Sodium 4-phenylbutyrate protects against spinal cord ischemia by inhibition of endoplasmic reticulum stress

ObjectiveDelayed paraplegia after operation on the thoracoabdominal aorta is considered to be related to vulnerability of motor neurons to ischemia. Previous studies have demonstrated the relationship between neuronal vulnerability and endoplasmic reticulum (ER) stress after transient ischemia in the spinal cord. The aim of this study was to investigate whether sodium 4-phenylbutyrate (PBA), a chemical chaperone that reduces the load of mutant or unfolded proteins retained in the ER during cellular stress, can protect against ischemic spinal cord damage.MethodsSpinal cord ischemia was induced in rabbits by direct aortic cross-clamping (below the renal artery and above the bifurcation) for 15 minutes at normothermia. Group A (n = 6) was a sham operation control group. In group B (n = 6) and group C (n = 6), vehicle or 15 mg/kg/h of sodium 4-PBA was infused intravenously, respectively, from 30 minutes before the induction of ischemia until 30 minutes after reperfusion. Neurologic function was assessed at 8 hours, and 2 and 7 days after reperfusion with a Tarlov score. Histologic changes were studied with hematoxylin-eosin staining. Immunohistochemistry analysis for ER stress-related molecules, including caspase12 and GRP78 were examined.ResultsThe mean Tarlov scores were 4.0 in every group at 8 hours, but were 4.0, 2.5, and 3.9 at 2 days; and 4.0, 0.7, and 4.0 at 7 days in groups A, B, and C, respectively. The numbers of intact motor neurons at 7 days after reperfusion were 47.4, 21.5, and 44.9 in groups A, B, and C, respectively. There was no significant difference in terms of viable neurons between groups A and C. Caspase12 and GRP78 immunoreactivities were induced in motor neurons in group B, whereas they were not observed in groups A and C.ConclusionReduction in ER stress-induced spinal cord injury was achieved by the administration of 4-PBA. 4-PBA may be a strong candidate for use as a therapeutic agent in the treatment of ischemic spinal cord injury.

Clinical RelevanceSpinal cord injury following surgical repair of thoracic or thoracoabdominal aorta is a disastrous complication. Previous studies have demonstrated the relationship between neuronal vulnerability and endoplasmic reticulum (ER) stress after transient ischemia of spinal cord. Sodium 4-phenylbutyrate (4-PBA) is a low molecular weight fatty acid that has been approved for clinical use as an ammonia scavenger in children with urea cycle disorders and for treatment of sickle cell disease and thalassemia. A number of investigators have recently reported utilization of 4-PBA as a chemical chaperone to reverse the mislocalization and/or aggregation of proteins associated with human disease. The 4-PBA of therapeutic dose has low toxicity and uniquely penetrates well into cerebrospinal fluid. In this study, we investigated whether intravenous administration of 4-PBA is beneficial to protecting the spinal cord against ischemic damage in a rabbit model. Spinal cord ischemia was induced by direct aortic cross-clamping while 4-PBA of therapeutic dose was infused intravenously. In this simple and less invasive model, reduction in ER stress-induced spinal cord damage was achieved by intravenous 4-PBA. Our results indicate that 4-PBA of therapeutic dose can be a promising strategy, which is clinically feasible without significant adverse effects. Although further investigations are mandatory before it is applied to the clinical practice, such as optimal timing or route for administration 4-PBA, intravenous administration of 4-PBA may be a new candidate as a therapeutic agent for protecting the spinal card against ischemic damage in thoracoabdominal aortic surgery.