Kollidon VA64, a Membrane-Resealing Agent, Reduces Histopathology and Improves Functional Outcome after Controlled Cortical Impact in Mice

Abstract

Loss of plasma membrane integrity is a feature of acute cellular injury/death in vitro and in vivo. Plasmalemma-resealing agents are protective in acute central nervous system injury models, but their ability to reseal cell membranes in vivo has not been reported. Using a mouse controlled cortical impact (CCI) model, we found that propidium iodide-positive (PI + ) cells pulse labeled at 6, 24, or 48 hours maintained a degenerative phenotype and disappeared from the injured brain by 7 days, suggesting that plasmalemma permeability is a biomarker of fatal cellular injury after CCI. Intravenous or intracerebroventricular administration of Kollidon VA64, poloxamer P188, or polyethylene glycol 8000 resealed injured cell membranes in vivo (P < 0.05 versus vehicle or poloxamer P407). Kollidon VA64 (1 mmol/L, 500 lL) administered intravenously to mice 1 hour after CCI significantly reduced acute cellular degeneration, chronic brain tissue damage, brain edema, blood-brain barrier damage, and postinjury motor deficits (all P < 0.05 versus vehicle). However, VA64 did not rescue pulse-labeled PI + cells from eventual demise. We conclude that PI permeability within 48 hours of CCI is a biomarker of eventual cell death/loss. Kollidon VA64 reduces secondary damage after CCI by mechanisms other than or in addition to resealing permeable cells.

Poloxamer 188 Attenuatesin vitroTraumatic Brain Injury-Induced Mitochondrial and Lysosomal Membrane Permeabilization Damage in Cultured Primary Neurons

“…However, plasmalemma resealing may not be sufficient for survival of injured cells. 7 In the current study, cultured primary neurons treated with post-injury P188 showed a remarkable recovery of the morphology characteristic of sham (uninjured) cells. Moreover, P188 treatment significantly attenuated cell death and LDH leakage in neurons following VCSD.…”

“…1,7 Previous experiments have tested poloxamer 188 following in vivo traumatic brain injury and these studies have indicated a therapeutic effect of the treatment. 7 The VCSD configuration applied to cells cultured on a rigid substrate is not intended to mimic explicitly the in vivo, three-dimensional tissue deformation that occurs during injury. 8,20 Rather, the mechanical loading profile was developed and used to replicate the characteristics of cellular injury observed in vivo.…”

“…6 The putative membrane-resealing agent P188 may repair injured (permeable) cells after controlled cortical impact in mice. 7 Using cortical and hippocampal neuron cultures, P188 was shown to protect neurons from excitotoxic or oxidative stress-related necrosis and electroporation by inserting the membrane and inhibiting membrane peroxidation. 5 Recently, in vitro models of mechanical injury have been developed via the utilization of an in vitro cell shearing device (VCSD).…”

HMGB1 a-Box Reverses Brain Edema and Deterioration of Neurological Function in a Traumatic Brain Injury Mouse Model

“…Motor test was performed as previously described [15]. Mice were gently grasped by the tail and placed on a 35 cm taut wire suspended between two upright wooden bars 50 cm above a padded table.…”

PEG-PDLLA Micelle Treatment Improves Axonal Function of the Corpus Callosum following Traumatic Brain Injury

“…39 Furthermore, it seems that neurons with plasmalemma damage will inevitably degenerate and die by 7 days after CCI, even though some neurons are found to undergo spontaneous resealing of the damaged plasma membrane, suggesting that permeable plasmalemma after TBI is probably fatal to neurons. 13,40 Similarly, although the ruptured somata membrane could be repaired by using a membrane-resealing agent Kollidon VA64, such effective repairing of the membrane does not rescue the injured neurons. 40 Repairing the injured CNS remains a major challenge in neurotrauma research.…”