Tauroursodeoxycholic acid prevents ER stress-induced apoptosis and improves cerebral and vascular function in mice subjected to subarachnoid hemorrhage

Chen, Xin; Wang, Jianhao; Gao, Xiangyang; Wu, Ye; Gu, Gang; Shi, Mingming; Chai, Yan; Yue, Shuyuan; Zhang, Jianning

doi:10.1016/j.brainres.2019.146566

Cited by 26 publications

(17 citation statements)

References 32 publications

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“…Here, we indeed found that TBI induced ROS production followed by UPR signaling. However, suppression of acute MAM formation alleviated ROS-dependent ER stress and reduced BBB leakage, which is also supported by our previous study on subarachnoid hemorrhage (SAH) that found that ER stress inhibitors attenuated acute brain injury by rescuing cerebrovascular dysfunction [41]. Recent reports note that inhibiting ER stress restores the dysfunction of retinal endothelial cells by decreasing NO production and downregulating the expression of ICAM-1, NOS, NF-κB, and VEGF [59] and improves endothelium- Together with our previous study on SAH [41], this observation validates a causal role of Caspase 12dependent ER stress in the induction of neuronal apoptosis following TBI.…”

Section: Discussionsupporting

confidence: 77%

“…Caspase 12-dependent ER stress-mediated apoptosis following increased ER-mitochondrion coupling in the mouse cerebral cortex ER stress-induced apoptosis involves triggering the PERK-eIF2α-ATF4 branch of the UPR, upregulating CHOP expression, and activating Caspase 12, a regulator speci c to ER stress-induced apoptosis [21,41,42]. To explore the possible pathological consequence of increased ER-mitochondrion crosstalk on subsequent ER stress-mediated apoptosis, we assessed the protein expression of cleaved Caspase-12, cleaved Caspase-3, cleaved PARP1, CHOP, Bcl-2, Bax and Cytc at different time points from 6 to 72 hr post injury.…”

Section: Resultsmentioning

confidence: 99%

“…Caspase 12 has been demonstrated to mediate ER-speci c apoptosis and neuroin ammation[64-67] and is a regulator speci c to ER stress-induced apoptosis but is not involved in non-ER stress-induced cell death[67]. Signi cant upregulation of caspase-12 expression was observed after experimental SAH or cerebral ischemia[41, 68, 69]. In the present study, we certainly demonstrated that TBI-induced MAM formation led to the activation of the PERK/eIF2α/ATF4/CHOP signaling pathway, procytokine release, and Caspase 12-dependent ER stress-mediated neuronal apoptosis.…”

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confidence: 99%

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Dysfunctional ER-mitochondrion Crosstalk Leads to Subsequent ER Stress-induced Neuronal Apoptosis and Neurological Deficits in an Experimental Rodent Model of Severe Head Injury

Chen¹,

Mi²,

Gu³

et al. 2021

Preprint

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Introduction: Previous studies have shown proper interorganelle communication between the endoplasmic reticulum (ER) and mitochondria (ER-mitochondrion crosstalk) is crucial for cellular homeostasis. Mitochondria-associated membranes (MAMs) provide an excellent platform and play an essential role in different signaling pathways to maintain cellular viability. However, the time course and potential pathological effects of this ER-mitochondrion physical and functional tethering in traumatic brain injury (TBI) remain unknown. We tested the hypothesis that dysfunctional ER-mitochondrion crosstalk at the acute phase of injury results in ER stress-induced neuronal apoptosis and neurological deficits in a mouse model of TBI. Methods: Male C57BL/6 mice were subjected to severe TBI (sTBI) using a controlled cortical impact (CCI) device. Transmission electron microscopy, western blot, immunofluorescence staining, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL), and MitoSOX assays were used to analyze posttraumatic ER-mitochondrion physical contact, Ca2+ transfer from the ER to mitochondria, mitochondrial reactive oxygen species (ROS) production, the unfolded protein response (UPR), the neuroinflammatory response and ER stress-mediated apoptosis in the perilesional cortex. The brain water content (BWC) and Evans blue dye extravasation were used to assess the blood-brain barrier (BBB) integrity, and a modified neurological severity score (mNSS) to evaluate neurological function in mice. Results: We showed sTBI led to significant MAM reorganization in the mouse cerebral cortex during the first 24 hr after injury. Enhanced ER-mitochondrion crosstalk peaked at 6 hr post injury and was significantly correlated with increased ER-mitochondrion Ca2+ transfer, mitochondrial ROS overproduction, elevated ER stress and UPR levels, and augmented levels of proinflammatory cytokines. In vivo experimental downregulation of PACS2, a protein essential for ER-mitochondrion tethering, restored mitochondrial Ca2+ homeostasis and alleviated mitochondrial oxidative stress by downregulating the IP3R1-GRP75-VDAC1 axis, inhibited ER stress and suppressed the inflammatory response through the PERK/eIF2α/ATF4/CHOP signaling pathway, blocked Caspase 12-dependent ER stress-mediated apoptosis, and reduced BBB permeability, resulting in significantly improved neurological function in mice subjected to sTBI. Conclusions: These results indicate that dysfunctional ER-mitochondrion crosstalk at the acute stage of injury might be primarily involved in the neuronal apoptosis and neurological deficits following sTBI, and specific modulation of ER-mitochondrion crosstalk might be a novel promising therapeutic strategy for sTBI.

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Section: Discussionsupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Dysfunctional ER-mitochondrion Crosstalk Leads to Subsequent ER Stress-induced Neuronal Apoptosis and Neurological Deficits in an Experimental Rodent Model of Severe Head Injury

Chen¹,

Mi²,

Gu³

et al. 2021

Preprint

Self Cite

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show abstract

“…Similarly, the taurine-conjugated UDCA reduces the DNA fragmentation and mitochondrial dysfunction induced by ischemia in rat brains and inhibits mitochondrial efflux of cytochrome C through PI3K signaling pathway activation in rat cortical neurons [ 93 , 94 ]. Also, tauro-UDCA reduces apoptosis by preventing the increase of caspase-12/Bax and the endoplasmic reticulum stress via AKT activation in mice with brain injury [ 95 , 96 ].…”

Section: Bile Acid Cytotoxicitymentioning

confidence: 99%

Redox‐Dependent Effects in the Physiopathological Role of Bile Acids

Orozco-Aguilar

Simón

Cabello-Verrugio

2021

Oxidative Medicine and Cellular Longevity

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Bile acids (BA) are recognized by their role in nutrient absorption. However, there is growing evidence that BA also have endocrine and metabolic functions. Besides, the steroidal-derived structure gives BA a toxic potential over the biological membrane. Thus, cholestatic disorders, characterized by elevated BA on the liver and serum, are a significant cause of liver transplant and extrahepatic complications, such as skeletal muscle, central nervous system (CNS), heart, and placenta. Further, the BA have an essential role in cellular damage, mediating processes such as membrane disruption, mitochondrial dysfunction, and the generation of reactive oxygen species (ROS) and oxidative stress. The purpose of this review is to describe the BA and their role on hepatic and extrahepatic complications in cholestatic diseases, focusing on the association between BA and the generation of oxidative stress that mediates tissue damage.

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“…It was beneficial to investigate new possible drug targets focused on autophagy. Endoplasmic reticulum (ER) is the largest cellular organelle, in which all secreted and membrane proteins are synthesized and properly folded 21 . Previous studies had confirmed that ER stress play a vital important role in the early brain injury after SAH [21][22][23] .…”

Section: Introductionmentioning

confidence: 99%

Hydrogen-rich saline alleviates early brain injury through regulating of ER stress and autophagy after experimental subarachnoid hemorrhage

Jiang

Dai

et al. 2021

Acta Cir. Bras.

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Purpose: Subarachnoid hemorrhage (SAH) is a common complication of cerebral vascular disease. Hydrogen has been reported to alleviate early brain injury (EBI) through oxidative stress injury, reactive oxygen species (ROS), and autophagy. Autophagy is a programmed cell death mechanism that plays a vital role in neuronal cell death after SAH. However, the precise role of autophagy in hydrogen-mediated neuroprotection following SAH has not been confirmed. Methods: In the present study, the objective was to investigate the neuroprotective effects and potential molecular mechanisms of hydrogen-rich saline in SAH-induced EBI by regulating neural autophagy in the C57BL/6 mice model. Mortality, neurological score, brain water content, ROS, malondialdehyde (MDA), and neuronal death were evaluated. Results: The results show that hydrogen-rich saline treatment markedly increased the survival rate and neurological score, increased neuron survival, downregulated the autophagy protein expression of Beclin-1 and LC3, and endoplasmic reticulum (ER) stress. That indicates that hydrogen-rich saline-mediated inhibition of autophagy and ER stress ameliorate neuronal death after SAH. The neuroprotective capacity of hydrogen-rich saline is partly dependent on the ROS/Nrf2/heme oxygenase-1 (HO-1) signaling pathway. Conclusion: The results of this study demonstrate that hydrogen-rich saline improves neurological outcomes in mice and reduces neuronal death by protecting against neural autophagy and ER stress.

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Tauroursodeoxycholic acid prevents ER stress-induced apoptosis and improves cerebral and vascular function in mice subjected to subarachnoid hemorrhage

Cited by 26 publications

References 32 publications

Dysfunctional ER-mitochondrion Crosstalk Leads to Subsequent ER Stress-induced Neuronal Apoptosis and Neurological Deficits in an Experimental Rodent Model of Severe Head Injury

Dysfunctional ER-mitochondrion Crosstalk Leads to Subsequent ER Stress-induced Neuronal Apoptosis and Neurological Deficits in an Experimental Rodent Model of Severe Head Injury

Redox‐Dependent Effects in the Physiopathological Role of Bile Acids

Hydrogen-rich saline alleviates early brain injury through regulating of ER stress and autophagy after experimental subarachnoid hemorrhage

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