摘要
Ischemic stroke is a severe disorder resulting from acute cerebral thrombosis.Here we demonstrated that post-ischemic treatment with ciclopirox olamine(CPX),a potent antifungal clinical drug,alleviated brain infarction,neurological deficits and brain edema in a classic rat model of ischemic stroke.Single dose post-ischemic administration of CPX provided a long-lasting neuroprotective effect,which can be further enhanced by multiple doses administration of CPX.CPX also effectively reversed ischemia-induced neuronal loss,glial activation as well as blood-brain barrier(BBB)damage.Employing quantitative phosphoproteomic analysis,130 phosphosites in 122 proteins were identified to be significantly regulated by CPX treatment in oxygen glucose deprivation(OGD)-exposed SH-SY5 Y cells,which revealed that phosphokinases and cell cycle-related phosphoproteins were largely influenced.Subsequently,we demonstrated that CPX markedly enhanced the AKT(protein kinase B,PKB/AKT)and GSK3β(glycogen synthase kinase 3β)phosphorylation in OGD-exposed SH-SY5 Y cells,and regulated the cell cycle progression and nitric oxide(NO)release in lipopolysaccharide(LPS)-induced B V-2 cells,which may contribute to its ameliorative effects against ischemia-associated neuronal death and microglial inflammation.Our study suggests that CPX could be a promising compound to reduce multiple ischemic injuries;however,further studies will be needed to clarify the molecular mechanisms involved.
Ischemic stroke is a severe disorder resulting from acute cerebral thrombosis.Here we demonstrated that post-ischemic treatment with ciclopirox olamine(CPX),a potent antifungal clinical drug,alleviated brain infarction,neurological deficits and brain edema in a classic rat model of ischemic stroke.Single dose post-ischemic administration of CPX provided a long-lasting neuroprotective effect,which can be further enhanced by multiple doses administration of CPX.CPX also effectively reversed ischemia-induced neuronal loss,glial activation as well as blood-brain barrier(BBB) damage.Employing quantitative phosphoproteomic analysis,130 phosphosites in 122 proteins were identified to be significantly regulated by CPX treatment in oxygen glucose deprivation(OGD)-exposed SH-SY5 Y cells,which revealed that phosphokinases and cell cycle-related phosphoproteins were largely influenced.Subsequently,we demonstrated that CPX markedly enhanced the AKT(protein kinase B,PKB/AKT) and GSK3β(glycogen synthase kinase 3β) phosphorylation in OGD-exposed SH-SY5 Y cells,and regulated the cell cycle progression and nitric oxide(NO) release in lipopolysaccharide(LPS)-induced B V-2 cells,which may contribute to its ameliorative effects against ischemia-associated neuronal death and microglial inflammation.Our study suggests that CPX could be a promising compound to reduce multiple ischemic injuries;however,further studies will be needed to clarify the molecular mechanisms involved.
基金
supported by the National Natural Science Foundation of China(Nos.81872859,81661148046,81522045,and 81703507)
the National Special Fund for State Key Laboratory of Bioreactor Engineering(No.2060204,China)
the National R&D Projects for major research instruments(ZDYZ2013-1,China)
the Institutional Technology Service Center of Shanghai Institute of Materia Medica,Chinese Academy of Sciences for technical support.
作者简介
Hongxuan Feng,These authors made equal contributions to this work;Linghao Hu,These authors made equal contributions to this work;Hongwen Zhu,These authors made equal contributions to this work;Lingxue Tao,These authors made equal contributions to this work;Corresponding authors:Hu Zhou,Tel./fax:+862150806710.E-mail addresses:zhouhu@simm.ac.cn;Corresponding authors:Jian Li,E-mail addresses:jianli@ecust.edu.cn;Corresponding authors:Haiyan Zhang,E-mail addresses:hzhang@simm.ac.cn
