Neuroprotection by a bile acid in an acute stroke model in the rat.

Abstract

Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, is a strong modulator of apoptosis in both hepatic and nonhepatic cells, and appears to function by inhibiting mitochondrial membrane perturbation. Excitotoxicity, metabolic compromise, and oxidative stress are major determinants of cell death after brain ischemia-reperfusion injury. However, some neurons undergo delayed cell death that is characteristic of apoptosis. Therefore, the authors examined whether TUDCA could reduce the injury associated with acute stroke in a well-characterized model of transient focal cerebral ischemia. Their model of middle cerebral artery occlusion resulted in marked cell death with prominent terminal deoxynucleotidyl transferase-mediated 2;-deoxyuridine 5;-triphosphate-biotin nick end labeling (TUNEL) within the ischemic penumbra, mitochondrial swelling, and caspase activation. Tauroursodeoxycholic acid administered 1 hour after ischemia resulted in significantly increased bile acid levels in the brain, improved neurologic function, and an approximately 50% reduction in infarct size 2 and 7 days after reperfusion. In addition, TUDCA significantly reduced the number of TUNEL-positive brain cells, mitochondrial swelling, and partially inhibited caspase-3 processing and substrate cleavage. These findings suggest that the mechanism for in vivo neuroprotection by TUDCA is, in part, mediated by inhibition of mitochondrial perturbation and subsequent caspase activation leading to apoptotic cell death. Thus, TUDCA, a clinically safe molecule, may be useful in the treatment of stroke and possibly other apoptosis-associated acute and chronic injuries to the brain.

• Authors: Cecilia M P Rodrigues, Stephen R Spellman, Susana Solá, Andrew W Grande, Cheryle Linehan-Stieers, Walter C Low, Clifford J Steer
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 22 Issue 4 Pg. 463-71 (Apr 2002) ISSN: 0271-678X [Print] United States
• PMID: 11919517 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cholagogues and Choleretics
• Neuroprotective Agents
• Taurochenodeoxycholic Acid
• ursodoxicoltaurine
• Poly(ADP-ribose) Polymerases
• Caspases

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Brain (drug effects, pathology, physiopathology)
• Caspases (metabolism)
• Cholagogues and Choleretics (pharmacology)
• Disease Models, Animal
• In Situ Nick-End Labeling
• Infarction, Middle Cerebral Artery
• Male
• Mitochondria (metabolism)
• Neurons (drug effects, metabolism, ultrastructure)
• Neuroprotective Agents (pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Rats
• Rats, Sprague-Dawley
• Stroke (pathology, physiopathology)
• Taurochenodeoxycholic Acid (pharmacology)