Abstract
In this study, we explored the effects of propofol on oxidative stress response, cytokine secretion, and autophagy in rats with ischemia–reperfusion (I/R) injury and oxygen–glucose deprivation (OGD)-stimulated primary microglia and analyzed the role of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway in this process. Rat models of I/R injury and OGD models of primary microglia were established. Neurobehavioral scores were evaluated 24 h after reperfusion, and oxidative stress indicators, cytokine levels, and autophagy-related markers of rats and OGD-activated primary microglia were evaluated. Activation of the PI3K/Akt pathway was also assessed. The results showed that propofol pretreatment can improve nerve function in rats with I/R injury, inhibit oxidative stress response and inflammatory cytokine secretion, and promote autophagy in rats with I/R injury and OGD-activated primary microglia, and that the PI3K-Akt pathway was activated in this process. Following the addition of a PI3K/Akt pathway inhibitor, the effects of propofol on autophagy in rats with I/R injury and primary microglia were inhibited significantly. The results indicate that propofol promotes autophagy via the PI3K/Akt pathway in cerebral I/R injury.
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References
Carloni S, Buonocore G, Balduini W (2008) Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis 32:329–339. https://doi.org/10.1016/j.nbd.2008.07.022
Chamorro Á, Dirnagl U, Urra X, Planas AM (2016) Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 15:869–881. https://doi.org/10.1016/s1474-4422(16)00114-9
Cui D, Wang L, Qi A, Zhou Q, Zhang X, Jiang W (2012) Propofol prevents autophagic cell death following oxygen and glucose deprivation in PC12 cells and cerebral ischemia-reperfusion injury in rats. PLoS One 7:e35324. https://doi.org/10.1371/journal.pone.0035324
Dai HB et al (2015) Mild hypothermia combined with hydrogen sulfide treatment during resuscitation reduces hippocampal neuron apoptosis via NR2A, NR2B, and PI3K-Akt signaling in a rat model of cerebral ischemia-reperfusion injury. Mol Neurobiol. https://doi.org/10.1007/s12035-015-9391-z
Diaz-Cañestro C et al (2018) Sirtuin 5 as a novel target to blunt blood-brain barrier damage induced by cerebral ischemia/reperfusion injury. Int J Cardiol 260:148–155. https://doi.org/10.1016/j.ijcard.2017.12.060
Ding Y, Du J, Cui F, Chen L, Li K (2019) The protective effect of ligustrazine on rats with cerebral ischemia-reperfusion injury via activating PI3K/Akt pathway. Hum Exp Toxicol:960327119851260. https://doi.org/10.1177/0960327119851260
Donkor ES (2018) Stroke in the 21(st) century: a snapshot of the burden, epidemiology, and quality of life. Stroke Res Treat 2018:3238165. https://doi.org/10.1155/2018/3238165
Gambardella V et al (2018) NRF2 activation via PI3K/AKT/mTOR/RPS6 causes resistance to anti-HER2 agents among HER2 amplified gastric cancer. Ann Oncol 29(Suppl 8):viii224. https://doi.org/10.1093/annonc/mdy282.049
Gentili A (2020) Propofol: an intravenous anesthetic suitable for pediatric age. Minerva Anestesiol. https://doi.org/10.23736/s0375-9393.20.14380-3
Jayaraj RL, Azimullah S, Beiram R, Jalal FY, Rosenberg GA (2019) Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation 16:142. https://doi.org/10.1186/s12974-019-1516-2
Kirkin V, Rogov VV (2019) A Diversity of selective autophagy receptors determines the specificity of the autophagy pathway Mol Cell https://doi.org/10.1016/j.molcel.2019.09.005
Li Y, Zhong D, Lei L, Jia Y, Zhou H, Yang B (2015) Propofol prevents renal ischemia-reperfusion injury via inhibiting the oxidative stress pathways. Cell Physiol Biochem 37:14–26. https://doi.org/10.1159/000430329
Liu Z, Zhang J, Zhang F, Chang Y (2020) Propofol post-conditioning lessens renal ischemia/reperfusion-induced acute lung injury associated with autophagy and apoptosis through MAPK signals in rats. Gene 741:144562. https://doi.org/10.1016/j.gene.2020.144562
Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91. https://doi.org/10.1161/01.str.20.1.84
Luo T et al (2013) Propofol limits microglial activation after experimental brain trauma through inhibition of nicotinamide adenine dinucleotide phosphate oxidase. Anesthesiology 119:1370–1388. https://doi.org/10.1097/aln.0000000000000020
Murugan AK (2019) mTOR: role in cancer, metastasis and drug resistance. Semin Cancer Biol. https://doi.org/10.1016/j.semcancer.2019.07.003
Piguet A-C, Dufour J-F (2010) PI(3)K/PTEN/AKT pathway. J Hepatol 54:1317–1319. https://doi.org/10.1016/j.jhep.2010.12.013
Sahin E et al (2014) Correction: macrophage PTEN regulates expression and secretion of arginase I modulating innate and adaptive immune responses. J Immunol (Baltimore, Md: 1950) 193:5350–5350. https://doi.org/10.4049/jimmunol.1490039
Shi SS, Zhang HB, Wang CH, Yang WZ, Liang RS, Chen Y, Tu XK (2015) Propofol attenuates early brain injury after subarachnoid hemorrhage in rats. J Mol Neurosci 57:538–545. https://doi.org/10.1007/s12031-015-0634-2
Spencer B et al (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. J Neurosci 29:13578–13588. https://doi.org/10.1523/jneurosci.4390-09.2009
Suto T, Karonitsch T (2019) The immunobiology of mTOR in autoimmunity. J Autoimmun 110:102373. https://doi.org/10.1016/j.jaut.2019.102373
Tewari D, Patni P, Bishayee A, Sah AN, Bishayee A (2019) Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: a novel therapeutic strategy. Semin Cancer Biol. https://doi.org/10.1016/j.semcancer.2019.12.008
Tian Z, Tang C, Wang Z (2019) Neuroprotective effect of ginkgetin in experimental cerebral ischemia/reperfusion via apoptosis inhibition and PI3K/Akt/mTOR signaling pathway activation. J Cell Biochem 120:18487–18495. https://doi.org/10.1002/jcb.29169
Tomoda T, Yang K, Sawa A (2019) Neuronal autophagy in synaptic functions and psychiatric disorders. Biol Psychiatry. https://doi.org/10.1016/j.biopsych.2019.07.018
Wang P, Shao BZ, Deng Z, Chen S, Yue Z, Miao CY (2018) Autophagy in ischemic stroke. Prog Neurobiol. https://doi.org/10.1016/j.pneurobio.2018.01.001
Wehrmann T, Triantafyllou K (2010) Propofol sedation in gastrointestinal endoscopy: a gastroenterologist’s perspective. Digestion 82:106–109. https://doi.org/10.1159/000285554
Wei Q, Zhao J, Zhou X, Yu L, Liu Z, Chang Y (2019) Propofol can suppress renal ischemia-reperfusion injury through the activation of PI3K/AKT/mTOR signal pathway. Gene 708:14–20. https://doi.org/10.1016/j.gene.2019.05.023
Yan BC et al (2018) Neuroprotective effects of gabapentin against cerebral ischemia reperfusion-induced neuronal Autophagic injury via regulation of the PI3K/Akt/mTOR signaling pathways. J Neuropathol Exp Neurol. https://doi.org/10.1093/jnen/nly119
Yoshida GJ (2017) Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. J Hematol Oncol 10:67. https://doi.org/10.1186/s13045-017-0436-9
Zhang L et al (2015) Effects of Propofol on excitatory and inhibitory amino acid neurotransmitter balance in rats with neurogenic pulmonary edema induced by subarachnoid hemorrhage. Neurocrit Care. https://doi.org/10.1007/s12028-015-0206-x
Zhang HB, Tu XK, Chen Q, Shi SS (2019) Propofol reduces inflammatory brain injury after subarachnoid hemorrhage: involvement of PI3K/Akt pathway. J Stroke Cerebrovasc Dis 28:104375. https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.104375
Zhao YN, Guo XF, Li JM, Chen CX, Li SX, Xu CJ (2017) mTOR/autophagy pathway in the hippocampus of rats suffering intermittent hypoxia preconditioning and global cerebral ischemia-reperfusion. Oncotarget. https://doi.org/10.18632/oncotarget.15058
Zhao Y, Gan Y, Xu G, Yin G, Liu D (2020) MSCs-derived exosomes attenuate acute brain injury and inhibit microglial inflammation by reversing CysLT2R-ERK1/2 mediated microglia M1 polarization. Neurochem Res 45:1180–1190. https://doi.org/10.1007/s11064-020-02998-0
Zu L, Zheng X, Wang B, Parajuli N, Steenbergen C, Becker LC, Cai ZP (2011) Ischemic preconditioning attenuates mitochondrial localization of PTEN induced by ischemia-reperfusion. Am J Phys Heart Circ Phys 300:H2177–H2186. https://doi.org/10.1152/ajpheart.01138.2010
Acknowledgments
This work was supported by the School-level project of Ningxia Medical University [grant number xm2016059].
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The data used to support the findings of this study are available from the corresponding author upon request.
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Yaru Chen and Zhenzhou Li are co-first authors.
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Chen, Y., Li, Z. Protective Effects of Propofol on Rats with Cerebral Ischemia–Reperfusion Injury Via the PI3K/Akt Pathway. J Mol Neurosci 71, 810–820 (2021). https://doi.org/10.1007/s12031-020-01703-8
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DOI: https://doi.org/10.1007/s12031-020-01703-8