HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

AbstractOBJECTIVE:
Delayed 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.
METHODS:
Spinal 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.
RESULTS:
The 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.
CONCLUSION:
Reduction 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.
AuthorsTaketomo Mizukami, Kazumasa Orihashi, Bagus Herlambang, Shinya Takahashi, Makoto Hamaishi, Kenji Okada, Taijiro Sueda
JournalJournal of vascular surgery (J Vasc Surg) Vol. 52 Issue 6 Pg. 1580-6 (Dec 2010) ISSN: 1097-6809 [Electronic] United States
PMID20843623 (Publication Type: Journal Article)
CopyrightCopyright © 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.
Chemical References
  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins
  • Phenylbutyrates
  • 4-phenylbutyric acid
  • Caspase 12
Topics
  • Animals
  • Aorta, Abdominal (physiology)
  • Aortic Aneurysm (surgery)
  • Apoptosis
  • Caspase 12 (metabolism)
  • Constriction
  • Endoplasmic Reticulum (drug effects, pathology, physiology)
  • Endoplasmic Reticulum Chaperone BiP
  • Female
  • Heat-Shock Proteins (metabolism)
  • Immunohistochemistry
  • Infusions, Intravenous
  • Paraparesis (etiology, pathology, prevention & control)
  • Phenylbutyrates (administration & dosage, therapeutic use)
  • Rabbits
  • Spinal Cord (pathology)
  • Spinal Cord Ischemia (etiology, pathology, prevention & control)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: