TY - JOUR
T1 - Activation of TGR5 with INT-777 attenuates oxidative stress and neuronal apoptosis via cAMP/PKCε/ALDH2 pathway after subarachnoid hemorrhage in rats
AU - Zuo, Gang
AU - Zhang, Tongyu
AU - Huang, Lei
AU - Araujo, Camila
AU - Peng, Jun
AU - Travis, Zachary
AU - Okada, Takeshi
AU - Ocak, Umut
AU - Zhang, Guangyu
AU - Tang, Jiping
AU - Lu, Xiaojun
AU - Zhang, John H.
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Background: Oxidative stress and neuronal apoptosis play important roles in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). The activation of TGR5, a novel membrane-bound bile acid receptor, possesses anti-oxidative stress and anti-apoptotic effects in hepatobiliary disease and kidney disease. The present study aimed to explore the neuroprotective effect of TGR5 activation against EBI after SAH and the potential underlying mechanisms. Methods: The endovascular perforation model of SAH was performed on 199 Sprague Dawley rats to investigate the beneficial effects of TGR5 activation after SAH. INT-777, a specific synthetic TGR5 agonist, was administered intranasally at 1 h after SAH induction. TGR5 CRISPR and ALDH2 CRISPR were administered intracerebroventricularly at 48 h before SAH to illuminate potential mechanisms. The SAH grade, short-term and long-term neurobehavioral tests, TUNEL staining, Fluoro-Jade C staining, Nissl staining, immunofluorescence staining, and western blots were performed at 24 h after SAH. Results: The expressions of endogenous TGR5 and ALDH2 gradually increased and peaked at 24 h after SAH. TGR5 was expressed primarily in neurons, as well as in astrocytes and microglia. The activation of TGR5 with INT-777 significantly improved the short-term and long-term neurological deficits, accompanied by reduced the oxidative stress and neuronal apoptosis at 24 h after SAH. Moreover, INT-777 treatment significantly increased the expressions of TGR5, cAMP, phosphorylated PKCε, ALDH2, HO-1, and Bcl-2, while downregulated the expressions of 4-HNE, Bax, and Cleaved Caspase-3. TGR5 CRISPR and ALDH2 CRISPR abolished the neuroprotective effects of TGR5 activation after SAH. Conclusions: In summary, the activation of TGR5 with INT-777 attenuated oxidative stress and neuronal apoptosis via the cAMP/PKCε/ALDH2 signaling pathway after SAH in rats. Furthermore, TGR5 may serve as a novel therapeutic target to ameliorate EBI after SAH.
AB - Background: Oxidative stress and neuronal apoptosis play important roles in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). The activation of TGR5, a novel membrane-bound bile acid receptor, possesses anti-oxidative stress and anti-apoptotic effects in hepatobiliary disease and kidney disease. The present study aimed to explore the neuroprotective effect of TGR5 activation against EBI after SAH and the potential underlying mechanisms. Methods: The endovascular perforation model of SAH was performed on 199 Sprague Dawley rats to investigate the beneficial effects of TGR5 activation after SAH. INT-777, a specific synthetic TGR5 agonist, was administered intranasally at 1 h after SAH induction. TGR5 CRISPR and ALDH2 CRISPR were administered intracerebroventricularly at 48 h before SAH to illuminate potential mechanisms. The SAH grade, short-term and long-term neurobehavioral tests, TUNEL staining, Fluoro-Jade C staining, Nissl staining, immunofluorescence staining, and western blots were performed at 24 h after SAH. Results: The expressions of endogenous TGR5 and ALDH2 gradually increased and peaked at 24 h after SAH. TGR5 was expressed primarily in neurons, as well as in astrocytes and microglia. The activation of TGR5 with INT-777 significantly improved the short-term and long-term neurological deficits, accompanied by reduced the oxidative stress and neuronal apoptosis at 24 h after SAH. Moreover, INT-777 treatment significantly increased the expressions of TGR5, cAMP, phosphorylated PKCε, ALDH2, HO-1, and Bcl-2, while downregulated the expressions of 4-HNE, Bax, and Cleaved Caspase-3. TGR5 CRISPR and ALDH2 CRISPR abolished the neuroprotective effects of TGR5 activation after SAH. Conclusions: In summary, the activation of TGR5 with INT-777 attenuated oxidative stress and neuronal apoptosis via the cAMP/PKCε/ALDH2 signaling pathway after SAH in rats. Furthermore, TGR5 may serve as a novel therapeutic target to ameliorate EBI after SAH.
KW - ALDH2
KW - Early brain injury
KW - INT-777
KW - Neuronal apoptosis
KW - Oxidative stress
KW - Subarachnoid hemorrhage
KW - TGR5
KW - Neuroprotective Agents
KW - Phosphorylation
KW - Signal Transduction
KW - Protein Kinase C-epsilon/genetics
KW - Rats
KW - Male
KW - Neurons/drug effects
KW - Rats, Sprague-Dawley
KW - Oxidative Stress/drug effects
KW - Subarachnoid Hemorrhage/complications
KW - Receptors, G-Protein-Coupled/genetics
KW - Animals
KW - Brain Injuries/drug therapy
KW - Cholic Acids/pharmacology
KW - Aldehyde Dehydrogenase, Mitochondrial/genetics
KW - Cyclic AMP/metabolism
KW - Gene Expression Regulation/drug effects
UR - http://www.scopus.com/inward/record.url?scp=85071922896&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071922896&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/3dc935d8-4e19-3855-a985-5e7ad3e1af7b/
U2 - 10.1016/j.freeradbiomed.2019.09.002
DO - 10.1016/j.freeradbiomed.2019.09.002
M3 - Article
C2 - 31493504
SN - 0891-5849
VL - 143
SP - 441
EP - 453
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -