Repurposing antimycotic ciclopirox olamine as a promising anti-ischemic stroke agent

Feng, Huijin; Hu, Linghao; Zhu, Hongwen; Tao, Lingxue; Wu, Lei; Zhao, Qinyuan; Gao, Yemi; Gong, Qi; Mao, Fei; Li, Xiaokang; Zhou, Hu; Li, Jian; Zhang, Haiyan

doi:10.1016/j.apsb.2019.08.002

Cited by 27 publications

(29 citation statements)

References 53 publications

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“…As a result, less intranuclear Fyn allows NRF2 unimpeded binding to ARE. GSK-3 β is a direct substrate with its activity regulated by active form of PKB, and Ser473 is an active site of PKB that targets cellular survival procedures 51 , 52 . DT significantly phosphorylates PKB at Ser473 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Activated PKB/GSK-3β synergizes with PKC-δ signaling in attenuating myocardial ischemia/reperfusion injury via potentiation of NRF2 activity: Therapeutic efficacy of dihydrotanshinone-I

Zeng

Wang

Zhang

et al. 2021

Acta Pharmaceutica Sinica B

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Disrupted redox status primarily contributes to myocardial ischemia/reperfusion injury (MIRI). NRF2, the endogenous antioxidant regulator, might provide therapeutic benefits. Dihydrotanshinone-I (DT) is an active component in Salvia miltiorrhiza with NRF2 induction potency. This study seeks to validate functional links between NRF2 and cardioprotection of DT and to investigate the molecular mechanism particularly emphasizing on NRF2 cytoplasmic/nuclear translocation. DT potently induced NRF2 nuclear accumulation, ameliorating post-reperfusion injuries via redox alterations. Abrogated cardioprotection in NRF2-deficient mice and cardiomyocytes strongly supports NRF2-dependent cardioprotection of DT. Mechanistically, DT phosphorylated NRF2 at Ser40, rendering its nuclear-import by dissociating from KEAP1 and inhibiting degradation. Importantly, we identified PKC- δ -(Thr505) phosphorylation as primary upstream event triggering NRF2-(Ser40) phosphorylation. Knockdown of PKC- δ dramatically retained NRF2 in cytoplasm, convincing its pivotal role in mediating NRF2 nuclear-import. NRF2 activity was further enhanced by activated PKB/GSK-3 β signaling via nuclear-export signal blockage independent of PKC- δ activation. By demonstrating independent modulation of PKC- δ and PKB/GSK-3 β /Fyn signaling, we highlight the ability of DT to exploit both nuclear import and export regulation of NRF2 in treating reperfusion injury harboring redox homeostasis alterations. Coactivation of PKC and PKB phenocopied cardioprotection of DT in vitro and in vivo , further supporting the potential applicability of this rationale.

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Section: Discussionmentioning

confidence: 99%

Activated PKB/GSK-3β synergizes with PKC-δ signaling in attenuating myocardial ischemia/reperfusion injury via potentiation of NRF2 activity: Therapeutic efficacy of dihydrotanshinone-I

Zeng

Wang

Zhang

et al. 2021

Acta Pharmaceutica Sinica B

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“…BBB disruption was evaluated using Evans blue dye (Sigma–Aldrich) extravasation on the 72 h after tMCAO as described previously 24 , 26 . Briefly, 2% solution of Evans blue (Sigma–Aldrich) dissolved in sterile saline was injected through the rat tail vein at a dose of four mL/kg of body weight at 1 h before the rat were sacrificed.…”

Section: Methodsmentioning

confidence: 99%

A novel PGAM5 inhibitor LFHP-1c protects blood–brain barrier integrity in ischemic stroke

Gao

Liang

et al. 2021

Acta Pharmaceutica Sinica B

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Blood–brain barrier (BBB) damage after ischemia significantly influences stroke outcome. Compound LFHP-1c was previously discovered with neuroprotective role in stroke model, but its mechanism of action on protection of BBB disruption after stroke remains unknown. Here, we show that LFHP-1c, as a direct PGAM5 inhibitor, prevented BBB disruption after transient middle cerebral artery occlusion (tMCAO) in rats. Mechanistically, LFHP-1c binding with endothelial PGAM5 not only inhibited the PGAM5 phosphatase activity, but also reduced the interaction of PGAM5 with NRF2, which facilitated nuclear translocation of NRF2 to prevent BBB disruption from ischemia. Furthermore, LFHP-1c administration by targeting PGAM5 shows a trend toward reduced infarct volume, brain edema and neurological deficits in nonhuman primate Macaca fascicularis model with tMCAO. Thus, our study identifies compound LFHP-1c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption in vitro and in vivo , and provides a potentially therapeutics for brain ischemic stroke.

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“…Because of the pathological and pathophysiological links between iron and ischemic stroke, iron chelators, including DFO, CPX, and 2,2-BP, have been extensively investigated for treating the disease. 209,211,212,214,214,215,[419][420][421][422] One of the most commonly studied chelators, DFO, has been shown to reduce brain injury and promote functional recovery in the MCAO model in rats and mice. 209,211 In other studies, iron regulatory proteins such as transferrin and ceruloplasmin have also been shown to attenuate neuronal damage in models of ischemic stroke.…”

Section: Targeting Ferroptosismentioning

confidence: 99%

Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications

Tuo

Zhang

Lei

2021

Medicinal Research Reviews

326

185

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Ischemic stroke caused by arterial occlusion is the most common type of stroke, which is among the most frequent causes of disability and death worldwide. Current treatment approaches involve achieving rapid reperfusion either pharmacologically or surgically, both of which are time-sensitive; moreover, blood flow recanalization often causes ischemia/reperfusion injury. However, even though neuroprotective intervention is urgently needed in the event of stroke, the exact mechanisms of neuronal death during ischemic stroke are still unclear, and consequently, the capacity for drug development has remained limited. Multiple cell death pathways are implicated in the pathogenesis of ischemic stroke. Here, we have reviewed these potential neuronal death pathways, including intrinsic and extrinsic apoptosis, necroptosis, autophagy, ferroptosis, parthanatos, phagoptosis, and pyroptosis. We have also reviewed the latest results of pharmacological studies on ischemic stroke and summarized emerging drug targets with a focus on clinical trials. These observations may help to further understand the pathological events in ischemic stroke and bridge the gap between basic and translational research to reveal novel neuroprotective interventions.

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Repurposing antimycotic ciclopirox olamine as a promising anti-ischemic stroke agent

Cited by 27 publications

References 53 publications

Activated PKB/GSK-3β synergizes with PKC-δ signaling in attenuating myocardial ischemia/reperfusion injury via potentiation of NRF2 activity: Therapeutic efficacy of dihydrotanshinone-I

Activated PKB/GSK-3β synergizes with PKC-δ signaling in attenuating myocardial ischemia/reperfusion injury via potentiation of NRF2 activity: Therapeutic efficacy of dihydrotanshinone-I

A novel PGAM5 inhibitor LFHP-1c protects blood–brain barrier integrity in ischemic stroke

Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications

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