Highlights
- •Meglumine cyclic adenylate protects neurons against ischemia/reperfusion injury.
- •Meglumine cyclic adenylate induces mitochondria translocation of STAT3.
- •Meglumine cyclic adenylate induces inhibition of apoptosis pathway.
Abstract
Objectives
Ischemia/reperfusion can induce neuronal apoptosis in the brain and lead to function
deficits. The activation of cyclic adenosine monophosphate (cAMP)-dependent protein
kinase (PKA) is neuroprotective against transient cerebral ischemia. The neuroprotective
mechanisms of PKA mainly involve the regulation of gene transcription via the PKA/CREB
pathway. The present study aims to investigate the neuroprotective effect of meglumine
cyclic adenylate, an activator of PKA, under a rat model of global cerebral ischemia/reperfusion
and to reveal the underlying mechanism involving signal transducer and activator of
transcription 3 (STAT3)-Ser727 phosphorylation and mitochondrion modulation.
Materials and methods
Male Sprague-Dawley rats were subjected to 15 min global cerebral ischemia, and meglumine
cyclic adenylate was treated through tail intravenous injection 30 min before ischemia.
Cresyl violet staining was used to evaluate neuron injury at 5 d of reperfusion. Western
blotting was used to detect p-Ser727-STAT3, total STAT3, cytochrome c (Cyt c) and active caspase-3 in the tissues of hippocampal
CA1 region at 6 h of reperfusion. STAT3-S727A was overexpressed in HT22 cells to reveal
the significance of STAT3-Ser727 phosphorylation in the neuroprotective effect of
meglumine cyclic adenylate.
Results
Pretreatment with meglumine cyclic adenylate not only significantly ameliorated neuron
loss in CA1 region after global cerebral ischemia but also enhanced STAT3-Ser727 phosphorylation,
increased mitochondrial STAT3, and decreased cytosolic Cyt c and active caspase-3.
Overexpression of STAT3-S727A in HT22 cells eliminated meglumine cyclic adenylate-induced
increase of p-Ser727-STAT3, mitochondrial STAT3, cytosolic Cyt c and active caspase-3.
Conclusion
Meglumine cyclic adenylate protects neurons against ischemia/reperfusion injury via
promoting p-Ser727-STAT3-associated mitochondrion modulation and inhibiting apoptosis pathway.
Keywords
Abbreviations:
signal transducer and activator of transcription 3 (STAT3), cAMP-dependent protein kinase (PKA), reactive oxygen species (ROS), mitochondrial permeability transition pore (MPTP), Janus kinases (JAKs), G protein-coupled receptors (GPCRs), ischemia/reperfusion (I/R), electron transport chain (ETC)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Stroke and Cerebrovascular DiseasesAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Studies on the properties and mode of action of the purified regulatory subunit of bovine heart adenosine 3′:5′-monophosphate-dependent protein kinase.J Biol Chem. 1978; 253: 3997-4003
- Dynamics of cAMP-dependent protein kinase.Chem Rev. 2001; 101: 2243-2270
- The regulation of PKA signaling in obesity and in the maintenance of metabolic health.Pharmacol Ther. 2022; 237108113
- Adiponectin confers neuroprotection against cerebral ischemia-reperfusion injury through activating the cAMP/PKA-CREB-BDNF signaling.Brain Res Bull. 2018; 143: 145-154
- Ginsenoside Rb1 Promotes Motor Functional Recovery and Axonal Regeneration in Post-stroke Mice through cAMP/PKA/CREB Signaling Pathway.Brain Res Bull. 2020; 154: 51-60
- Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection.Antioxid Redox Signal. 2011; 14: 1505-1517
- A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury.Cell Metab. 2016; 23: 254-263
- Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death.Nature. 2005; 434: 658-662
- Mitochondria as a therapeutic target for ischemic stroke.Free Radic Biol Med. 2020; 146: 45-58
- Zinc oxide nanoparticles induce human multiple myeloma cell death via reactive oxygen species and Cyt-C/Apaf-1/Caspase-9/Caspase-3 signaling pathway in vitro.Biomed Pharmacother. 2020; 122109712
- Exposure to Fluoride induces apoptosis in liver of ducks by regulating Cyt-C/Caspase 3/9 signaling pathway.Ecotoxicol Environ Saf. 2021; 224112662
- Interleukin-6-induced JAK2/STAT3 signaling pathway in endothelial cells is suppressed by hemodynamic flow.Am J Physiol Cell Physiol. 2004; 287: C771-C780
- Adiponectin attenuates oxygen-glucose deprivation-induced mitochondrial oxidative injury and apoptosis in hippocampal HT22 cells via the JAK2/STAT3 pathway.Cell Transplant. 2018; 27: 1731-1743
- Zinc improves mitochondrial respiratory function and prevents mitochondrial ROS generation at reperfusion by phosphorylating STAT3 at Ser 727.J Mol Cell Cardiol. 2018; 118: 169-182
- Leptin attenuates cerebral ischemic injury in rats by modulating the mitochondrial electron transport chain via the mitochondrial STAT3 pathway.Brain Behav. 2019; 9: e01200
- Y705 and S727 are required for the mitochondrial import and transcriptional activities of STAT3, and for regulation of stem cell proliferation.Development. 2021; 148dev199477
- Function of mitochondrial Stat3 in cellular respiration.Science. 2009; 323: 793-797
- The STAT3 inhibitor stattic impairs cardiomyocyte mitochondrial function through increased reactive oxygen species formation.Curr Pharm Des. 2013; 19: 6890-6895
- Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727.J Biol Chem. 2013; 288: 31280-31288
- Cardioprotective function of mitochondrial-targeted and transcriptionally inactive STAT3 against ischemia and reperfusion injury.Basic Res Cardiol. 2015; 110: 53
- Exendin-4 improved rat cortical neuron survival under oxygen/glucose deprivation through PKA pathway.Neuroscience. 2012; 226: 388-396
- Ischemia-induced translocation of Ca2+/calmodulin-dependent protein kinase II: potential role in neuronal damage.J Neurochem. 1992; 58: 1743-1753
- Cyclic AMP concentrations in rat neocortex and hippocampus during and following incomplete ischemia: effects of central noradrenergic neurons, prostaglandins, and adenosine.J Neurochem. 1985; 44: 1345-1353
- Rh-CSF1 attenuates oxidative stress and neuronal apoptosis via the CSF1R/PLCG2/PKA/UCP2 signaling pathway in a rat model of neonatal HIE.Oxid Med Cell Longev. 2020; 20206801587
- A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.Nature. 2011; 476: 336-340
- Mitochondrial STAT3 supports Ras-dependent oncogenic transformation.Science. 2009; 324: 1713-1716
- Mitochondrial dynamics following global cerebral ischemia.Mol Cell Neurosci. 2016; 76: 68-75
- Porcine deltacoronavirus induces caspase-dependent apoptosis through activation of the cytochrome c-mediated intrinsic mitochondrial pathway.Virus Res. 2018; 253: 112-123
Article info
Publication history
Published online: November 17, 2022
Accepted:
November 10,
2022
Received in revised form:
November 2,
2022
Received:
October 10,
2022
Identification
DOI: https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106892
Copyright
© 2022 Elsevier Inc. All rights reserved.
