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.

Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats

“…Furthermore, TUDCA reduced apoptosis, infarct volumes, and neurobehavioral impairment in an ischemia͞reperfusion model of stroke (24). The present study extends our previous reports and shows a neuroprotective effect of TUDCA in an ICH model of stroke.…”

“…They may also significantly modulate the mitogen-activated protein kinase survival pathway (21). Finally, TUDCA is neuroprotective not only in pharmacologic and transgenic animal models of Huntington disease (22,23), but also for acute ischemic stroke (24). The bile acid reduced infarct size and improved neurological function, while significantly preserving mitochondrial membrane stability and inhibiting caspase activation.…”

Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease

“…Previous studies with TUDCA have focused on the antiapoptotic and cytoprotective effects in hepatic systems, and most recently in acute stroke (61). This study, combined with previous work in the 3-NP rat model (32), supports the continued evaluation of TUDCA for the treatment of HD.…”

Mannitol enhances delivery of marrow stromal cells to the brain after experimental intracerebral hemorrhage

“…These small chemicals apparently attenuate the endoplasmic reticulum stress, one of the universal inducers of cell death. Recent pre-clinical studies support the possibility of using these small chemicals to treat or delay cell injury (Rodrigues et al, 2002). However, to our knowledge, mannitol, which is similar to tauroursodeoxycholic acid, has not been shown to be a classic chaperone (Scumpia et al, 2007).…”