Evaluation of Polyethylene Glycol as a Neuroprotective Strategy for Acute Spinal Cord Injury

The pathophysiology of traumatic spinal cord injury (SCI) involves abnormal activation of the proteolytical enzymes calpain-1 and caspase-3. In the present study we examined the effect of a single intravenous injection of the putative neuroprotective compound polyethylene glycol (PEG) on cytoskeletal protection following cervical SCI in mature Wistar rats.

PEG (2000 Da; 30% w/w in sterile lactate ringers (SLR)) or SLR vehicle was administered in the rat tail vein at times 1 or 4 hours after a 35g clip extradural compression injury at C7/T1. To assess the neuroprotective efficacy of PEG in the acute setting postinjury, we measured the levels of dephosphorylated neurofilament 200 (NF200) together with the accumulation of spectrin break down product 150 (SBDP 150) at times 2, 4, 8, or 24 hours post-SCI using Western blot approaches to assess calpain-1 activity. Western blots were also used to assess caspase-3 activity at 24 hours post-SCI via measurement of the accumulation of processed 17-kDa caspase-3 fragments. The mean ± SEM relative optical density values for dephosphorylated NF200 corresponding to the SLR and PEG treatments at times 2, 4, 8, and 24 hours post-SCI were 0.64 ± 0.049 and 0.48 ± 0.166, 0.3 ± 0.028 and 0.48 ± 0.134, 0.33 ± 0.077 and 0.46 ± 0.076, and 0.24 ± 0.018 and 0.38 ± 0.040, respectively. Moreover, the levels of dephosphorylated NF200 were significantly greater following PEG-treatment by 24 hours post-SCI (p = 0.0362). Moreover, PEG-mediated preservation of dephosphorylated NF200 was correlated with reduced calpain-1 activity at 2 and 4 hours post-SCI. Furthermore, PEG treatment resulted in reduced levels of accumulated 17-kDa caspase-3 fragments.

In conclusion, these data obtained in a clinically relevant model of cervical SCI suggest that PEG protects the injured cord by preserving cytoskeletal protein NF200, possibly through reducing calpain-1 and caspase-3 activities. Moreover, the protective effects afforded by PEG may occur within a relevant therapeutic window of opportunity, as the efficacy of PEG treatments occurred even when the drug was administered 4 hours postinjury. These data are critical in establishing the therapeutic potential for translation of PEG into the clinical arena.