Advances in stroke pharmacology

Zhou, Zhenhua; Lu, Jingfen; Liu, Wenwu; Manaenko, Anatol; Hou, Xianhua; Mei, Qiyong; Huang, Jun; Tang, Jiping; Zhang, Junyi; Yao, Honghong; Hu, Qin

doi:10.1016/j.pharmthera.2018.05.012

Cited by 127 publications

(86 citation statements)

References 307 publications

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“…As the leading cause of death, ischemic stroke (>80% of stroke) is a medical emergency with high morbidity and mortality (1,2). It causes multiple pathophysiological events including mitochondrial response, excitotoxicity, protein misfolding and immune response, which lead to the delayed neuronal loss (3). These evidences providea range of molecular mechanisms that are potential targets for intervention.…”

Section: Introductionmentioning

confidence: 99%

IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway

et al. 2019

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We previously reported that astrocyte-derived proinflammatory cytokine interleukin (IL)-17A could aggravate neuronal ischemic injuries and strength autophagy both in oxygen-glucose deprivation (OGD)/reoxygenation (R)-treated neurons and peri-infarct region of mice with middle cerebral artery occlusion (MCAO)/reperfusion (R)-simulated ischemic stroke. In this study, the role and molecular mechanism of IL-17A in autophagy were further explored under ischemic condition. We found that exogenous addition of rmIL-17A remarkably (P < 0.001) decreased cell viability, which companying with the increases of LC3 II accumulation (P < 0.05 or 0.01) and Beclin 1 levels (P < 0.05 or 0.001), and reduction of p62 levels (P < 0.01 or 0.001) in OGD/R-treated cortical neurons (n = 6). The levels of P-mTOR (Ser 2448) (P < 0.001) and P-S6 (Ser 240/244) (P < 0.01) significantly decreased without the involvement of Akt, ERK1/2 and AMPK in cortical neurons under rmIL-17A and OGD/R treatments (n = 6). Interestingly, the co-IP analysis exhibited that PP2B and mTOR could be reciprocally immunoprecipitated; and the addition of rmIL-17A increased their interactions, PP2B activities (P < 0.001), P-Src (P < 0.001), and P-PLCγ1 (P < 0.01) levels in OGD/R-treated neurons (n = 6 or 5). The PP2B inhibitor Cyclosporin A blocked the induction of excessive autophagy (P < 0.05 or <0.001) and increased cell viability (P < 0.001) after OGD/R and rmIL-17A treatments (n = 6). In addition, the ICV injection of IL-17A neutralizing mAb could attenuate autophagy levels (P < 0.01 or 0.001, n = 6) and improve neurological functions (P < 0.01 or 0.001, n = 10) of mice after 1 h MCAO/R 24 h or 7 d. These results suggested that IL-17A-mediated excessive autophagy aggravates neuronal ischemic injuries via Src-PP2B-mTOR pathway, and IL-17A neutralization may provide a potential therapeutic effect for ischemic stroke.

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Section: Introductionmentioning

confidence: 99%

IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway

et al. 2019

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“…Stroke, including ischemic stroke caused by the block of cerebral blood vessel and hemorrhagic stroke with ruptured cerebral blood vessel, is a medical emergency that causes the devastating neurological function deficit (Zhou et al 2018). With the treatment of acute stroke and world population health having improved substantially, the incidence and case fatality rates have declined over the past 10 years (Bushnell et al 2018;Go et al 2014), but stroke is still the major cause of death and adult disability worldwide (Zhou et al 2018). Furthermore, in contrast with the declining incidence of stroke Qiu Liu, Zhiquan Jin and Zhiliang Xu contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

“…Ischemic stroke, responsible for about 87% of total strokes, causes neuronal cell death and injury of the neurovascular unit, which result in severe neurological symptoms (Zhou et al 2018). The molecular mechanism of ischemic stroke is extremely complicated and remains not completely clear (Pradeep et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Antioxidant effects of ginkgolides and bilobalide against cerebral ischemia injury by activating the Akt/Nrf2 pathway in vitro and in vivo

Qiu

Jin

et al. 2019

Cell Stress and Chaperones

145

109

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Ginkgolide terpenoid lactones, including ginkgolides and bilobalide, are two crucial bioactive constituents of extract of Ginkgo biloba (EGb) which was used in the treatment of cardiovascular and cerebrovascular diseases. The aims of this study were to investigate the antioxidant effects and mechanism of ginkgolides (ginkgolide A (GA), ginkgolide B (GB), ginkgolide K (GK)) and bilobalide (BB) against oxidative stress induced by transient focal cerebral ischemia. In vitro, SH-SY5Y cells were exposed to oxygen-glucose deprivation (OGD) for 4 h followed by reoxygenation with ginkgolides and BB treatments for 6 h, and then cell viability, superoxide dismutase (SOD), and ROS were respectively detected using kit. Western blot was used to confirm the protein levels of hemeoxygenase-1 (HO-1), quinone oxidoreductase l (Nqo1), Akt, phosphorylated Akt (p-Akt), nuclear factor-E2-related factor2 (Nrf2), and phosphorylated Nrf2 (p-Nrf2). GB combined with different concentrations of LY294002 (PI3K inhibitor) were administrated to SH-SY5Y cells for 1 h after OGD, and then p-Akt and p-Nrf2 levels were detected by western blot. In vivo, 2 h of middle cerebral artery occlusion (MCAO) model was established, followed with reperfusion and GB treatments for 24 and 72 h. The infarct volume ratios were confirmed by TTC staining. The protein levels of HO-1, Nqo1, SOD1, Akt, p-Akt, Nrf2, and p-Nrf2 were detected using western blot and immunohistochemistry (IHC). Experimental data in vitro confirm that GA, GB, GK, and BB resulted in significant decrease of ROS and increase of SOD activities and protein levels of HO-1 and Nqo1; however, GB group had a significant advantage in comparison with the GA and GK groups. Moreover, after ginkgolides and BB treatments, p-Akt and p-Nrf2 were significantly upregulated, which could be inhibited by LY294002 in a dose-dependent manner, meanwhile, GB exhibited more effective than GA and GK. In vivo, TTC staining indicated that the infarct volume ratios in MCAO rats were dramatically decreased by GB in a dose-dependent manner. Furthermore, GB significantly upregulated the protein levels of HO-1, Nqo1, SOD, p-Akt, p-Nrf2, and Nrf2. In conclusion, GA, GB, GK, and BB significantly inhibited oxidative stress damage caused by cerebral ischemia reperfusion. Compared with GA, GK, and BB, GB exerts the strongest antioxidant stress effects against ischemic stroke. Moreover, ginkgolides and BB upregulated the levels of antioxidant proteins through mediating the Akt/Nrf2 signaling pathway to protect neurons from oxidative stress injury.

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“…Responsible for ∼88% of global stroke subtypes, cerebral ischemic stroke (CIS) occurs in a cerebral vascular obstruction, which causes pathological processes such as metabolic disorders, inflammation, and cellular apoptosis, and leads to severe neurological symptoms (2). Rapid restoration of the cerebral blood flow and neuronal protection are the major therapeutic strategies for CIS (3). Until now, recombinant tissue plasminogen activator is the only thrombolytic drug approved by the US Food and Drug Administration for CIS treatment (4).…”

Section: Introductionmentioning

confidence: 99%

A Network-Based Method for Mechanistic Investigation and Neuroprotective Effect on Post-treatment of Senkyunolid-H Against Cerebral Ischemic Stroke in Mouse

Zhang

Jiang

Liu³

et al. 2019

Front. Neurol.

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activation of PI3K/Akt/nuclear factor kappa B pathway, and the therapeutic effect of SEH was obviously inhibited by 10 µM LY294002. In summary, these results suggested that SEH carries a therapeutic potential in CIS involving multiple targets and pathways, and the most crucial mechanism might be through the activation of PI3K/Akt/nuclear factor kappa B (NF-κB) signaling pathway to inhibit inflammatory factor releases and increase the antiapoptosis capacity. Our study furnishes the future traditional Chinese medicine research with a network pharmacology framework.

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Advances in stroke pharmacology

Cited by 127 publications

References 307 publications

IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway

IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway

Antioxidant effects of ginkgolides and bilobalide against cerebral ischemia injury by activating the Akt/Nrf2 pathway in vitro and in vivo

A Network-Based Method for Mechanistic Investigation and Neuroprotective Effect on Post-treatment of Senkyunolid-H Against Cerebral Ischemic Stroke in Mouse

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