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

Abstract

Outcome after cerebral ischemia is often dismal. Reperfusion adds significantly to the ischemic injury itself. Therefore, new strategies targeting ischemia/reperfusion (I/R) injury are critically needed. Poloxamer (P)188, an amphiphilic triblock copolymer, is a highly promising pharmacological therapeutic as its capability to insert into injured cell membranes has been reported to protect against I/R injury in various models. Although mitochondrial function particularly profits from P188 treatment after I/R, it remains unclear if this beneficial effect occurs directly or indirectly. Here, rat isolated brain mitochondria underwent oxidative stress in vivo by asphyxial cardiac arrest or in vitro by the addition of hydrogen peroxide (H2O2) after isolation. Mitochondrial function was assessed by adenosine triphosphate synthesis, oxygen consumption, and calcium retention capacity. Both asphyxia and H2O2 exposure significantly impaired mitochondrial function. P188 did not preserve mitochondrial function after either injury mechanism. Further research is indicated.

No Direct Postconditioning Effect of Poloxamer 188 on Mitochondrial Function after Ischemia Reperfusion Injury in Rat Isolated Hearts

“…A bigger sample size might be able to assert whether P188 has a direct impact on mitochondrial IR injury but with the current set of data, this seems unlikely. Albeit disappointing, this matches recent findings by Pille and Riess in rat isolated brain mitochondria [ 28 ].…”

“…in-vivo early upon reperfusion and improved CRC but did not see similar results with PEG or delayed P188 treatment [ 16 ]. Similar to our own model, isolated brain mitochondria could not mirror the promising beneficial effects of P188 on CRC [ 28 ].…”

“…Complex I’s vulnerability to acidosis and oxidative damage may be a cardioprotective reaction to limit Ca 2+ -overload and ROS production during reperfusion [ 4 , 5 ]. Incidentally, injured, healthy and P188-treated mitochondria showed no difference in a similar assay in isolated mitochondria from a rat brain [ 28 ].…”

“…In recent years, a few studies have been conducted with isolated mitochondria to determine direct mitochondrial protection of P188. A study by Pille and Riess [ 28 ] could not duplicate the benefits of P188 in rat isolated brain mitochondria that Wang et al [ 18 ] reported. Tests for mitochondrial function (CRC, ATP synthesis and O 2 -consumption) did not improve upon treatment with 250 µM P188 during reperfusion.…”

“…Our study also used a complex injury mechanism that could very closely resemble in-vivo IR injury by subjecting the ex-vivo isolated rat heart to 30 min of ischemia with 10 min of reperfusion. In contrast to Pille and Riess [ 28 ], our mitochondria were subjected to both the ischemic injury and reperfusion before they were isolated. This way, we tried to account for mitochondrial damage that might only occur in the intact cell and organ.…”