Mitochondrial mechanisms of neuronal rescue by F-68, a hydrophilic Pluronic block co-polymer, following acute substrate deprivation

Neurochem Int. 2017 Oct:109:126-140. doi: 10.1016/j.neuint.2017.04.007. Epub 2017 Apr 19.

Abstract

Global brain ischemia can lead to widespread neuronal death and poor neurologic outcomes in patients. Despite detailed understanding of the cellular and molecular mechanisms mediating neuronal death following focal and global brain hypoxia-ischemia, treatments to reduce ischemia-induced brain injury remain elusive. One pathway central to neuronal death following global brain ischemia is mitochondrial dysfunction, one consequence of which is the cascade of intracellular events leading to mitochondrial outer membrane permeabilization. A novel approach to rescuing injured neurons from death involves targeting cellular membranes using a class of synthetic molecules called Pluronics. Pluronics are triblock copolymers of hydrophilic poly[ethylene oxide] (PEO) and hydrophobic poly[propylene oxide] (PPO). Evidence is accumulating to suggest that hydrophilic Pluronics rescue injured neurons from death following substrate deprivation by preventing mitochondrial dysfunction. Here, we will review current understanding of the nature of interaction of Pluronic molecules with biological membranes and the efficacy of F-68, an 80% hydrophilic Pluronic, in rescuing neurons from injury. We will review data indicating that F-68 reduces mitochondrial dysfunction and mitochondria-dependent death pathways in a model of neuronal injury in vitro, and present new evidence that F-68 acts directly on mitochondria to inhibit mitochondrial outer membrane permeabilization. Finally, we will present results of a pilot, proof-of-principle study suggesting that F-68 is effective in reducing hippocampal injury induced by transient global ischemia in vivo. By targeting mitochondrial dysfunction, F-68 and other Pluronic molecules constitute an exciting new approach to rescuing neurons from acute injury.

Keywords: Apoptosis; Hippocampal neurons; MOMP; Poloxamer 188; Poloxamer 188 (Pluronic F-68) (PubChem CID: 10129990 (PEG-PPG-PEG)); STORM super resolution microscopy.

Publication types

  • Review

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Gerbillinae
  • Humans
  • Hydrophobic and Hydrophilic Interactions / drug effects
  • Male
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Membranes / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Pilot Projects
  • Polyethylene Glycols / chemistry*
  • Polyethylene Glycols / metabolism
  • Polyethylene Glycols / pharmacology*
  • Propylene Glycols / chemistry*
  • Propylene Glycols / metabolism
  • Propylene Glycols / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Substrate Specificity / drug effects
  • Substrate Specificity / physiology

Substances

  • PEO-PPO-PEO
  • Propylene Glycols
  • Polyethylene Glycols