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

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 an...

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Bibliographic Details
Published in:The Journal of neuroscience 2013-07, Vol.33 (30), p.12287-12299
Main Authors: Shelat, Phullara B, Plant, Leigh D, Wang, Janice C, Lee, Elizabeth, Marks, Jeremy D
Format: Article
Language:English
Subjects:
Amino Acid Chloromethyl Ketones - pharmacology
Animals
Apoptosis - drug effects
Apoptosis - physiology
bcl-2-Associated X Protein - metabolism
Caspase 1 - metabolism
Caspase Inhibitors - pharmacology
Cell Hypoxia - drug effects
Cell Hypoxia - physiology
Cytochromes c - metabolism
Enzyme Activation - drug effects
Enzyme Activation - physiology
Female
Fetus - cytology
Glucose - metabolism
Glucose - pharmacology
Hippocampus - cytology
Male
Membrane Potentials - drug effects
Membrane Potentials - physiology
Mitochondria - metabolism
Neurons - cytology
Neurons - drug effects
Neurons - physiology
Oxygen - metabolism
Oxygen - pharmacology
Patch-Clamp Techniques
Polyethylene Glycols - pharmacology
Pregnancy
Primary Cell Culture
Propylene Glycols - pharmacology
Rats
Rats, Sprague-Dawley
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Summary: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.
ISSN:0270-6474
1529-2401
1529-2401
DOI:10.1523/jneurosci.5731-12.2013