title: The membrane-active tri-block copolymer pluronic F-68 profoundly rescues rat hippocampal neurons from oxygen-glucose deprivation-induced death through early inhibition of apoptosis.
abstract: Pluronic F-68, an 80% hydrophilic member of the Pluronic family of polyethylene-polypropylene-polyethylene tri-block copolymers, protects non-neuronal cells from traumatic injuries and rescues hippocampal neurons from excitotoxic and oxidative insults. F-68 interacts directly with lipid membranes and restores membrane function after direct membrane damage. Here, we demonstrate the efficacy of Pluronic F-68 in rescuing rat hippocampal neurons from apoptosis after oxygen-glucose deprivation (OGD). OGD progressively decreased neuronal survival over 48 h in a severity-dependent manner, the majority of cell death occurring after 12 h after OGD. Administration of F-68 for 48 h after OGD rescued neurons from death in a dose-dependent manner. At its optimal concentration (30 μm), F-68 rescued all neurons that would have died after the first hour after OGD. This level of rescue persisted when F-68 administration was delayed 12 h after OGD. F-68 did not alter electrophysiological parameters controlling excitability, NMDA receptor-activated currents, or NMDA-induced increases in cytosolic calcium concentrations. However, F-68 treatment prevented phosphatidylserine externalization, caspase activation, loss of mitochondrial membrane potential, and BAX translocation to mitochondria, indicating that F-68 alters apoptotic mechanisms early in the intrinsic pathway of apoptosis. The profound neuronal rescue provided by F-68 after OGD and the high level of efficacy with delayed administration indicate that Pluronic copolymers may provide a novel, membrane-targeted approach to rescuing neurons after brain ischemia. The ability of membrane-active agents to block apoptosis suggests that membranes or their lipid components play prominent roles in injury-induced apoptosis.
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Phullara B
authors.initials: PB
authors.lastname: Shelat
authors.forename: Leigh D
authors.initials: LD
authors.lastname: Plant
authors.forename: Janice C
authors.initials: JC
authors.lastname: Wang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lee
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Marks
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005333:Fetus / Q000166:cytology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011247:Pregnancy; D061251:Primary Cell Culture; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; C116176:PEO-PPO-PEO; D011409:Propylene Glycols; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D011092:Polyethylene Glycols; D045304:Cytochromes c; D020170:Caspase 1; D005947:Glucose; D010100:Oxygen