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Involvement of acute neuroinflammation in postoperative delirium-like cognitive deficits in rats

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Abstract

Purpose

The purpose of this study was to investigate the age-, time-, and brain region-dependent postoperative neuroinflammatory trajectory, and its association with neurocognitive outcomes in rats.

Methods

Adult and aged rats were randomly assigned to one of three groups: control, isoflurane anesthesia alone, and isoflurane anesthesia with abdominal surgery. On either postoperative day 2 (early phase) or 7 (late phase), all rats were tested for trace and context fear memory retention after acquisition of trace fear conditioning. Freezing behavior was used as an index of fear memory. Following the cognitive testing, the levels of pro-inflammatory cytokines in several brain regions were measured using enzyme-linked immunosorbent assay (n = 8 in each group).

Results

In the early postoperative period, surgery under isoflurane anesthesia induced acute neuroinflammation along with related trace and context memory dysfunction. Such acute neuroinflammatory responses were comparably observed in both adult and aged animals, whereas the aged rats were more likely to exhibit behavioral changes. On the other hand, in the late postoperative period, neither neuroinflammation in all tested brain regions nor concomitant memory decline were found in adult animals. Significant neuroinflammation was detected only in the hippocampus of aged rats, which was associated with context, but not trace memory dysfunction.

Conclusion

Our findings indicate that surgery-induced acute, transient, brain-wide neuroinflammation may be involved in the pathogenesis of the postoperative delirium-like cognitive deficits in rats. Furthermore, neuroinflammation may convert from acute to chronic in an age- and hippocampal-specific manner, likely resulting in the development of sustained cognitive dysfunction.

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References

  1. Deiner S, Silverstein JH. Postoperative delirium and cognitive dysfunction. Br J Anaesth. 2009;103:i41-46.

    Article  PubMed  Google Scholar 

  2. Marcantonio ER. Postoperative delirium: a 76-year-old woman with delirium following surgery. JAMA. 2012;308:73–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Aldecoa C, Bettelli G, Bilotta F, Sanders RD, Audisio R, Borozdina A, Cherubini A, Jones C, Kehlet H, MacLullich A, Radtke F, Riese F, Slooter AJ, Veyckemans F, Kramer S, Neuner B, Weiss B, Spies CD. European Society of Anaesthesiology evidence-based and consensus-based guideline on postoperative delirium. Eur J Anaesthesiol. 2017;34:192–214.

    Article  PubMed  Google Scholar 

  4. American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults. American Geriatrics Society abstracted clinical practice guideline for postoperative delirium in older adults. J Am Geriatr Soc. 2015; 63: 142 – 50.

    Article  Google Scholar 

  5. Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, Jones RN. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012;367:30 – 9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Koster S, Hensens AG, van der Palen J. The long-term cognitive and functional outcomes of postoperative delirium after cardiac surgery. Ann Thorac Surg. 2009;87:1469–74.

    Article  PubMed  Google Scholar 

  7. Schreuder L, Eggen BJ, Biber K, Schoemaker RG, Laman JD, de Rooij SE. Pathophysiological and behavioral effects of systemic inflammation in aged and diseased rodents with relevance to delirium: a systematic review. Brain Behav Immun. 2017;62:362–81.

    Article  PubMed  CAS  Google Scholar 

  8. Cunningham C. Microglia and neurodegeneration: the role of systemic inflammation. Glia. 2013;61:71–90.

    Article  PubMed  Google Scholar 

  9. Murray CL, Skelly DT, Cunningham C. Exacerbation of CNS inflammation and neurodegeneration by systemic LPS treatment is independent of circulating IL-1β and IL-6. J Neuroinflammation. 2011;8:50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Munster BC, Aronica E, Zwinderman AH, Eikelenboom P, Cunningham C, Rooij SE. Neuroinflammation in delirium: a postmortem case-control study. Rejuvenation Res. 2011;14:615 – 22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Kawano T, Eguchi S, Iwata H, Tamura T, Kumagai N, Yokoyama M. Impact of preoperative environmental enrichment on prevention of development of cognitive impairment following abdominal surgery in a rat model. Anesthesiology. 2015;123:160 – 70.

    Article  PubMed  Google Scholar 

  12. Runyan JD, Moore AN, Dash PK. A role for prefrontal cortex in memory storage for trace fear conditioning. J Neurosci. 2004;24:1288–95.

    Article  PubMed  CAS  Google Scholar 

  13. Han CJ, O’Tuathaigh CM, van Trigt L, Quinn JJ, Fanselow MS, Mongeau R, Koch C, Anderson DJ. Trace but not delay fear conditioning requires attention and the anterior cingulate cortex. Proc Natl Acad Sci USA. 2003;100:13087–92.

    Article  PubMed  CAS  Google Scholar 

  14. Song C, Ehlers VL, Moyer JR. Trace fear conditioning differentially modulates intrinsic excitability of medial prefrontal cortex-basolateral complex of amygdala projection neurons in infralimbic and prelimbic cortices. J Neurosci. 2015;35:13511–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Kawano T, Eguchi S, Iwata H, Yamanaka D, Tateiwa H, Locatelli FM, Yokoyama M. Pregabalin can prevent, but not treat, cognitive dysfunction following abdominal surgery in aged rats. Life Sci. 2016;148:211–9.

    Article  PubMed  CAS  Google Scholar 

  16. Kawano T, Iwata H, Aoyama B, Nishigaki A, Yamanaka D, Tateiwa H, Eguchi S, Locatelli FM, Yokoyama M. The role of hippocampal insulin signaling on postoperative cognitive dysfunction in an aged rat model of abdominal surgery. Life Sci. 2016;162:87–94.

    Article  PubMed  CAS  Google Scholar 

  17. Sotocinal SG, Sorge RE, Zaloum A, Tuttle AH, Martin LJ, Wieskopf JS, Mapplebeck JC, Wei P, Zhan S, Zhang S, McDougall JJ, King OD, Mogil JS. The Rat Grimace Scale: a partially automated method for quantifying pain in the laboratory rat via facial expressions. Mol Pain. 2011;7:55.

    PubMed  PubMed Central  Google Scholar 

  18. Gilmartin MR, Helmstetter FJ. Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex. Learn Mem. 2010;17:289–296.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Glowinski J, Iversen LL. Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain. J Neurochem. 1966;13:655 – 69.

    Article  PubMed  CAS  Google Scholar 

  20. Leal MC, Casabona JC, Puntel M, Pitossi FJ. Interleukin-1β and tumor necrosis factor-α: reliable targets for protective therapies in Parkinson’s Disease? Front Cell Neurosci. 2013;7:53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. European Delirium Association; American Delirium Society. The DSM-5 criteria, level of arousal and delirium diagnosis: inclusiveness is safer. BMC Med. 2014;12:141.

    Article  Google Scholar 

  22. Field RH, Gossen A, Cunningham C. Prior pathology in the basal forebrain cholinergic system predisposes to inflammation-induced working memory deficits: reconciling inflammatory and cholinergic hypotheses of delirium. J Neurosci. 2012;32:6288–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Perry VH, Holmes C. Microglial priming in neurodegenerative disease. Nat Rev Neurol. 2014;10:217–224.

    Article  PubMed  CAS  Google Scholar 

  24. Hoeijmakers L, Heinen Y, van Dam AM, Lucassen PJ, Korosi A. Microglial priming and Alzheimer’s disease: a possible role for (early) immune challenges and epigenetics? Front Hum Neurosci. 2016;10:398.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39:151 – 70.

    Article  PubMed  CAS  Google Scholar 

  26. Lee YM, Song BC, Yeum KJ. Impact of volatile anesthetics on oxidative stress and inflammation. Biomed Res Int. 2015;2015:242709.

    PubMed  PubMed Central  Google Scholar 

  27. Cao L, Li L, Lin D, Zuo Z. Isoflurane induces learning impairment that is mediated by interleukin 1β in rodents. PLoS One. 2012;7:e51431.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Blum FE, Zuo Z. Volatile anesthetics-induced neuroinflammatory and anti-inflammatory responses. Med Gas Res. 2013;3:16.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Whitlock EL, Torres BA, Lin N, Helsten DL, Nadelson MR, Mashour GA, Avidan MS. Postoperative delirium in a substudy of cardiothoracic surgical patients in the BAG-RECALL clinical trial. Anesth Analg. 2014;118:809 – 17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Fritz BA, Kalarickal PL, Maybrier HR, Muench MR, Dearth D, Chen Y, Escallier KE, Ben Abdallah A, Lin N, Avidan MS. Intraoperative electroencephalogram suppression predicts postoperative delirium. Anesth Analg. 2016;122:234 – 42.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Vacas S, Degos V, Feng X, Maze M. The neuroinflammatory response of postoperative cognitive decline. Br Med Bull. 2013;106:161 – 78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Hovens IB, Schoemaker RG, van der Zee EA, Absalom AR, Heineman E, van Leeuwen BL. Postoperative cognitive dysfunction: Involvement of neuroinflammation and neuronal functioning. Brain Behav Immun. 2014;38:202 – 10.

    Article  PubMed  CAS  Google Scholar 

  33. Hein AM, Stasko MR, Matousek SB, Scott-McKean JJ, Maier SF, Olschowka JA, Costa AC, O’Banion MK. Sustained hippocampal IL-1β overexpression impairs contextual and spatial memory in transgenic mice. Brain Behav Immun. 2010;24:243 – 53.

    Article  PubMed  CAS  Google Scholar 

  34. Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-α. Nature. 2006;440:1054–9.

    Article  PubMed  CAS  Google Scholar 

  35. Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M. Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci USA. 2010;107:20518–22.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a Grant-in Aid for Scientific Research (C): [Grant number 15K10538 to TK] from the Japan Society for the Promotion of Science, Tokyo, Japan.

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Authors and Affiliations

  1. Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan

    Takashi Kawano, Daiki Yamanaka, Bun Aoyama, Hiroki Tateiwa, Marie Shigematsu-Locatelli, Atsushi Nishigaki, Hideki Iwata, Fabricio M. Locatelli & Masataka Yokoyama

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  1. Takashi Kawano
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  2. Daiki Yamanaka
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  3. Bun Aoyama
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  5. Marie Shigematsu-Locatelli
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  6. Atsushi Nishigaki
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  9. Masataka Yokoyama
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Correspondence to Takashi Kawano.

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Kawano, T., Yamanaka, D., Aoyama, B. et al. Involvement of acute neuroinflammation in postoperative delirium-like cognitive deficits in rats. J Anesth 32, 506–517 (2018). https://doi.org/10.1007/s00540-018-2504-x

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