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

Cecilia M.P. Rodrigues, Susana Solá, Zhenhong Nan, Rui E. Castro, Paulo S. Ribeiro, Walter C Low, Clifford J Steer

Research output: Contribution to journalArticle

141 Scopus citations

Abstract

Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, modulates cell death by interrupting classic pathways of apoptosis. Intracerebral hemorrhage (ICH) is a devastating acute neurological disorder, without effective treatment, in which a significant loss of neuronal cells is thought to occur by apoptosis. In this study, we evaluated whether TUDCA can reduce brain injury and improve neurological function after ICH in rats. Administration of TUDCA before or up to 6 h after stereotaxic collagenase injection into the striatum reduced lesion volumes at 2 days by as much as 50%. Apoptosis was ≈50% decreased in the area immediately surrounding the hematoma and was associated with a similar inhibition of caspase activity. These changes were also associated with improved neurobehavioral deficits as assessed by rotational asymmetry, limb placement, and stepping ability. Furthermore, TUDCA treatment modulated expression of certain Bcl-2 family members, as well as NF-κB activity. In addition to its protective action at the mitochondrial membrane, TUDCA also activated the Akt-1/protein kinase Bα survival pathway and induced Bad phosphorylation at Ser-136. In conclusion, reduction of brain injury underlies the wide-range neuroprotective effects of TUDCA after ICH. Thus, given its clinical safety, TUDCA may provide a potentially useful treatment in patients with hemorrhagic stroke and perhaps other acute brain injuries associated with cell death by apoptosis.

Original languageEnglish (US)
Pages (from-to)6087-6092
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number10
DOIs
StatePublished - May 13 2003

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