Recently this laboratory, in collaboration with the Veterinary Clinical Sciences Department of Purdue University and the College of Veterinary Medicine at Texas A&M University, has shown that intravenous injections of an ~30% solution of polyethylene glycol (PEG; 3500路Da) in sterile saline can produce unexpected recovery of functions in naturally produced, severe, canine spinal cord injury. This occurred in neurologically complete, paraplegic dogs treated in a hospital setting (Laverty et al., 2004). Supportive laboratory animal data for initiating this preliminary clinical trial will be described below; however, the long record of safe usage of PEG in human medicine (Working et al., 1997) has pressed these experiments to the brink of human clinical trials in spinal cord injury (SCI) and traumatic brain injury (TBI) (Sofamor Danek/Medtronics Corporation).Though the behavioral responses to injected and topically applied PEG in various models of neurotrauma are consistently positive Here we provide further evidence that the ability of PEG to reduce or limit secondary injury and/or lipid peroxidation (LPO) of membranes requires entry of PEG into the cytosol, further suggesting a physical interaction with the membranes of organelles such as mitochondria as the initial event leading to neurorepair/neuroprotection.We have evaluated this relationship in vitro using acrolein, a potent endogenous toxin that is a product of LPO. Acrolein can pass through cell membranes with ease, inducing progressive LPO in 'bystander' cells, and the production of even more acrolein by inducing its own production. Immediate application of PEG (10路mmol路l -1 , 2000路Da) to poisoned neurons in vitro was unable to rescue them from necrosis and death. Furthermore, threedimensional confocal microscopy of fluorescently decorated PEG shows that it does not enter these cells for up to 2路h after application. By this time the mechanisms of necrosis are likely irreversible. Additionally, severe oxygen and or glucose deprivation of spinal cord white matter in vitro also initiates LPO. Addition of potent free radical scavengers such as ascorbic acid or superoxide dismutase (SOD) is able to interfere with this process, but PEG is not. Taken together, these data are consistent with the hypothesis that PEG is able to rescue mechanically damaged cells, based on a restructuring of the damaged plasmalemma. Furthermore, in compromised cells with an intact cell membrane, PEG must first gain access to the cytosol where this same capability may be useful in restoring the integrity of cellular organelles such as mitochondria, though the intracellular concentration of the polymer must be significant relative to the concentration of toxins produced by LPO in order to rescue the cell.