Hostname: page-component-848d4c4894-wg55d Total loading time: 0 Render date: 2024-05-01T12:37:56.186Z Has data issue: false hasContentIssue false

Anaesthesia and brain development: a review of propofol-induced neurotoxicity in pediatric populations

Published online by Cambridge University Press:  07 March 2024

Weixin Zhang
Affiliation:
Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
Qi Liu
Affiliation:
Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
Junli Wang
Affiliation:
Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
Li Liu*
Affiliation:
Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
*
Corresponding author: L. Liu; Email: liul@hrbmu.edu.cn

Abstract

With the advancement of medical technology, there are increasing opportunities for new-borns, infants, and pregnant women to be exposed to general anaesthesia. Propofol is commonly used for the induction of anaesthesia, maintenance of general intravenous anaesthesia and sedation of intensive-care children. Many previous studies have found that propofol has organ-protective effects, but growing evidence suggests that propofol interferes with brain development, affecting learning and cognitive function. The purpose of this review is to summarize the latest progress in understanding the neurotoxicity of propofol. Evidence from case studies and clinical studies suggests that propofol has neurotoxicity on the developing brain. We classify the findings on propofol-induced neurotoxicity based on its damage mechanism. We end by summarizing the current protective strategies against propofol neurotoxicity. Fully understanding the neurotoxic mechanisms of propofol can help us use it at a reasonable dosage, reduce its side effects, and increase patient safety.

Type
Review
Copyright
© The Author(s), 2024. Published by Cambridge University Press in association with The International Society for Developmental Origins of Health and Disease (DOHaD)

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Zhang, W, Liu, Q, Ma, C, et al. Propofol induces the apoptosis of neural stem cells via microRNA-9-5p / chemokine CXC receptor 4 signaling pathway. Bioengineered. 2022; 13(1), 10621072.CrossRefGoogle ScholarPubMed
Xintong, Z, Jinghua, Z, Tian, C, Qi, W, Wenhan, L, Li, G. Ketamine exerts neurotoxic effects on the offspring of pregnant rats via the Wnt/β-catenin pathway. Environ Sci Pollut R Int. 2020; 27(1), 305314.Google Scholar
Zhang, W, Chen, Y, Qin, J, et al. Prolonged sevoflurane exposure causes abnormal synapse development and dysregulates beta-neurexin and neuroligins in the hippocampus in neonatal rats. J Affect Disorders. 2022; 312, 2229.CrossRefGoogle ScholarPubMed
Zuo, C, Ma, J, Pan, Y, et al. Isoflurane and sevoflurane induce cognitive impairment in neonatal rats by inhibiting neural stem cell development through microglial activation, neuroinflammation, and suppression of VEGFR2 signaling pathway. Neurotox Res. 2022; 40(3), 775790.CrossRefGoogle ScholarPubMed
Franks, NP, Lieb, WR. Molecular and cellular mechanisms of general anaesthesia. Nature. 1994; 367(6464), 607614.CrossRefGoogle ScholarPubMed
Tagawa, T, Sakuraba, S, Mizoguchi, A. In reply: is propofol more neurotoxic in the developing brain? J Anesth. 2015; 29(2), 314314.CrossRefGoogle ScholarPubMed
Jiang, W, Duong, T, de Lanerolle, N. The neuropathology of hyperthermic seizures in the rat. Epilepsia. 1999; 40(1), 519.CrossRefGoogle ScholarPubMed
Jevtovictodorovic, V, Hartman, RE, Izumi, Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003; 23(3), 876882.CrossRefGoogle ScholarPubMed
Olney, JW, Ikonomidou, C, Mosinger, JL, Frierdich, G. MK-801 prevents hypobaric-ischemic neuronal degeneration in infant rat brain. J Neurosci. 1989; 9(5), 17011704.CrossRefGoogle ScholarPubMed
Zhang, Z, Xu, Y, Chi, S, Cui, L. MicroRNA-582-5p reduces propofol-induced apoptosis in developing neurons by targeting ROCK1. Curr Neurovasc Res. 2020; 17(2), 140146.CrossRefGoogle ScholarPubMed
Huang, J, Jing, S, Chen, X, et al. Propofol administration during early postnatal life suppresses hippocampal neurogenesis. Mol Neurobiol. 2016; 53(2), 10311044.CrossRefGoogle ScholarPubMed
Xiong, M, Li, J, Alhashem, HM, Tilak, V, Bekker, A. Propofol exposure in pregnant rats induces neurotoxicity and persistent learning deficit in the offspring. Brain Sci. 2014; 4(2), 356375.CrossRefGoogle ScholarPubMed
Millar, K, Bowman, AW, Burns, D, et al. Children’s cognitive recovery after day-case general anesthesia: a randomized trial of propofol or isoflurane for dental procedures. Pediatr Anesth. 2014; 24(2), 201207.CrossRefGoogle ScholarPubMed
Lanigan, C, et al. M. Neurological sequelae in children after prolonged propofol infusion. Anaesthesia. 1992; 47(9), 810–1.CrossRefGoogle ScholarPubMed
Meyer, P, Langlois, C, So?Te, S, et al. Unexpected neurological sequelae following propofol anesthesia in infants: three case reports. Brain Dev-JPN. 2010; 32(10), 872878.CrossRefGoogle ScholarPubMed
Olutoye, O, Baker, B, Belfort, M, Olutoye, O. Food and drug administration warning on anesthesia and brain development: implications for obstetric and fetal surgery. Am J Obstet Gynecol. 2018; 218(1), 98102.CrossRefGoogle ScholarPubMed
Zhou, H, Xie, Z, Brambrink, AM, Yang, G. Behavioural impairments after exposure of neonatal mice to propofol are accompanied by reductions in neuronal activity in cortical circuitry. Brit J Anaesth. 2021; 126(6), 11411156.CrossRefGoogle ScholarPubMed
Qin, J, Li, Y, Wang, K. Propofol induces impairment of mitochondrial biogenesis through inhibiting the expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha. J Cell Biochem. 2019; 120(10), 1828818297.CrossRefGoogle ScholarPubMed
Xiao, F, Lv, J, Liang, YB, et al. The expression of glucose transporters and mitochondrial division and fusion proteins in rats exposed to hypoxic preconditioning to attenuate propofol neurotoxicity. Int J Neurosci. 2020; 130(2), 161169.CrossRefGoogle ScholarPubMed
Liang, C, Sun, M, Zhong, J, Miao, C, Han, X. The role of Pink1-mediated mitochondrial pathway in propofol-induced developmental neurotoxicity. Neurochem Res. 2021; 7(9), 112.Google Scholar
Liu, X, Shirley, etal. REST and stress resistance in ageing and Alzheimer’s disease. Nature. 2016; 507, 448.CrossRefGoogle Scholar
Crotty, GF, Ascherio, A, Schwarzschild, MA. Targeting urate to reduce oxidative stress in Parkinson disease. Experiment Neurol. 2017; 298, 210224.CrossRefGoogle ScholarPubMed
Ma, AS, Reverter-Branchat, G, Tamarit, J, Ferrer, I, Ros, J, abiscol, EC. Proteomic and oxidative stress analysis in human brain samples of Huntington disease. Free Radical Bio Med. 2008; 45(5), 667678.Google Scholar
Araceli, DR, Patricia, VA, Antonio, MN, et al. Metallothionein-II inhibits lipid peroxidation and improves functional recovery after transient brain ischemia and reperfusion in rats. Oxidative Med Cell Longev. 2014; 2014, 436429.Google Scholar
Zhang, Y, Dong, Y, Wu, X, et al. The mitochondrial pathway of anesthetic isoflurane-induced apoptosis. J Biol Chem. 2010; 285(6), 40254037.CrossRefGoogle ScholarPubMed
Liang, C, Du, F, Cang, J, Xue, Z. Pink1 attenuates propofol-induced apoptosis and oxidative stress in developing neurons. J Anesth. 2018; 32(1), 6269.CrossRefGoogle ScholarPubMed
Tang, F, Zhao, L, Yu, Q, et al. Upregulation of miR-215 attenuates propofol-induced apoptosis and oxidative stress in developing neurons by targeting LATS2. Mol Med. 2020; 26(1), 38.CrossRefGoogle ScholarPubMed
Wei, H, Xie, Z. Anesthesia, calcium homeostasis and Alzheimer’s disease. Curr Alzheimer Res. 2009; 6(1), 3035.CrossRefGoogle ScholarPubMed
Zhu, X, Yao, Y, Guo, M, Li, J, Lin, D. Sevoflurane increases intracellular calcium to induce mitochondrial injury and neuroapoptosis. Toxicol Lett. 2021; 336, 1120.CrossRefGoogle ScholarPubMed
Satoshi, S, Tomotaka, M, Jun, K. Intravenous anesthetic-induced calcium dysregulation and neurotoxic shift with age during development in primary cultured neurons. NeuroToxicology. 2018; 69, S0161813X1830322X–.Google Scholar
Xu, ZD, Wang, Y, Liang, G, et al. Propofol affects mouse embryonic fibroblast survival and proliferation in vitro via ATG5- and calcium-dependent regulation of autophagy. Acta Pharmacol Sin. 2020; 41(3), 303310.CrossRefGoogle ScholarPubMed
Peng, X, Li, C, Yu, W, Liu, S, Qi, S. Propofol attenuates hypoxia-induced inflammation in BV2 microglia by inhibiting oxidative stress and NF- κ B/Hif-1 α signaling. Biomed Res Int. 2020; 2020, 1–11.Google Scholar
Liu, J, Li, Y, Xia, X, et al. Propofol reduces microglia activation and neurotoxicity through inhibition of extracellular vesicle release. J Neuroimmunol. 2019; 333, 476962.CrossRefGoogle Scholar
Jiang, P, Jiang, Q, Yan, Y, Hou, Z, Luo, D. Propofol ameliorates neuropathic pain and neuroinflammation through PPAR γ up-regulation to block Wnt/β-catenin pathway. Neurol Res. 2020; 43(1), 17.Google ScholarPubMed
Wang, S, Fu, X, Duan, R, et al. TREML2The Alzheimer’s disease-associated gene modulates inflammation by regulating microglia polarization and NLRP3 inflammasome activation. Neural Regen Res. 2023; 18(2), 434438.Google ScholarPubMed
Wang, M, Suo, L, Yang, S, Zhang, W. CircRNA 001372 reduces inflammation in propofol-induced neuroinflammation and neural apoptosis through PIK3CA/Akt/NF-κB by miRNA-148b-3p. J Invest Surg. 2021; 34(11), 11671177.CrossRefGoogle ScholarPubMed
Chen, B, Deng, X, Wang, B, Liu, H. Etanercept, an inhibitor of TNF-a, prevents propofol-induced neurotoxicity in the developing brain. Int J Dev Neurosci. 2016; 55(1), 91100.CrossRefGoogle ScholarPubMed
Yang, Y, Yi, J, Pan, M, Hu, B, Duan, H. Edaravone alleviated propofol-induced neural injury in developing rats by BDNF/TrkB pathway. J Cell Mol Med. 2021; 25(11), 49744987.CrossRefGoogle ScholarPubMed
Milanovic, D, Pesic, V, Loncarevic-Vasiljkovic, N, et al. The fas ligand/Fas death receptor pathways contribute to propofol-induced apoptosis and neuroinflammation in the brain of neonatal rats. Neurotox Res. 2016; 30(3), 434452.CrossRefGoogle ScholarPubMed
Mehta, SL, Chokkalla, AK, Vemuganti, R. Noncoding RNA crosstalk in brain health and diseases. Neurochem Int. 2021; 149, 105139.CrossRefGoogle ScholarPubMed
Ang, CE, Trevino, AE, Chang, HY. Diverse lncRNA mechanisms in brain development and disease. Curr Opin Genet Dev. 2020; 65, 4246.CrossRefGoogle ScholarPubMed
Xiu, M, Luan, H, Gu, X, Liu, C, Xu, D. MicroRNA-17-5p protects against propofol anesthesia-induced neurotoxicity and autophagy impairment via targeting BCL2L11. Comput Math Method M. 2022; 2022, 6018037–11.Google ScholarPubMed
Xu, Y, Luo, Y, Cao. J, etal, lncRNA BDNF-AS attenuates propofol-induced apoptosis in HT22 cells by modulating the BDNF/TrkB pathway. Mol Neurobiol. 2022; 59(6), 35043511.CrossRefGoogle Scholar
He, L, Hannon, GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004; 5(7), 522531.CrossRefGoogle ScholarPubMed
Bahmad, HF, Darwish, B, Dargham, KB, Machmouchi, R, Chamaa, F. Role of MicroRNAs in anesthesia-induced neurotoxicity in animal models and neuronal cultures: a systematic review. Neurotox Res. 2020; 37(3), 479490.CrossRefGoogle ScholarPubMed
Li, GF, Li, ZB, Zhuang, SJ, Li, GC. Inhibition of microRNA-34a protects against propofol anesthesia-induced neurotoxicity and cognitive dysfunction via the MAPK/ERK signaling pathway. Neurosci Lett. 2018; 675, 152159.CrossRefGoogle ScholarPubMed
Yao, Y, Zhang, J. Propofol induces oxidative stress and apoptosis in vitro via regulating miR-363-3p/CREB signalling axis. Cell Biochem Funct. 2020; 38(8), 11191128.CrossRefGoogle ScholarPubMed
Mao, Z, Wang, W, Gong, H, Wu, Y, Zhang, Y, Wang, X. Upregulation of miR-496 rescues propofol-induced neurotoxicity by targeting rho associated coiled-coil containing protein kinase 2 (ROCK2) in prefrontal cortical neurons. Curr Neurovasc Res. 2020; 17(2), 188195.CrossRefGoogle ScholarPubMed
Zhu, X, Li, H, Tian, M, Zhou, S, He, Y, Zhou, M. miR-455-3p alleviates propofol-induced neurotoxicity by reducing EphA4 expression in developing neurons. Biomarkers. 2020; 25(8), 685692.CrossRefGoogle ScholarPubMed
Jxcab, C, Ypw, D, Xin, Z, Gxla, B, Kuang, Z, Czda, B. lncRNA Mtss1 promotes inflammatory responses and secondary brain injury after intracerebral hemorrhage by targeting miR-709 in mice. Brain Res Bull. 2020; 162, 2029.Google Scholar
Chen, J, Wang, Y, Zhang, X, Li, G, Zheng, K, Duan, C. lncRNA Mtss1 promotes inflammatory responses and secondary brain injury after intracerebral hemorrhage by targeting miR-709 in mice. Brain Res Bull. 2020; 162, 2029.CrossRefGoogle ScholarPubMed
Aliperti, V, Skonieczna, J, Cerase, A. Long non-coding RNA (lncRNA) roles in cell biology, neurodevelopment and neurological disorders. Non-coding RNA. 2021; 7(2), 36.CrossRefGoogle ScholarPubMed
Khani-Habibabadi, F, Zare, L, Sahraian, M, Javan, M, Behmanesh, M. Hotair and Malat1 long noncoding RNAs regulate bdnf expression and oligodendrocyte precursor cell differentiation. Mol Neurobiol. 2022; 59(7), 42094222.CrossRefGoogle ScholarPubMed
Wang, J-Y, Feng, Y, Fu, Y-H, Liu, G-L. Effect of sevoflurane anesthesia on brain is mediated by lncRNA HOTAIR. J Mol Neurosci. 2018; 64(3), 346351.CrossRefGoogle ScholarPubMed
Gong, H, Wan, X, Zhang, Y, Liang, S. Downregulation of HOTAIR reduces neuronal pyroptosis by targeting miR-455-3p/NLRP1 axis in propofol-treated neurons in vitro. Neurochem Res. 2021; 46(5), 11411150.CrossRefGoogle ScholarPubMed
Zeng, Z, Yao, J, Zhong, J, et al. The role of the lncRNA-LRCF in propofol-induced oligodendrocyte damage in neonatal mouse. Neurochem Res. 2021; 46(4), 778791.CrossRefGoogle ScholarPubMed
Briner, A, Nikonenko, I, De Roo, M, Dayer, A, Muller, D, Vutskits, L. Developmental stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology. 2011; 115(2), 282293.CrossRefGoogle ScholarPubMed
Jevtovic-Todorovic, V. Developmental synaptogenesis and general anesthesia: a kiss of death? Curr Pharm Design. 2012; 18(38), 62256231.CrossRefGoogle Scholar
Xu, J, Mathena, RP, Xu, M, et al. Early developmental exposure to general anesthetic agents in primary neuron culture disrupts synapse formation via actions on the mTOR pathway. Int J Mol Sci. 2018; 19(8), 2183.CrossRefGoogle ScholarPubMed
Pearn, ML, Schilling, JM, Jian, M, et al. Inhibition of RhoA reduces propofol-mediated growth cone collapse, axonal transport impairment, loss of synaptic connectivity, and behavioural deficits. Br J Anaesth. 2018; 120(4), 745760.CrossRefGoogle ScholarPubMed
Milanovic, D, Pesic, V, Loncarevic-Vasiljkovic, N, et al. Neonatal propofol anesthesia changes expression of synaptic plasticity proteins and increases stereotypic and anxyolitic behavior in adult rats. Neurotox Res. 2017; 32(2), 247263.CrossRefGoogle ScholarPubMed
Dennis, C, Suh, L, Rodriguez, M, Kril, J, Sutherland, G. Human adult neurogenesis across the ages: an immunohistochemical study. Neuropath Appl Neuro. 2016; 42(7), 621638.CrossRefGoogle ScholarPubMed
Piermartiri, T, Dos Santos, B, Barros-Aragão, F, Prediger, R, Tasca, C. Guanosine promotes proliferation in neural stem cells from hippocampus and neurogenesis in adult mice. Mol Neurobiol. 2020; 57(9), 38143826.CrossRefGoogle ScholarPubMed
Long, B, Li, S, Xue, H, Sun, L, Kim, DH, Ying, L. Effects of propofol treatment in neural progenitors derived from human-induced pluripotent stem cells. Neural Plast. 2017; 2017, 9182748–12.CrossRefGoogle ScholarPubMed
Jiang, Q, Wang, Y, Shi, X. Propofol inhibits neurogenesis of rat neural stem cells by upregulating MicroRNA-141-3p. Stem Cells Dev. 2017; 26(3), 189–196.CrossRefGoogle ScholarPubMed
Hu, Q, Huang, L, Zhao, C, et al. Ca-PKCα-ERK1/2 signaling pathway is involved in the suppressive effect of propofol on proliferation of neural stem cells from the neonatal rat hippocampus. Brain Res Bull. 2019; 149, 148155.CrossRefGoogle ScholarPubMed
Bailey, A, Hou, H, Song, M, et al. GFAP expression and social deficits in transgenic mice overexpressing human sAPPα. Glia. 2013; 61(9), 15561569.CrossRefGoogle ScholarPubMed
Allen, J, Oberdorster, G, Morris-Schaffer, K, et al. Developmental neurotoxicity of inhaled ambient ultrafine particle air pollution: parallels with neuropathological and behavioral features of autism and other neurodevelopmental disorders. Neurotoxicology. 2017; 59, 140154.CrossRefGoogle ScholarPubMed
Liang, C, Du, F, Wang, J, Cang, J, Xue, Z. Propofol regulates neural stem cell proliferation and differentiation via Calmodulin-dependent protein kinase II/AMPK/ATF5 signaling axis. Anesth Analg. 2019; 129(2), 608617.CrossRefGoogle ScholarPubMed
Liu, F, Liu, S, Patterson, T, et al. Protective effects of xenon on propofol-induced neurotoxicity in human neural stem cell-derived models. Mol Neurobiol. 2020; 57(1), 200207.CrossRefGoogle ScholarPubMed
Cao, J, Li, Y, Zeng, F, Liu, X, Qin, Z. Propofol exposure disturbs the differentiation of rodent neural stem cells via an miR-124-3p/Sp1/Cdkn1b axis. Front Cell Dev Biol. 2020; 8, 838.CrossRefGoogle ScholarPubMed
Mahmoud, M, Mason, K. Dexmedetomidine: review, update, and future considerations of paediatric perioperative and periprocedural applications and limitations. Brit J Anaesth. 2015; 115(2), 171182.CrossRefGoogle ScholarPubMed
Li, J, Guo, M, Liu, Y, et al. Both GSK-3β/CRMP2 and CDK5/CRMP2 pathways participate in the protection of dexmedetomidine against propofol-induced learning and memory impairment in neonatal rats. Toxicol Sci. 2019; 1(1), 1210.Google Scholar
Xiao, Y, Zhou, L, Tu, Y, et al. Dexmedetomidine attenuates the propofol-induced long-term neurotoxicity in the developing brain of rats by enhancing the PI3K/Akt signaling pathway. Neuropsych Dis Treat. 2018; 14, 21912206.CrossRefGoogle ScholarPubMed
He, W, Yuan, Q, Zhou, Q. Histamine H3 receptor antagonist clobenpropit protects propofol-induced apoptosis of hippocampal neurons through PI3K/AKT pathway. Eur Rev Med Pharmaco. 2018; 22(22), 80138020.Google ScholarPubMed
Song, S, Kong, X, Wang, B, Sanchez-Ramos, J. Recovery from traumatic brain injury following treatment with Δ9-tetrahydrocannabinol is associated with increased expression of granulocyte-colony stimulating factor and other neurotrophic factors. Cannabis Cannabinoid Res. 2022; 7(4), 415423.CrossRefGoogle ScholarPubMed
Liu, C, Peng, S, Li, Q. RE-1 silencing transcription factor alleviates the growth-suppressive effects of propofol on mouse neuronal cells. Neuroreport. 2019; 30(15), 10251030.CrossRefGoogle ScholarPubMed
Li, X, Zhao, Z, Huang, L, Kang, R, Liu, X, Dong, Z. The anti-apoptotic effect of nerve growth factor on propofol-induced neurotoxicity in hippocampal neurons is Rac1 dependent. Pharmazie. 2018; 73(12), 706710.Google ScholarPubMed
Maze, M, Laitio, T. Neuroprotective properties of xenon. Mol Neurobiol. 2020; 57(1), 118124.CrossRefGoogle ScholarPubMed
Ma, D, Williamson, P, Januszewski, A, et al. Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. Anesthesiology. 2007; 106(4), 746753.CrossRefGoogle ScholarPubMed