Evidence map›Paper›PMID 31493504›Full record

ArticleFree radical biology & medicine2019

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

Gang Zuo, Tongyu Zhang, Lei Huang, Camila Araujo, Jun Peng, Zachary Travis, Takeshi Okada, Umut Ocak, Guangyu Zhang, Jiping Tang and 2 more

Erratum issuedOpen access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Free radical biology & medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 54 papers.

0numbers the graph read from it
0cells of the map it votes in
54citing papers in PubMed
8.6field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

54 citing papers in PubMed, 112 citations in OpenAlex.

  1. Review
  2. Discovery of Obacunone as a TGR5 Agonist fromInternational journal of molecular sciences · 2026
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  10. Biological Actions of Bile Acids via Cell Surface Receptors.International journal of molecular sciences · 2025
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors at 2 institutions in 2 countries.

Gang ZuoDepartment 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.
Tongyu ZhangDepartment 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.
Lei HuangDepartment of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA; Department of Neurosurgery, Loma Linda University, Loma Linda, CA, 92350, USA.
Camila AraujoDepartment of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA.
Jun PengDepartment of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA.
Zachary TravisDepartment of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA.
Takeshi OkadaDepartment of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA.
Umut OcakDepartment of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA.
Guangyu ZhangMass Spectrometry Core Facility, Loma Linda University, Loma Linda, CA, 92350, USA.
Jiping TangDepartment of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, 92350, USA.
Xiaojun LuDepartment of Neurosurgery, The Affiliated Taicang Hospital, Soochow University, Taicang, Suzhou, Jiangsu, 215400, China. Electronic address: luxiaojun5215@163.com.
John H ZhangDepartment 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: jhzhang@llu.edu.
Loma Linda University · USSoochow University · CN

Funding

Vascular Biology Core FacilityP01NS082184 · NINDS · LOMA LINDA UNIVERSITY · PI PEARCE, WILLIAM J. · 2014 to 2018
$6.1M
Neurovascular Protection for Early Brain Injury after SAHR01NS081740 · NINDS · LOMA LINDA UNIVERSITY · PI ZHANG, JOHN H · 2013 to 2017
$1.6M
NINDS NIH HHS P01 NS082184NINDS NIH HHS R01 NS081740
6 · The paper itself

Abstract

backgroundOxidative 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.

methodsThe 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.

resultsThe 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.

conclusionsIn 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.

Indexed as

Aldehyde Dehydrogenase, MitochondrialAnimalsBrain InjuriesCholic AcidsCyclic AMPGene Expression RegulationMaleNeuronsNeuroprotective AgentsOxidative StressPhosphorylationProtein Kinase C-epsilonRatsRats, Sprague-DawleyReceptors, G-Protein-CoupledSignal Transduction6alpha-ethyl-23(S)-methylcholic acidAldehyde Dehydrogenase, MitochondrialAldh2 protein, ratCholic AcidsCyclic AMPGpbar1 protein, ratNeuroprotective AgentsProtein Kinase C-epsilonReceptors, G-Protein-CoupledALDH2Early brain injuryINT-777Neuronal apoptosisOxidative stressSubarachnoid hemorrhageTGR5

Identifiers

PMID31493504
PMCPMC6848789
OpenAlexW2971387841

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.