Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Anesthesiology
Published in: BMC Anesthesiology 1/2020

Open Access 01-12-2020 | Research article

Perioperative Dexmedetomidine attenuates brain ischemia reperfusion injury possibly via up-regulation of astrocyte Connexin 43

Authors: Xiaoyang Zheng, Xiaoying Cai, Fang Ye, Ying Li, Qin Wang, Zhiyi Zuo, Wenqi Huang, Zhongxing Wang

Published in: BMC Anesthesiology | Issue 1/2020

Login to get access

Abstract

Background

Astrocyte Connexin 43 (Cx43) is essential for the trophic and protective support of neurons during brain ischemia reperfusion (I/R) injury. It is believed that dexmedetomidine participates in Cx43-mediated effects. However, its mechanisms remained unclear. This study aims to address the relationship and regulation among them.

Methods

Adult male Sprague-Dawley rats were allocated to the 90-min right middle cerebral arterial occlusion with or without dexmedetomidine pretreatment (5 μg/kg). Neurological functions were evaluated and brain lesions, as well as inflammatory factors (IL-1β, IL-6, TNF-α), were assessed. Ischemic penumbral cortex was harvested to determine the expression of astrocyte Cx43. Primary astrocytes were cultured to evaluate the effect of dexmedetomidine on Cx43 after oxygen-glucose deprivation.

Results

Dexmedetomidine pretreatment attenuated neurological injury, brain lesions and expression of inflammatory factors (IL-1β, IL-6, TNF-α) after brain ischemia (P < 0.05). Astrocyte Cx43 was down-regulated by brain I/R injury, both in vivo and in vitro, which were reversed by dexmedetomidine (P < 0.05). This effect was mediated by the phosphorylation of Akt and GSK-3β. Further studies with LY294002 (PI3K inhibitor) or SB216763 (GSK-3β inhibitor) confirmed the effect of dexmedetomidine on astrocyte Cx43.

Conclusions

Perioperative dexmedetomidine administration attenuates neurological injury after brain I/R injury, possibly through up-regulation of astrocyte Cx43. Activation of PI3K-Akt-GSK-3β pathway might contribute to this protective effect.
Appendix
Available only for authorised users
Literature
1.
Pan J, Konstas AA, Bateman B, Ortolano GA, Pile-Spellman J. Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies. Neuroradiology. 2007;49(2):93–102.CrossRef
2.
3.
Eugenin EA, Basilio D, Saez JC, Orellana JA, Raine CS, Bukauskas F, Bennett MV, Berman JW. The role of gap junction channels during physiologic and pathologic conditions of the human central nervous system. J NeuroImmune Pharmacol. 2012;7(3):499–518.CrossRef
4.
Rossi DJ, Brady JD, Mohr C. Astrocyte metabolism and signaling during brain ischemia. Nat Neurosci. 2007;10(11):1377–86.CrossRef
5.
Kozoriz MG, Bechberger JF, Bechberger GR, Suen MW, Moreno AP, Maass K, Willecke K, Naus CC. The connexin43 C-terminal region mediates neuroprotection during stroke. J Neuropathol Exp Neurol. 2010;69(2):196–206.CrossRef
6.
Bhana N, Goa KL, McClellan KJ. Dexmedetomidine. Drugs. 2000;59(2):263–8 discussion 269-270.CrossRef
7.
Liu X, Gangoso E, Yi C, Jeanson T, Kandelman S, Mantz J, Giaume C. General anesthetics have differential inhibitory effects on gap junction channels and hemichannels in astrocytes and neurons. Glia. 2016;64(4):524–36.CrossRef
8.
Wang Z, Zhou W, Dong H, Ma X, He Z. Dexmedetomidine pretreatment inhibits cerebral ischemia/reperfusioninduced neuroinflammation via activation of AMPK. Mol Med Rep. 2018;18(4):3957–64.PubMed
9.
Tang Y, Jia C, He J, Zhao Y, Chen H, Wang S. The application and analytical pathway of Dexmedetomidine in ischemia/reperfusion injury. J Analytical Methods Chemistry. 2019;2019:7158142.
10.
Zhang XY, Liu ZM, Wen SH, Li YS, Li Y, Yao X, Huang WQ, Liu KX. Dexmedetomidine administration before, but not after, ischemia attenuates intestinal injury induced by intestinal ischemia-reperfusion in rats. Anesthesiology. 2012;116(5):1035–46.CrossRef
11.
Luo C, Yuan D, Yao W, Cai J, Zhou S, Zhang Y, Hei Z. Dexmedetomidine protects against apoptosis induced by hypoxia/reoxygenation through the inhibition of gap junctions in NRK-52E cells. Life Sci. 2015;122:72–7.CrossRef
12.
Gray JJ, Bickler PE, Fahlman CS, Zhan X, Schuyler JA. Isoflurane neuroprotection in hypoxic hippocampal slice cultures involves increases in intracellular Ca2+ and mitogen-activated protein kinases. Anesthesiology. 2005;102(3):606–15.CrossRef
13.
Wang J, Bai T, Wang N, Li H, Guo X. Neuroprotective potential of imatinib in global ischemia-reperfusion-induced cerebral injury: possible role of Janus-activated kinase 2/signal transducer and activator of transcription 3 and connexin 43. The Korean J Physiol Pharmacol. 2020;24(1):11–8.CrossRef
14.
Wang Y, Wu C, Han B, Xu F, Mao M, Guo X, Wang J. Dexmedetomidine attenuates repeated propofol exposure-induced hippocampal apoptosis, PI3K/Akt/Gsk-3beta signaling disruption, and juvenile cognitive deficits in neonatal rats. Mol Med Rep. 2016;14(1):769–75.CrossRef
15.
Lee JJ, Li L, Jung HH, Zuo Z. Postconditioning with isoflurane reduced ischemia-induced brain injury in rats. Anesthesiology. 2008;108(6):1055–62.CrossRef
16.
Wang Z, Huang W, Zuo Z. Perioperative aspirin improves neurological outcome after focal brain ischemia possibly via inhibition of notch 1 in rat. J Neuroinflammation. 2014;11:56.CrossRef
17.
Li L, Zuo Z. Isoflurane preconditioning improves short-term and long-term neurological outcome after focal brain ischemia in adult rats. Neuroscience. 2009;164(2):497–506.CrossRef
18.
Zheng S, Zuo Z. Isoflurane preconditioning induces neuroprotection against ischemia via activation of P38 mitogen-activated protein kinases. Mol Pharmacol. 2004;65(5):1172–80.CrossRef
19.
Zhang J, Jiang W, Zuo Z. Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor kappaB. Neuroscience. 2014;261:1–10.CrossRef
20.
Frangakis MV, Kimelberg HK. Dissociation of neonatal rat brain by dispase for preparation of primary astrocyte cultures. Neurochem Res. 1984;9(12):1689–98.CrossRef
21.
Kim JA, Li L, Zuo Z. Isoflurane induces a postconditioning effect on bovine pulmonary arterial endothelial cells exposed to oxygen-glucose deprivation. Eur J Pharmacol. 2009;615(1–3):144–9.CrossRef
22.
Liu Y, Zeng X, Hui Y, Zhu C, Wu J, Taylor DH, Ji J, Fan W, Huang Z, Hu J. Activation of alpha7 nicotinic acetylcholine receptors protects astrocytes against oxidative stress-induced apoptosis: implications for Parkinson's disease. Neuropharmacology. 2015;91:87–96.CrossRef
23.
Desplantez T, Dupont E, Severs NJ, Weingart R. Gap junction channels and cardiac impulse propagation. J Membr Biol. 2007;218(1–3):13–28.CrossRef
24.
Schulz R, Gorge PM, Gorbe A, Ferdinandy P, Lampe PD, Leybaert L. Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection. Pharmacol Ther. 2015;153:90–106.CrossRef
25.
Danon A, Zeevi-Levin N, Pinkovich DY, Michaeli T, Berkovich A, Flugelman M, Eldar YC, Rosen MR, Binah O. Hypoxia causes connexin 43 internalization in neonatal rat ventricular myocytes. Gen Physiol Biophys. 2010;29(3):222–33.CrossRef
26.
de Pina-Benabou MH, Szostak V, Kyrozis A, Rempe D, Uziel D, Urban-Maldonado M, Benabou S, Spray DC, Federoff HJ, Stanton PK, et al. Blockade of gap junctions in vivo provides neuroprotection after perinatal global ischemia. Stroke. 2005;36(10):2232–7.CrossRef
27.
Nakase T, Fushiki S, Naus CC. Astrocytic gap junctions composed of connexin 43 reduce apoptotic neuronal damage in cerebral ischemia. Stroke. 2003;34(8):1987–93.CrossRef
28.
Siushansian R, Bechberger JF, Cechetto DF, Hachinski VC, Naus CC. Connexin43 null mutation increases infarct size after stroke. J Comp Neurol. 2001;440(4):387–94.CrossRef
29.
Haupt C, Witte OW, Frahm C. Up-regulation of Connexin43 in the glial scar following photothrombotic ischemic injury. Mol Cell Neurosci. 2007;35(1):89–99.CrossRef
30.
Wang Y, Han R, Zuo Z. Dexmedetomidine-induced neuroprotection: is it translational? Transl Perioper Pain Med. 2016;1(4):15–9.PubMedPubMedCentral
31.
Zhang Y, Tan X, Xue L. The alpha2-adrenoreceptor agonist dexmedetomidine protects against lipopolysaccharide-induced apoptosis via inhibition of gap junctions in lung fibroblasts. Biochem Biophys Res Commun. 2018;495(1):92–7.CrossRef
32.
Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996;15(23):6541–51.CrossRef
33.
Srivastava AK, Pandey SK. Potential mechanism(s) involved in the regulation of glycogen synthesis by insulin. Mol Cell Biochem. 1998;182(1–2):135–41.CrossRef
34.
Dewachter I, Ris L, Jaworski T, Seymour CM, Kremer A, Borghgraef P, De Vijver H, Godaux E, Van Leuven F. GSK3beta, a Centre-staged kinase in neuropsychiatric disorders, modulates long term memory by inhibitory phosphorylation at serine-9. Neurobiol Dis. 2009;35(2):193–200.CrossRef
35.
Salameh A, Wustmann A, Karl S, Blanke K, Apel D, Rojas-Gomez D, Franke H, Mohr FW, Janousek J, Dhein S. Cyclic mechanical stretch induces cardiomyocyte orientation and polarization of the gap junction protein connexin43. Circ Res. 2010;106(10):1592–602.CrossRef
36.
De Bock M, Decrock E, Wang N, Bol M, Vinken M, Bultynck G, Leybaert L. The dual face of connexin-based astroglial Ca(2+) communication: a key player in brain physiology and a prime target in pathology. Biochim Biophys Acta. 2014;1843(10):2211–32.CrossRef
37.
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Munch AE, Chung WS, Peterson TC, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481–7.CrossRef
Metadata
Title
Perioperative Dexmedetomidine attenuates brain ischemia reperfusion injury possibly via up-regulation of astrocyte Connexin 43
Authors
Xiaoyang Zheng
Xiaoying Cai
Fang Ye
Ying Li
Qin Wang
Zhiyi Zuo
Wenqi Huang
Zhongxing Wang
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Anesthesiology / Issue 1/2020
Electronic ISSN: 1471-2253
DOI
https://doi.org/10.1186/s12871-020-01211-7

Other articles of this Issue 1/2020

BMC Anesthesiology 1/2020 Go to the issue

Research article

Incidence of airway complications associated with deep extubation in adults

Research article

No radiographic index predicts difficult intubation using the Optiscope™ in cervical spine surgery patients: a retrospective study

Research article

Effects of ultrasound-guided paravertebral block on MMP-9 and postoperative pain in patients undergoing VATS lobectomy: a randomized, controlled clinical trial

Research article

Randomized crossover trial comparing cervical spine motion during tracheal intubation with a Macintosh laryngoscope versus a C-MAC D-blade videolaryngoscope in a simulated immobilized cervical spine

Research article

Methylation in HT22 cells and primary hippocampal neurons with and without isoflurane exposure

Research article

Effects of nitroglycerin versus labetalol on peripheral perfusion during deliberate hypotension for sinus endoscopic surgery: a randomized, controlled, double-blinded trial