ursodoxicoltaurine and Cerebral-Hemorrhage

Intracerebral hemorrhage (ICH) is a form of stroke, characterized by high morbidity and mortality and currently lacks specific therapy. ICH leads to endoplasmic reticulum (ER) stress, which can induce neurological impairment through crosstalk with programmed cell death (PCD). Pyroptosis, a newly discovered form of PCD, has received attention because of its close relationship with some certain diseases, such as traumatic brain injury and ischemic and hemorrhagic stroke. However, the relationship between ER stress and pyroptosis in ICH remains unclear. In this study, we investigated the role of ER stress in evoking neuronal pyroptosis and related mechanisms in a mouse ICH model. We used tauroursodeoxycholic acid (TUDCA) to inhibit ER stress and observed that TUDCA reduces neuronal pyroptosis and has a neuroprotective role. We explored the potential mechanisms underlying the regulation of neuronal pyroptosis by ER stress through testing the expression of interleukin-13 (IL-13). We found that ER stress inhibition alleviates neuronal pyroptosis through decreasing the expression of IL-13 after ICH. In summary, this study revealed that IL-13 is involved in ER stress-induced neuronal pyroptosis after ICH, pointing to IL-13 as a novel therapeutic target for ICH treatment.

Topics: Animals; Brain Edema; Cell Membrane; Cerebral Hemorrhage; Collagenases; Disease Models, Animal; Endoplasmic Reticulum Stress; Interleukin-13; Male; Mice, Inbred C57BL; Models, Biological; Motor Activity; Neurons; Neuroprotective Agents; Pyroptosis; Spatial Memory; Stroke; Taurochenodeoxycholic Acid

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.

Topics: Animals; Apoptosis; Bile; Brain; Caspases; Cerebral Hemorrhage; Cholagogues and Choleretics; Collagenases; Disease Models, Animal; DNA Primers; Female; In Situ Nick-End Labeling; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Substrate Specificity; Taurochenodeoxycholic Acid