title: 4-Phenylbutyric Acid (4-PBA) and Lithium Cooperatively Attenuate Cell Death during Oxygen-Glucose Deprivation (OGD) and Reoxygenation.
abstract: Hypoxia is an important cause of brain injury in ischemic stroke. It is known that endoplasmic reticulum (ER) stress is an important determinant of cell survival or death during hypoxia. However, the signaling pathways and molecular mechanisms involved remain to be studied in more detail. To investigate whether inhibition of ER stress promotes neuroprotection pathways, we applied an in vitro oxygen-glucose deprivation (OGD) followed by reoxygenation model of human SK-N-MC neuronal cell cultures in this study. Our results showed that neuronal cell death was induced in this model during the OGD reoxygenation by the sustained ER stress, but not during OGD phase. However, treatment of the cultures with lithium with the OGD reoxygenation insult did not result in neuroprotection, whereas concomitant treatment of chemical chaperon 4-phenylbutyric acid (4-PBA) provides protective effects in ER stress-exposed cells. Moreover, 4-PBA rescued ER stress-suppressed Akt protein biosynthesis, which works cooperatively with lithium in the activation of Akt downstream signaling by inhibition of autophagy-induced cell death. Taken together, our finding provides a possible mechanism by which 4-PBA and lithium contribute to mediate neuroprotection cooperatively. This result may potentially be a useful therapeutic strategy for ischemic stroke.
authors.affiliation: Section of Neurology, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan.
authors.forename: Wai-Fai
authors.initials: WF
authors.lastname: Tung
authors.forename: Wei-Jen
authors.initials: WJ
authors.lastname: Chen
authors.forename: Hui-Chih
authors.initials: HC
authors.lastname: Hung
authors.forename: Guang-Yaw
authors.initials: GY
authors.lastname: Liu
authors.forename: Jai-Nien
authors.initials: JN
authors.lastname: Tung
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Huang
authors.forename: Chih-Li
authors.initials: CL
authors.lastname: Lin
mesh_terms: D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008094:Lithium / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010654:Phenylbutyrates / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
chemical_list: D018696:Neuroprotective Agents; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D008094:Lithium; D005947:Glucose; D010100:Oxygen