Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats.
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 approximately 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-kappaB activity. In addition to its protective action at the mitochondrial membrane, TUDCA also activated the Akt-1protein kinase Balpha 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.
Department of Medicine, University of Minnesota Medical School, Minneapolis 55455, USA.
Cecilia M P
CM
Rodrigues
Susana
S
Sola
Zhenhong
Z
Nan
Rui E
RE
Castro
Paulo S
PS
Ribeiro
Walter C
WC
Low
Clifford J
CJ
Steer
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001646:Bile / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D002756:Cholagogues and Choleretics / Q000627:therapeutic use; D017364:Collagenases; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D020287:In Situ Nick-End Labeling; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity; D013655:Taurochenodeoxycholic Acid / Q000627:therapeutic use*
D002756:Cholagogues and Choleretics; D017931:DNA Primers; D019253:Proto-Oncogene Proteins c-bcl-2; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D020169:Caspases; D017364:Collagenases