TABLE 2.
A summary of underlying mechanisms of POCD other than neuroinflammation in animal studies in recent years.
| Study focus | Main effects found | References |
| 1. Oxidative stress | Oxidative stress ↑→ POCD↑ | Netto et al., 2018; Liu et al., 2019; Ho et al., 2020 |
| 2. Mitochondrial function | Mitochondrial dysfunction→POCD↑ | Netto et al., 2018; Chen et al., 2020; Wang et al., 2022 |
| 3. Synaptic function | Synaptic dysfunction→POCD↑ | Zhang X. et al., 2013; Xiao et al., 2018; Gao et al., 2021 |
| 4. Neurotrophic support | BDNF↓→POCD↑ | Zhang et al., 2014; Fan et al., 2016; Yin et al., 2022 |
| 5. Neurodegeneration | (1) Chronic cerebral hypoperfusion→neuronal death→POCD↑ (2) Cerebrospinal Fluid Biomarker for Alzheimer’s Disease contributes to Predicting POCD |
Evered et al., 2016; Yamamoto et al., 2018 |
| 6. BBB permeability | BBB permeability↑→POCD↑ | Wang B. et al., 2017; Cao et al., 2018; Ni et al., 2018 |
| 7. Gut-brain axis | (1) Gut microbiome →BBB permeability↑→POCD↓ (2) Unfavorable alterations in gut microbiota and fecal metabolites→POCD↑ |
Yang et al., 2018; Wen et al., 2020; Lian et al., 2021 |
| 8. Epigenetic regulation | (1) Inaction of METTL3→perturbation in m6A RNA methylation signals (2) Histone deacetylases may contribute cognitive impairment (3) Preoperative environment enrichment→preserved neuroligin 1 expression→POCD↓ |
Luo et al., 2020; He and Wang, 2021; Min et al., 2021 |
| 9. Amyloid beta | Amyloid beta↑→POCD↑ | Zhang et al., 2020; Kim et al., 2021 |
| 10. Tau protein | Tau acetylation↑→POCD↑ | Yan et al., 2020 |
| 10. NMDAR/Ca2+/calpain | NMDAR/Ca2+/calpain signal↑→BDNF/TrkB↓→POCD↑ | Qiu et al., 2020 |
| 11. CX3CR1/L1 | CX3CR/L1→astrocyte activation↑→GABA↑ and proinflammatory cytokine expression↑→POCD↑ | Cho et al., 2021 |
| 12. VEGF | VEGF overexpression→POCD↑ | Cao et al., 2019 |
| 13. A1A receptor | Activation of the A1A receptor→POCD↑ | Zuo et al., 2018 |
| 14. Obesity | High-fat diet →Obesity→SIRT1/PGC-1α/FNDC5/BDNF pathway↓→POCD↑ | Zhao et al., 2020 |
| 15. Iron and glucose metabolism | Cross-dysfunction of iron and glucose metabolism→POCD↑ | Ge et al., 2021 |
| 16. CeGC | CeGC degradation→BBB permeability↑→POCD↑ | Stoddart et al., 2022 |
BBB, blood–brain barrier; VEGF, vascular endothelial growth factor; A1A receptor, A1 adenosine receptor; CeGC, cerebral microvascular endothelial glycocalyx. The table above summarizes the results of recent animal studies on the possible pathogenesis of POCD (excluding neuroinflammatory mechanisms). First of all, we must understand that the content of this table is not sufficient and rigorous, and can only be used as a general reference. The table mainly includes two parts, one is the more mature classical pathogenic mechanism, and the other is relatively new and controversial arguments. In addition, through the table content and the review of a large number of related literature, it can be found that the relationship between the various underlying mechanisms of POCD is intricate and difficult to be completely independent. It is likely that one mechanism will play an important role in some part of the other. Furthermore, according to numerous preclinical and clinical studies, neuroinflammation is involved in the pathophysiological process of most of the pathogenic mechanisms of POCD and plays a key role in triggering or maintaining it. For this reason, neuroinflammation has become a research hotspot in recent years.