Neuroprotective Effect of Danhong Injection on Cerebral Ischemia-Reperfusion Injury in Rats by Activation of the PI3K-Akt Pathway

Chen, Feng; Wan, Haofang; Zhang, Yangyang; Yu, Li; Shao, Chongyu; He, Yu; Jin, Weifeng

doi:10.3389/fphar.2020.00298

Cited by 76 publications

(44 citation statements)

References 57 publications

(52 reference statements)

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“…PI3K/AKT pathway is a common signaling pathway associated with cell proliferation and migration [27]. We studied its changes when DHI acts on RSC96 cells, and found that PI3K/AKT is signi cantly activated, which was consistent with Zhou's ndings in atherosclerosis [28] and Feng's study on cerebral ischemia/reperfusion injury [29] in which DHI activates the PI3K/AKT pathway.…”

Section: Discussionsupporting

confidence: 78%

DHI increases the proliferation and migration of Schwann cells through PI3K/AKT pathway and the expression of CXCL12 and GDNF to promote facial nerve function repair

Gao¹,

Sun²,

Sun³

et al. 2021

Preprint

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BackgroundDanhong injection (DHI) is a commonly used drug in the treatment of cardiovascular and cerebrovascular diseases, and its neuroprotective research has been fully confirmed. Schwann cells, as myelin forming cells of peripheral nerve, play an important role in the process of injury and repair. The purpose of this study was to explore the effect of DHI on Schwann cells and its role in facial nerve injury.MethodsRSC 96 Schwann cells were treated with different concentrations (0 –2%) of DHI for different time intervals (12 and 36 h). Effect of DHI on cell viability and migration were determined by CCK8 and Transwell assays. The levels of PI3K-Akt signaling related proteins were measured by western blotting analysis, and the effects of DHI on GDNF and CXCL12 using Western Blot, RT-qPCR, and ELISA assays at the cellular and animal levels, respectively. Then LY294002, an inhibitor of PI3K, was used to study the effect of DHI on cell migration and secretion of CXCL12 and GDNF in RSC96 cells by Transwell, Western Blot, RT-qPCR, and ELISA assays. Finally, facial nerve scoring and S-100 immunofluorescence staining were used to study the therapeutic effects of DHI on facial nerve injury.ResultsOur study found that DHI can promote the proliferation and migration of RSC96 cells, and this effect is related to the activation of PI3K/AKT pathway. LY294002 inhibits the proliferation and migration of RSC96 cells. Besides, DHI can also promote the expression of CXCL12 and GDNF at gene and protein levels, and CXCL12 is, while GDNF is not, PI3K/AKT pathway-dependent. Animal experiments confirmed that DHI could promote CXCL12 and GDNF expression, and promote facial nerve function recovery and myelin regeneration. Conclusion Our in vitro and in vivo experiments demonstrated that DHI could promote proliferation and migration of Schwann cells through the PI3K/AKT pathway, and increase the expression of CXCL12 and GDNF to promote facial nerve function repair.

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Section: Discussionsupporting

confidence: 78%

DHI increases the proliferation and migration of Schwann cells through PI3K/AKT pathway and the expression of CXCL12 and GDNF to promote facial nerve function repair

Gao¹,

Sun²,

Sun³

et al. 2021

Preprint

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“…DHI has been used extensively in the clinical treatment of coronary heart disease and acutely cerebral infarction for many years (He et al, 2012). More experimental evidences show that DHI exerts diverse pharmacological properties by modulating multiple molecular targets (Feng et al, 2019), including recovery of cerebral glucose metabolism by serial 18 F-labeled fluoro-2-deoxyglucose ( 18 F-FDG)-micro positron emission tomography (PET) imaging and enhancing neurogenesis (Wang et al, 2014), angiogenesis-promoting actions by up-regulating expressions of the related factors of angiogenesis (Wan et al, 2018), and antiapoptotic by activating phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway (Feng et al, 2020). Clinically, a network meta-analysis of randomized controlled trials found that DHI combined with other regimens had the highest effective rate in the treatment of acute cerebral infarction (Liu et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Danhong Injection Attenuates Cerebral Ischemia-Reperfusion Injury in Rats Through the Suppression of the Neuroinflammation

Yingjie

Zhao

et al. 2021

Front. Pharmacol.

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Neuroinflammation is one of the major causes of damage of the central nervous system (CNS) and plays a vital role in the pathogenesis of cerebral ischemia, which can result in long-term disability and neuronal death. Danhong injection (DHI), a traditional Chinese medicine injection, has been applied to the clinical treatment of cerebral stoke for many years. In this study, we investigated the protective effects of DHI on cerebral ischemia-reperfusion injury (CIRI) in rats and explored its potential anti-neuroinflammatory properties. CIRI in adult male SD rats was induced by middle cerebral artery occlusion (MCAO) for 1 h and reperfusion for 24 h. Results showed that DHI (0.5, 1, and 2 ml/kg) dose-dependently improved the neurological deficits and alleviated cerebral infarct volume and histopathological damage of the cerebral cortex caused by CIRI. Moreover, DHI (0.5, 1, and 2 ml/kg) inhibited the mRNA expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), intercellular cell adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in ischemic brains, downregulated TNF-α, IL-1β, and monocyte chemotactic protein-1 (MCP-1) levels in serum, and reduced the neutrophil infiltration (myeloperoxidase, MPO) in ischemic brains, in a dose-dependent manner. Immunohistochemical staining results also revealed that DHI dose-dependently diminished the protein expressions of ICAM-1 and COX-2, and suppressed the activation of microglia (ionized calcium-binding adapter molecule 1, Iba-1) and astrocyte (glial fibrillary acidic protein, GFAP) in the cerebral cortex. Western blot analysis showed that DHI significantly downregulated the phosphorylation levels of the proteins in nuclear factor κB (NF-κB) and mitogen-activated protein kinas (MAPK) signaling pathways in ischemic brains. These results indicate that DHI exerts anti-neuroinflammatory effects against CIRI, which contribute to the amelioration of CNS damage.

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“…e PI3K-Akt signalling pathway has a neuroprotective effect in MCAO rats through inhibition of cell apoptosis [48,49]. By activating the PI3K-Akt signalling pathway, Danhong injection increases the expression of antiapoptotic factors, inhibits the expression of apoptotic factors, and exerts a neuroprotective effect in MCAO rats [50]. Electroacupuncture reduces the cerebral infarct volume and the activation of cleaved caspase-3 in MCAO rats by activating the PI3K-Akt signalling pathway [51].…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Approach for Exploring the Mechanisms of Panax notoginseng Saponins in Ischaemic Stroke

Wang

Chen

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Background. Panax notoginseng saponins (PNS) have been deemed effective herb compounds for treating ischaemic stroke (IS) and improving the quality of life of IS patients. This study aimed to investigate the underlying mechanisms of PNS in the treatment of IS based on network pharmacology. Methods. PNS were identified from the Traditional Chinese Medicine System Pharmacology (TCMSP) database, and their possible targets were predicted using the PharmMapper database. IS-related targets were identified from the GeneCards database, OMIM database, and DisGeNET database. A herb-compound-target-disease network was constructed using Cytoscape, and protein-protein interaction (PPI) networks were established with STRING. GO enrichment and KEGG pathway analysis were performed using DAVID. The binding of the compounds and key targets was validated by molecular docking studies using AutoDock Vina. The neuroprotective effect of TFCJ was substantiated in terms of oxidative stress (superoxide dismutase, glutathione peroxidase, catalase, and malondialdehyde) and the levels of IGF1/PI3K/Akt pathway proteins. Results. A total of 375 PNS targets and 5111 IS-related targets were identified. Among these targets, 241 were common to PNS, and IS network analysis showed that MAPK1, AKT1, PIK3R1, SRC, MAPK8, EGFR, IGF1, HRAS, RHOA, and HSP90AA1 are key targets of PNS against IS. Furthermore, GO and KEGG enrichment analysis indicated that PNS probably exert therapeutic effects against IS by regulating many pathways, such as the Ras, oestrogen, FoxO, prolactin, Rap1, PI3K-Akt, insulin, PPAR, and thyroid hormone signalling pathways. Molecular docking studies further corroborated the experimental results.The network pharmacology results were further verified by molecular docking and in vivo experiments. Conclusions. The ameliorative effects of PNS against IS were predicted to be associated with the regulation of the IGF1-PI3K-Akt signalling pathway. Ginsenoside Re and ginsenoside Rb1 may play an important role in the treatment of IS.

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Neuroprotective Effect of Danhong Injection on Cerebral Ischemia-Reperfusion Injury in Rats by Activation of the PI3K-Akt Pathway

Cited by 76 publications

References 57 publications

DHI increases the proliferation and migration of Schwann cells through PI3K/AKT pathway and the expression of CXCL12 and GDNF to promote facial nerve function repair

DHI increases the proliferation and migration of Schwann cells through PI3K/AKT pathway and the expression of CXCL12 and GDNF to promote facial nerve function repair

Danhong Injection Attenuates Cerebral Ischemia-Reperfusion Injury in Rats Through the Suppression of the Neuroinflammation

A Network Pharmacology Approach for Exploring the Mechanisms of Panax notoginseng Saponins in Ischaemic Stroke

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