Month: April 2022

Post-operative cognitive dysfunction (POCD) is an expansive definition for the wide spectrum of cognitive deficits seen in patients after anesthesia and surgery. Most common deficits of POCD include cognitive impairments, such as memory and information processing, which can also be present in the aftermath of anesthetics. Current data suggests that POCD is most directly caused by neuroinflammation and microglial activation, which triggers an immuno-hormonal cascade increasing the permeability of the blood-brain barrier, ultimately promoting the influx of macrophages into the brain parenchyma. The pro-inflammatory cytokines synthesized by these macrophages cause neuronal damage, apoptosis, and impaired neurotransmission to the hippocampus, medial prefrontal cortex, amygdala, and the cingulate cortex, brain regions critical in memory, reward, emotion, and judgement [1-3].  

Eckenhoff et. al.’s research in 2004 demonstrated clinically relevant concentrations of inhaled anesthetics such as halothane and isoflurane could induce the oligomerization of amyloid β (peptides that compose the amyloid plaques in Alzheimer’s patients) and amyloid-β-induced cytotoxicity [4]. However, intravenous anesthetics such as ethanol and propofol did not have this effect. While desflurane (another inhalational agent) alone does not induce caspase-3 activation or affect amyloid precursor protein cells, a combination of desflurane and hypoxia does both [5]. Additionally, abnormal tau tangles are one of the hallmarks of AD. In 2007, a murine study found anesthetics including chloral hydrate, pentobarbital and isoflurane produced rapid and massive tau protein hyperphosphorylation and inhibition of Ser/Thr phosphatase (PP) activity. These researchers confirmed PP2A (a subtype of PPs) is the main phosphatase driving tau dephosphorylation; their inhibition is a direct result of hypothermia induced by anesthesia [6,7]. Another preclinical study found the inhaled anesthetic sevoflurane generated behavioral deficits in spatial learning and memory in aged rats; the rats also experienced hippocampal alterations, most notably a downregulation of the cAMP/CREB signaling pathway, a pathway extensively implicated as a “hot spot” of long-term potentiation, memory, and neuroprotection [8].  

Following the use of intravenous agents, specific neurological and behavioral changes have been reported. A prolonged infusion of propofol significantly impaired spatial learning in mice, as measured by the Morris water maze behavioral assessment. The CA1 region of the hippocampus showed significant autophagy inhibition, leading to the observed cognitive deficits [9]. Autophagy is the fundamental catabolic process involving degradation of dysfunctional cellular molecules to supply energy and compounds for further biosynthesis. Defective autophagy is associated with increased aging as well as diseases like cancer or neurodegenerative and muscular disorders [10]. Inhaled anesthetics also affect this process, as sevoflurane may cause impaired memory performance and increase hippocampal neuronal apoptosis through its suppression of autophagic processes, potentially increasing the risk of POCD [11]. However, rapamycin, an immunosuppressive drug, reduced the cognitive effects of sevoflurane by inducing autophagy [9,11].

POCD in human patients is often thought to be induced by increased activity of GABA_A receptors, which most general anesthetics act on. The subtypes of GABA_A receptors may be responsible for the different effects of general anesthesia, such as amnesia, sedation, and hypnosis [13]. Preclinical investigations have pinpointed the alpha-5 subunit of GABA_A receptors to be especially responsible, given their significant upregulation after administration of GABAergic anesthetics [12]. Sevoflurane may damage synaptic plasticity by decreasing postsynaptic density protein in mPFC, highlighting another potential mechanism ultimately generating POCD [14].

Although research has proposed plausible mechanisms by which general anesthetics may lead to POCD, interesting perspectives for future consideration involve in-depth study of predisposing and precipitating factors of POCD.

References 

1. Wang, B., Li, S., Cao, X., Dou, X., Li, J., Wang, L., Wang, M., & Bi, Y. (2017). Blood-brain barrier disruption leads to postoperative cognitive dysfunction. Current Neurovascular Research, 14(4), 359–367. https://doi.org/10.2174/1567202614666171009105825 

2. Vacas, S., Degos, V., Feng, X., & Maze, M. (2013). The neuroinflammatory response of postoperative cognitive decline. British Medical Bulletin, 106, 161–178. https://doi.org/10.1093/bmb/ldt006  

3. Cascella, M., & Bimonte, S. (2017). The role of general anesthetics and the mechanisms of hippocampal and extra-hippocampal dysfunctions in the genesis of postoperative cognitive dysfunction. Neural Regeneration Research, 12(11), 1780–1785. https://doi.org/10.4103/1673-5374.219032  

4. Eckenhoff, R. G., Johansson, J. S., Wei, H., Carnini, A., Kang, B., Wei, W., Pidikiti, R., Keller, J. M., & Eckenhoff, M. F. (2004). Inhaled anesthetic enhancement of amyloid-β oligomerization and cytotoxicity. Anesthesiology, 101(3), 703–709. https://doi.org/10.1097/00000542-200409000-00019  

5. Zhang, B., Dong, Y., Zhang, G., Moir, R. D., Xia, W., Yue, Y., Tian, M., Culley, D. J., Crosby, G., Tanzi, R. E., & Xie, Z. (2008). The inhalation anesthetic desflurane induces caspase activation and increases amyloid β-protein levels under hypoxic conditions *. Journal of Biological Chemistry, 283(18), 11866–11875. https://doi.org/10.1074/jbc.M800199200  

6. Planel, E., Richter, K. E. G., Nolan, C. E., Finley, J. E., Liu, L., Wen, Y., Krishnamurthy, P., Herman, M., Wang, L., Schachter, J. B., Nelson, R. B., Lau, L.-F., & Duff, K. E. (2007). Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. Journal of Neuroscience, 27(12), 3090–3097. https://doi.org/10.1523/JNEUROSCI.4854-06.2007  

7. Nicolson, S. C., Montenegro, L. M., Cohen, M. S., O’Neill, D., Calfin, D., Jones, L. A., & Jobes, D. R. (2010). A comparison of the efficacy and safety of chloral hydrate versus inhaled anesthesia for sedating infants and toddlers for transthoracic echocardiograms. Journal of the American Society of Echocardiography: Official Publication of the American Society of Echocardiography, 23(1), 38–42. https://doi.org/10.1016/j.echo.2009.11.019  

8. Xiong, W.-X., Zhou, G.-X., Wang, B., Xue, Z.-G., Wang, L., Sun, H.-C., & Ge, S.-J. (2013). Impaired spatial learning and memory after sevoflurane–nitrous oxide anesthesia in aged rats is associated with down-regulated cAMP/CREB signaling. PLOS ONE, 8(11), e79408. https://doi.org/10.1371/journal.pone.0079408  

9. Yang, N., Li, L., Li, Z., Ni, C., Cao, Y., Liu, T., Tian, M., Chui, D., & Guo, X. (2017). Protective effect of dapsone on cognitive impairment induced by propofol involves hippocampal autophagy. Neuroscience Letters, 649, 85–92. https://doi.org/10.1016/j.neulet.2017.04.019  

10. Papáčková, Z., & Cahová, M. (2014). Important role of autophagy in regulation of metabolic processes in health, disease and aging. Physiological Research, 63(4), 409–420. https://doi.org/10.33549/physiolres.932684  

11. Zhang, X., Zhou, Y., Xu, M., & Chen, G. (2016). Autophagy is involved in the sevoflurane anesthesia-induced cognitive dysfunction of aged rats. PLOS ONE, 11(4), e0153505. https://doi.org/10.1371/journal.pone.0153505  

12. Zurek, A. A., Yu, J., Wang, D.-S., Haffey, S. C., Bridgwater, E. M., Penna, A., Lecker, I., Lei, G., Chang, T., Salter, E. W. R., & Orser, B. A. (2014). Sustained increase in α5GABA_A receptor function impairs memory after anesthesia. The Journal of Clinical Investigation, 124(12), 5437–5441. https://doi.org/10.1172/JCI76669  

13. Bonin, R. P., & Orser, B. A. (2008). GABA_A receptor subtypes underlying general anesthesia. Pharmacology Biochemistry and Behavior, 90(1), 105–112. https://doi.org/10.1016/j.pbb.2007.12.011 

14. Ling, Y., Ma, W., Yu, L., Zhang, Y., & Liang, Q. (2015). Decreased PSD95 expression in medial prefrontal cortex (mPFC) was associated with cognitive impairment induced by sevoflurane anesthesia. Journal of Zhejiang University-SCIENCE B, 16(9), 763–771. https://doi.org/10.1631/jzus.B1500006