenesis of stroke such as oxidative stress, inflammation, excitotoxicity, calcium overload and apoptosis, the delivery of stroke therapies is still a great challenge. In this study, we designed and synthesized a series of novel twin compounds containing tetramethylpyrazine and carnitine substructures and explored their therapeutic potential and mechanism in stroke-related neuronal injury. We first screened the neuropro ...[more]

PMID: 29387294

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Project description:Background: Stroke is one of the most common deadly diseases with an estimated 780,000 new cases globally, of which ischemic stroke accounts for over 80% of all cases. Ferroptosis is a new form of programmed cell death that plays a vital role in many diseases, including ischemic stroke and heart diseases. The role of the ferroptosis-related gene in the diagnosis, prognosis, or therapy of ischemic stroke was not fully clarified. Methods: Ferroptosis-related differentially expressed genes (DEGs) in ischemic stroke were identified by bioinformatic analysis of the GSE16561 and GSE22255 datasets. Subsequently, receiver operator characteristic (ROC) monofactor analysis was performed to evaluate the diagnostic value of ferroptosis-related biomarkers in ischemic stroke. Results: A total of 10 ferroptosis-related DEGs were identified in ischemic stroke vs. normal control. GO and KEGG analysis revealed that these 10 ferroptosis-related DEGs were mainly enriched in response to oxidative stress, HIF-1 signaling pathway, ferroptosis, lipid, and atherosclerosis. Moreover, the random forest model suggested three ferroptosis-related biomarkers, namely, PTGS2, MAP1LC3B, and TLR4, for ischemic stroke. Interestingly, the expression of PTGS2, MAP1LC3B, and TLR4 was upregulated in ischemic stroke. ROC monofactor analysis demonstrated a good performance of MAP1LC3B, PTGS2, and TLR4 in the diagnosis of ischemic stroke. The expression and diagnostic value of MAP1LC3B, PTGS2, and TLR4 in ischemic stroke were also verified using GSE22255. We also revealed the transcription factor regulation network and co-expressed protein network of ferroptosis-related biomarkers. Several potential therapeutic compounds corresponding to MAP1LC3B, PTGS2, and TLR4 were also identified for ischemic stroke, including Zinc12503187 (Conivaptan), Zinc3932831 (Avodart), Zinc64033452 (Lumacaftor), Zinc11679756 (Eltrombopag), Zinc100378061 (Naldemedine), and Zinc3978005 (Dihydroergotamine). Conclusion: Our results suggested MAP1LC3B, PTGS2, and TLR4 as potential diagnostic biomarkers for ischemic stroke, providing more evidence about the vital role of ferroptosis in ischemic stroke.

Project description:Transplantation of various types of stem cells as a possible therapy for stroke has been tested for years, and the results are promising. Recent investigations have shown that the administration of the conditioned media obtained after stem cell cultivation can also be effective in the therapy of the central nervous system pathology (hypothesis of their paracrine action). The aim of this study was to evaluate the therapeutic effects of the conditioned medium of hiPSC-derived glial and neuronal progenitor cells in the rat middle cerebral artery occlusion model of the ischemic stroke. Secretory activity of the cultured neuronal and glial progenitor cells was evaluated by proteomic and immunosorbent-based approaches. Therapeutic effects were assessed by overall survival, neurologic deficit and infarct volume dynamics, as well as by the end-point values of the apoptosis- and inflammation-related gene expression levels, the extent of microglia/macrophage infiltration and the numbers of formed blood vessels in the affected area of the brain. As a result, 31% of the protein species discovered in glial progenitor cells-conditioned medium and 45% in neuronal progenitor cells-conditioned medium were cell type specific. The glial progenitor cell-conditioned media showed a higher content of neurotrophins (BDNF, GDNF, CNTF and NGF). We showed that intra-arterial administration of glial progenitor cells-conditioned medium promoted a faster decrease in neurological deficit compared to the control group, reduced microglia/macrophage infiltration, reduced expression of pro-apoptotic gene Bax and pro-inflammatory cytokine gene Tnf, increased expression of anti-inflammatory cytokine genes (Il4, Il10, Il13) and promoted the formation of blood vessels within the damaged area. None of these effects were exerted by the neuronal progenitor cell-conditioned media. The results indicate pronounced cytoprotective, anti-inflammatory and angiogenic properties of soluble factors secreted by glial progenitor cells.

Dataset Information

Therapeutic Potential of Novel Twin Compounds Containing Tetramethylpyrazine and Carnitine Substructures in Experimental Ischemic Stroke.

Publications

Therapeutic Potential of Novel Twin Compounds Containing Tetramethylpyrazine and Carnitine Substructures in Experimental Ischemic Stroke.

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