Lipid Peroxidation in Secondary Central Nervous System Injury

There is much we do not understand about the role of lipid peroxidation (LPO) during secondary injury after central nervous system (CNS) trauma. Although the general mechanisms of cellular destruction due to oxidative stress are well understood after spinal cord or traumatic brain injury, attempts to prevent this damage has not been very successful (Shi, Rickett and Sun 2011). The major goals of this thesis are to better understand the clinical progression of oxidative stress in vivo and evaluate potential therapeutic interventions. To better elucidate the clinical progression of oxidative stress we investigated a unique pathology occurring in dogs after spinal cord injury (SCI) called ascending-descending (A-D) myelomalacia. We compared dogs with severe SCI whose injuries remained localized to those that developed progressive A-D myelomalacia. We found that 8-isoprostane, a marker of LPO, was increased in dogs with A-D myelomalacia in urine while glutathione, an endogenous antioxidant, was reduced in damaged spinal cord tissue. A moderate increase in inflammation as observed by CD18 + leukocytes was seen in A-D myelomalacia (Marquis et al., 2015). We attempted to induce the pathology of progressive A-D myelomalacia in rodents after experimental traumatic SCI by recreating in situ the conditions of enhanced oxidative stress that have been observed in dogs and in humans as subacute progressive ascending myelopathy (Schmidt, 2006). We administrated acrolein, a well-known reactive aldehyde that causes lipid peroxidation during secondary injury, directly to the subarachnoid space of the spinal cord of guinea pigs after experimental SCI. Epinephrine was also applied topically to the spinal cord in order to trigger vasospasm in spinal cord vasculature. Rose Bengal, a photosensitive dye, was experimented with to create focal ischemia in the spinal cord (Borgens, Shi and Bohnert 2002) (Watson, et al. 1986) (Macdonald and Weir 1991). Findings indicate that A-D myelomalacia occurring in dogs and less frequently in humans is a unique instance of exacerbated oxidative stress after SCI intrinsic to these species. A promising approach to significantly reduce oxidative stress has been demonstrated by blocking acrolein in vitro and ex vivo (Hamann 2008). Using similar investigative techniques and biomarkers for oxidative stress in dogs, we evaluated the effect of acrolein and hydralazine, an acrolein scavenger, in vivo subacute and chronic spinal cord and brain injury in rodents. After experimental SCI in rats an increase in acrolein-modified proteins was observed. When an acrolein scavenger, hydralazine, was administered after experimental SCI we observed a significant reduction in cyst volume and increased sparing of intact spinal cord tissue (Park 2014)