Abstract
In a previous study, we utilized a proteomic approach and found a significant reduction in phosphatidylethanolamine-binding protein 1 (PEBP1) protein level in the spinal cord at 3 h after ischemia. In the present study, we investigated the role of PEBP1 against oxidative stress in NSC34 cells in vitro, and ischemic damage in the rabbit spinal cord in vivo. We generated a PEP-1-PEBP1 fusion protein to facilitate the penetration of blood-brain barrier and intracellular delivery of PEBP1 protein. Treatment with PEP-1-PEBP1 significantly decreased cell death and the induction of oxidative stress in NSC34 cells. Furthermore, administering PEP-1-PEBP1 did not show any significant side effects immediately before and after ischemia/reperfusion. Administration of PEP-PEBP1 improved the Tarlov’s neurological score at 24 and 72 h after ischemia, and significantly improved neuronal survival at 72 h after ischemia based on neuronal nuclei (NeuN) immunohistochemistry, Flouro-Jade B staining, and western blot study for cleaved caspase 3. PEP-1-PEBP1 administration decreased oxidative stress based on malondialdehyde level, advanced oxidation protein products, and 8-iso-prostaglandin F2α in the spinal cord. In addition, inflammation based on myeloperoxidase level, tumor necrosis factor-α level, and high mobility group box 1 level was decreased by PEP-1-PEBP1 treatment at 72 h after ischemia. Thus, PEP-1-PEBP1 treatment, which decreases oxidative stress, inflammatory cytokines, and neuronal death, may be an effective therapeutic strategy for spinal cord ischemia.
Highlights
Interruption of the aorta or its segmental arteries results devastating and unpredictable complications, such as paraplegia caused by ischemia in spinal cord [1] during en bloc spondylectomy or aortic repair surgery [2,3]
phosphatidylethanolamine-binding protein 1 (PEBP1) is involved in neuronal cell death and cognitive deficits in neurodegenerative diseases [27]
Our previous proteomic study demonstrated that PEBP1 expression was decreased in the spinal cord 3 h after ischemia [15], and we observed PEP-1-PEBP1 protected pyramidal neurons from transient forebrain ischemia in gerbils [16]
Summary
Interruption of the aorta or its segmental arteries results devastating and unpredictable complications, such as paraplegia caused by ischemia in spinal cord [1] during en bloc spondylectomy or aortic repair surgery [2,3]. Transient occlusion of aorta causes decreased blood flow in the spinal cord, and increases the cellular damage in the motor neurons of spinal cord [4]. The more caudal origin of the Adamkiewicz artery compared to that of other mammals is the rationale for using rabbits as an animal model for ischemia in the caudal half of the spinal cord [5]. Neurons have many unsaturated fatty acids and utilize glucose as an energy source, and an interruption of blood supply and reoxygenation enormously increases the formation of ROS [9]. PEBP1 stimulates acetylcholine synthesis in the median septal nuclei [10] and PEBP1 expression is decreased in hippocampus of Alzheimer patients [11]
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