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

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.

Potential Effects of Poloxamer 188 on Rat Isolated Brain Mitochondria after Oxidative Stress In Vivo and In Vitro

“…The triblock copolymer P188 has been shown to rescue a variety of tissues and cell types from I/R injury in different settings [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 36 , 37 , 38 ]. More recently, profound improvements in mitochondrial function through P188 after I/R injury have become apparent [ 9 , 10 , 11 , 12 , 18 , 39 , 40 ], suggesting possible direct interactions of P188 with mitochondria, specifically by stabilizing their membrane.…”

“…P188′s superb protective effects after I/R injury have been recreated in various experimental settings [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 36 , 37 , 38 ]. Therefore, injuring mitochondria in a way that mimics the patho-physiological processes of I/R in living cells was the premise to show any direct effects of P188 on mitochondria.…”

“…These results led to the hypothesis that mitochondria might be directly affected by P188 and consequently led to the present study. Bartos et al, however, were not the only ones that specifically examined mitochondrial function after treating animals or cell cultures with P188 [ 10 , 11 , 12 , 18 , 39 , 40 , 54 , 55 ].…”

“…These results prove to be highly concordant with Shelat et al’s, accentuating the potential for direct interaction of P188 with mitochondria [ 40 ]. In addition, in a study by Wang et al, embryonic rat hippocampal cells were exposed to 45 min of OGD followed by 2 h of reoxygenation and incubation with fluorescently labeled P188 [ 18 ]. Wang et al were able to observe that P188 localizes to neuronal mitochondria but only in cells subjected to OGD [ 18 ].…”

“…Although the triblock copolymer Poloxamer (P)188, an amphiphilic triblock copolymer, has been shown to protect different cell types, likely based on its cell-membrane-sealing effect [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ], the frequently observed beneficial effect on mitochondrial function remains intriguing [ 9 , 18 ]. It is possible that the protection of cell membranes with subsequent cellular recovery generally leads to better preserved mitochondrial function as an indirect, downstream consequence.…”