title: Poloxamer 188 Attenuates Cerebral Hypoxia/Ischemia Injury in Parallel with Preventing Mitochondrial Membrane Permeabilization and Autophagic Activation.
abstract: While the previous studies have shown poloxamer 188 (P188)'s neuroprotection in cultured HT22 cells under oxygen-glucose deprivation (OGD) insults, we investigated whether P188 is a potential neuroprotective agent in primary cortical neurons (PCNs) and in cerebral ischemia in vivo and whether the possible underlying mechanisms correlate with regulating mitochondrial membrane permeability (MMP) and autophagy. The protective effects of P188 were tested in PCNs in vitro exposed to OGD, as well as in cerebral ischemia in vivo. Cell death and viability were detected with LDH and MTT assay, and mitochondrial membrane potential was assessed using fluorescence microscopy. The apoptosis and autophagy of PCNs were investigated by expressions of cyt-c, caspase-3, light chain 3 (LC3), and Beclin-1. In addition, a mouse middle cerebral artery occlusion (MCAO) model was used to produce focal ischemia, and mice were treated with P188 and rapamycin after MCAO 10 min. The infarct volume, neurological scores, and phosphorylation of mammalian target of rapamycin (mTOR) were evaluated. The in vitro results showed that P188 prevented OGD-induced primary cerebrocortical neuron death and inhibited loss of mitochondrial membrane potential, the release of mitochondrial apoptogenic factor cytochrome c from mitochondria to the cytoplasm, and activation of caspase-3. P188 suppressed the activation of autophagy by decreasing LC3-II and Beclin-1 levels under OGD accordingly. Moreover, the in vivo results showed that P188 and rapamycin remarkably reduced the infarct volume and neurological deficits in the MCAO mouse model of cerebral ischemia, respectively. Both P188 and rapamycin induced phosphorylation of mTOR and reversed the decreased level upon MCAO. These data indicate that P188 prevents neuronal cell death resulting from ischemic brain injury and that its neuroprotective effects are mediated by preventing mitochondrial membrane integrity damage and autophagic activation. Given that it has low toxicity, P188 might become a potential novel therapy for ischemic injury.
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, 215123, China.
authors.forename: Chengliang
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Forensic Medicine, Wannan Medical College, Wuhu, 241002, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, 215123, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, 215123, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, 215123, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, 215123, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, 215123, China.
authors.forename: Zufeng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, 215123, China.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Forensic Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Ziqin
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, 215123, China. xipingchen@suda.edu.cn.
authors.forename: Xiping
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou, 215123, China. taoluyang@suda.edu.cn.
authors.forename: Luyang
authors.initials: L
authors.lastname: Tao
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002478:Cells, Cultured; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020442:Poloxamer / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D020442:Poloxamer