2. Academic Validation
  3. Activation of TGR5 with INT-777 attenuates oxidative stress and neuronal apoptosis via cAMP/PKCε/ALDH2 pathway after subarachnoid hemorrhage in rats

Activation of TGR5 with INT-777 attenuates oxidative stress and neuronal apoptosis via cAMP/PKCε/ALDH2 pathway after subarachnoid hemorrhage in rats

  • Free Radic Biol Med. 2019 Nov 1;143:441-453. doi: 10.1016/j.freeradbiomed.2019.09.002.
Gang Zuo 1,  Tongyu Zhang 2,  Lei Huang 3,  Camila Araujo 4,  Jun Peng 4,  Zachary Travis 4,  Takeshi Okada 4,  Umut Ocak 4,  Guangyu Zhang 5,  Jiping Tang 4,  Xiaojun Lu 6,  John H Zhang 7
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Affiliated Taicang Hospital, Soochow University, Taicang, Suzhou, Jiangsu, 215400, China; Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA.
  • 2 Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA; Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, China.
  • 3 Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA; Department of Neurosurgery, Loma Linda University, Loma Linda, CA, 92350, USA.
  • 4 Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA.
  • 5 Mass Spectrometry Core Facility, Loma Linda University, Loma Linda, CA, 92350, USA.
  • 6 Department of Neurosurgery, The Affiliated Taicang Hospital, Soochow University, Taicang, Suzhou, Jiangsu, 215400, China. Electronic address: [email protected].
  • 7 Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA; Department of Neurosurgery, Loma Linda University, Loma Linda, CA, 92350, USA; Department of Anesthesiology, Loma Linda University, Loma Linda, CA, 92350, USA. Electronic address: [email protected].
PMID: 31493504 DOI: 10.1016/j.freeradbiomed.2019.09.002
Abstract

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.

Keywords

ALDH2; Early brain injury; INT-777; Neuronal apoptosis; Oxidative stress; Subarachnoid hemorrhage; TGR5.

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