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Propofol Administration During Early Postnatal Life Suppresses Hippocampal Neurogenesis

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Abstract

Propofol is currently one of the most widely used intravenous anesthetics and has been indicated to induce cognitive dysfunction in adults. Here, we investigated the effects of propofol exposure during early postnatal life on hippocampal neurogenesis. Propofol (30 or 60 mg/kg) was administered to mice on either postnatal day (P) 7 or P7–P9; cell proliferation and neurogenesis in the dentate gyrus (DG) were evaluated on P8 or P17. It showed that exposure to propofol on P7 decreased hippocampal cell proliferation as indicated by BrdU and Sox2 immunostaining at P8 in propofol treatment at the dosage of 60 mg/kg but not at the dosage of 30 mg/kg. Western blots revealed propofol treatment decreased Akt or extracellular signal-related kinase (ERK) 1/2 phosphorylation in the hippocampus at P8. Propofol treatment on P7 to P9 reduced the numbers of newly formed neurons in the DG at P17, which was accompanied by delay of granule neuron maturation and decreased the density of dendritic spines, particularly the mushroom-shaped mature spines. Furthermore, the in vitro findings indicated propofol suppressed cell proliferation and cell mitosis and activated apoptosis of C17.2 neural stem cell line in a dose-dependent manner. These findings suggest that propofol impairs cell proliferation and inhibits neurogenesis in the immature mouse brain and thus is possibly involved in the cognitive dysfunction induced by propofol anesthesia.

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References

  1. Istaphanous GK, Loepke AW (2009) General anesthetics and the developing brain. Curr Opin Anesthesiol 22(3):368–373

    Article  Google Scholar 

  2. McCann ME, Soriano SG (2012) General anesthetics in pediatric anesthesia: influences on the developing brain. Curr Drug Targets 13(7):944–951

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Reddy SV (2012) Effect of general anesthetics on the developing brain. J Anaesthesiol Clin Pharmacol 28(1):6–10

    Article  PubMed Central  PubMed  Google Scholar 

  4. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF (2003) Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosc: Off J Soc Neurosci 23(3):876–882

    CAS  Google Scholar 

  5. Cattano D, Young C, Straiko MM, Olney JW (2008) Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg 106(6):1712–1714

    Article  CAS  PubMed  Google Scholar 

  6. Fredriksson A, Ponten E, Gordh T, Eriksson P (2007) Neonatal exposure to a combination of N-methyl-D-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 107(3):427–436

    Article  CAS  PubMed  Google Scholar 

  7. Ikonomidou C (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283(5398):70–74

    Article  CAS  PubMed  Google Scholar 

  8. Satomoto M, Satoh Y, Terui K, Miyao H, Takishima K, Ito M, Imaki J (2009) Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology 110(3):628–637

    Article  CAS  PubMed  Google Scholar 

  9. Yu D, Jiang Y, Gao J, Liu B, Chen P (2013) Repeated exposure to propofol potentiates neuroapoptosis and long-term behavioral deficits in neonatal rats. Neurosci Lett 534:41–46

    Article  CAS  PubMed  Google Scholar 

  10. Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO (2009) Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 110(4):796–804

    Article  PubMed Central  PubMed  Google Scholar 

  11. Franks NP, Lieb WR (1994) Molecular and cellular mechanisms of general anaesthesia. Nature 367(6464):607–614

    Article  CAS  PubMed  Google Scholar 

  12. Hudson AE, Hemmings HC Jr (2011) Are anaesthetics toxic to the brain? Br J Anaesth 107(1):30–37

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Irifune M, Takarada T, Shimizu Y, Endo C, Katayama S, Dohi T, Kawahara M (2003) Propofol-induced anesthesia in mice is mediated by gamma-aminobutyric acid-A and excitatory amino acid receptors. Anesth Analg 97(2):424–429, table of contents

    Article  CAS  PubMed  Google Scholar 

  14. Harris KM, Jensen FE, Tsao B (1992) Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J Neurosc: Off J Soc Neurosci 12(7):2685–2705

    CAS  Google Scholar 

  15. Stratmann G (2011) Review article: neurotoxicity of anesthetic drugs in the developing brain. Anesth Analg 113(5):1170–1179

    Article  CAS  PubMed  Google Scholar 

  16. Vutskits L (2012) Anesthetic-related neurotoxicity and the developing brain: shall we change practice? Paediatric Drugs 14(1):13–21

    Article  PubMed  Google Scholar 

  17. Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250

    Article  CAS  PubMed  Google Scholar 

  18. Deng W, Aimone JB, Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11(5):339–350

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Eichenbaum H (2004) Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron 44(1):109–120

    Article  CAS  PubMed  Google Scholar 

  20. Winocur G, Wojtowicz JM, Sekeres M, Snyder JS, Wang S (2006) Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus 16(3):296–304

    Article  PubMed  Google Scholar 

  21. Erasso DM, Camporesi EM, Mangar D, Saporta S (2013) Effects of isoflurane or propofol on postnatal hippocampal neurogenesis in young and aged rats. Brain Res 1530:1–12

    Article  CAS  PubMed  Google Scholar 

  22. Erasso DM, Chaparro RE, del Rio CEQ, Karlnoski R, Camporesi EM, Saporta S (2012) Quantitative assessment of new cell proliferation in the dentate gyrus and learning after isoflurane or propofol anesthesia in young and aged rats. Brain Res 1441:38–46

    Article  CAS  PubMed  Google Scholar 

  23. Thal SC, Timaru-Kast R, Wilde F, Merk P, Johnson F, Frauenknecht K, Sebastiani A, Sommer C, Staib-Lasarzik I, Werner C (2014) Propofol impairs neurogenesis and neurological recovery and increases mortality rate in adult rats after traumatic brain injury. Crit Care Med 42(1):129–141

  24. Krzisch M, Sultan S, Sandell J, Demeter K, Vutskits L, Toni N (2013) Propofol anesthesia impairs the maturation and survival of adult-born hippocampal neurons. Anesthesiology 118(3):602–610

    Article  CAS  PubMed  Google Scholar 

  25. Sall JW, Stratmann G, Leong J, Woodward E, Bickler PE (2012) Propofol at clinically relevant concentrations increases neuronal differentiation but is not toxic to hippocampal neural precursor cells in vitro. Anesthesiology 117(5):1080–1090

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Popic J, Pesic V, Milanovic D, Todorovic S, Kanazir S, Jevtovic-Todorovic V, Ruzdijic S (2012) Propofol-induced changes in neurotrophic signaling in the developing nervous system in vivo. PLoS One 7(4):e34396

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Whittington RA, Virag L, Marcouiller F, Papon MA, El Khoury NB, Julien C, Morin F, Emala CW, Planel E (2011) Propofol directly increases tau phosphorylation. PLoS One 6(1):e16648

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Li DB, Tang J, Xu HW, Fan XT, Bai Y, Yang L (2008) Decreased hippocampal cell proliferation correlates with increased expression of BMP4 in the APPswe/PS1DeltaE9 mouse model of Alzheimer’s disease. Hippocampus 18(7): 692–698

  29. Gao X, Deng P, Xu ZC, Chen J (2011) Moderate traumatic brain injury causes acute dendritic and synaptic degeneration in the hippocampal dentate gyrus. PLoS One 6(9):e24566

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Yau SY, Lau BW, Tong JB, Wong R, Ching YP, Qiu G, Tang SW, Lee TM, So KF (2011) Hippocampal neurogenesis and dendritic plasticity support running-improved spatial learning and depression-like behaviour in stressed rats. PLoS One 6(9):e24263

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Wang SJ, Weng CH, Xu HW, Zhao CJ, Yin ZQ (2014) Effect of optogenetic stimulus on the proliferation and cell cycle progression of neural stem cells. J membr Biol 247(6):493–500

    Article  CAS  PubMed  Google Scholar 

  32. Snyder EY, Deitcher DL, Walsh C, Arnold-Aldea S, Hartwieg EA, Cepko CL (1992) Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 68(1):33–51

    Article  CAS  PubMed  Google Scholar 

  33. Chen X, Li QY, Xu HW, Yin ZQ (2014) Sodium iodate influences the apoptosis, proliferation and differentiation potential of radial glial cells in vitro. Cell Physiol Biochem 34(4):1109–1124

    Article  CAS  PubMed  Google Scholar 

  34. Fan XT, Xu HW, Cai WQ, Yang H, Liu S (2004) Antisense Noggin oligodeoxynucleotide administration decreases cell proliferation in the dentate gyrus of adult rats. Neurosci Lett 366(1):107–111

    Article  CAS  PubMed  Google Scholar 

  35. Mullen RJ, Buck CR, Smith AM (1992) NeuN, a neuronal specific nuclear protein in vertebrates. Development 116(1):201–211

    CAS  PubMed  Google Scholar 

  36. Snyder JS, Hong NS, McDonald RJ, Wojtowicz JM (2005) A role for adult neurogenesis in spatial long-term memory. Neuroscience 130(4):843–852

    Article  CAS  PubMed  Google Scholar 

  37. Kuhn HG, Dickinson-Anson H, Gage FH (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosc: Off J Soc Neurosci 16(6):2027–2033

    CAS  Google Scholar 

  38. Pevny LH, Nicolis SK (2010) Sox2 roles in neural stem cells. Int J Biochem Cell Biol 42(3):421–424

    Article  CAS  PubMed  Google Scholar 

  39. Bonaguidi MA, Wheeler MA, Shapiro JS, Stadel RP, Sun GJ, Ming GL, Song H (2011) In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell 145(7):1142–1155

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Feng R, Zhou S, Liu Y, Song D, Luan Z, Dai X, Li Y, Tang N, Wen J, Li L (2013) Sox2 protects neural stem cells from apoptosis via up-regulating survivin expression. Biochem J 450(3):459–468

    Article  CAS  PubMed  Google Scholar 

  41. Wang H, Luo M, Li C, Wang G (2011) Propofol post-conditioning induced long-term neuroprotection and reduced internalization of AMPAR GluR2 subunit in a rat model of focal cerebral ischemia/reperfusion. J Neurochem 119(1):210–219

    Article  CAS  PubMed  Google Scholar 

  42. Peters A, Kaiserman-Abramof IR (1970) The small pyramidal neuron of the rat cerebral cortex. The perikaryon, dendrites and spines. Am J Anat 127(4):321–355

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Nature Science Foundation of China (No. 81371197) and the Natural Science Foundation Project of CQ CSTC 2013jjB10028.

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Authors and Affiliations

  1. Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People’s Republic of China

    Jing Huang, Sheng Jing, Xiaohang Bao, Zhiyong Du, Hong Li & Tiande Yang

  2. School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of China

    Xi Chen

  3. Department of Ophthalmology, Chinese People’s Liberation Army General Hospital, Beijing, 100853, People’s Republic of China

    Xi Chen

  4. Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Xiaotang Fan

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  1. Jing Huang
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Correspondence to Tiande Yang or Xiaotang Fan.

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Jing Huang and Sheng Jing contributed equally to this work.

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Huang, J., Jing, S., Chen, X. et al. Propofol Administration During Early Postnatal Life Suppresses Hippocampal Neurogenesis. Mol Neurobiol 53, 1031–1044 (2016). https://doi.org/10.1007/s12035-014-9052-7

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