Chris O’Sullivan

Introduction. Postoperative Cognitive Dysfunction (POCD) is serious post-anesthesia complication characterized by varied neurological deficits such as loss of spatial memory and executive functions.¹ POCD can affect over 50% of all elderly patients undergoing surgery, with about 10% continuing symptoms over 3 months after surgery.² The most important risk factor for POCD is age which is concerning because the United States elderly population is expected to double in the next 40 years.³ The mechanism, and treatment, of POCD involves the NFκB pathway.⁴ NFκB is a transcription factor that enters the nucleus to promote production of inflammatory cytokines such as IL-1, IL-6, and TNF. Volatile anesthetics, such as isoflurane and sevoflurane, promote POCD by over activating this pathway. Methods. Rat studies show increased phosphorylation of the NFκB inhibitor, IκB, after volatile anesthetic exposure, causing the overactivation of NFκB.⁵ The aim of all studies was to show both a cellular effect and a cognitive effect. Cellular effects were quantified using Western Blots to measure the amount of IκB and p-IκB. Cognitive effects were measured mainly using a Morris Water Maze (MWM). These were short-term studies, and results were typically measured at 1 day, 3 days, and 7 days after anesthesia exposure.^{5, 6, 7} Results. In the three studies that looked at treating POCD, all showed positive outcomes when the NFκB pathway was inhibited at various steps. YC-1 inhibits Hypoxia-inducible factor-1α (HIF-1α), an upstream mediator of NFκB.⁵ By blocking this, western blots showed decreased p-IκB and MWM showed improvement 4 days post-anesthesia.⁵ MicroRNA-146a, an anti-inflammatory RNA, was also researched as a potential treatment for POCD.⁶ It binds to RNA in the NFκB pathway to prevent them from being translated into functional proteins, essentially halting the pathway. Western blot and a fear conditioning test confirmed its efficacy.⁶ Finally, a tripeptide, Annexin A1, that binds to the p65 subunit of NFκB, was found to prevent its translocation into the nucleus, therefore preventing its action.⁷ Conclusions. Increased activity of NFκB after exposure to anesthesia has been shown to cause POCD through constitutive inflammation leading to problems with long term potentiation and synapsing between neurons in the hippocampus. All of the treatments researched showed promise in ameliorating the effects of the overactivation of this pathway on both a cellular and cognitive level. Future studies are needed to prove their efficacy in elderly human populations.

1. Nakao S, Yamamoto T, Kimura S, Mino T, Iwamoto T. Brain white matter lesions and postoperative cognitive dysfunction: a review. Journal of Anesthesia. 2019. doi:10.1007/s00540-019-02613-9.
2. Safavynia SA, Goldstein PA. The Role of Neuroinflammation in Postoperative Cognitive Dysfunction: Moving From Hypothesis to Treatment. Frontiers in Psychiatry. 2019;9. doi:10.3389/fpsyt.2018.00752.
3. Fact Sheet: Aging in the United States. Population Reference Bureau. https://www.prb.org/aging- unitedstates-fact-sheet/. Accessed February 26, 2019.
4. Li Z, Ni C, Xia C, et al. Calcineurin/nuclear factor-κB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats. Molecular Medicine Reports. 2016;15(1):201-209. doi:10.3892/mmr.2016.5967.
5. Cao Y, Li Z, Ma L, et al. Isoflurane-induced postoperative cognitive dysfunction is mediated by hypoxia-inducible factor-1α-dependent neuroinflammation in aged rats. Molecular medicine reports. https://www.ncbi.nlm.nih.gov/pubmed/29620198. Published June 2018. Accessed April 8, 2019.
6. Chen L, Dong R, Lu Y, et al. MicroRNA-146a protects against cognitive decline induced by surgical trauma by suppressing hippocampal neuroinflammation in mice. Brain, Behavior, and Immunity. 2019. doi:10.1016/j.bbi.2019.01.020.
7. Zhang Z, Ma Q, Shah B, et al. Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats. Frontiers in immunology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582068/. Published August 30, 2017. Accessed April 8, 2019.