Table 1.
Selected relevant pre-clinical studies on etiology of POCD.
| Study | Animal model | Experimental model | Cognitive testing | Cellular/Molecular findings | Neurocognitive findings |
|---|---|---|---|---|---|
| Cao et al. (70) | Adult (3–6 month) and aged (20–24 month) old Sprague Dawley rats | Partial hepatectomy under sevoflurane anesthesia vs. sevoflurane alone | Morris water maze | Upregulated expression of IL-1β and IL-6 on postoperative day 1 in all rats, and in aged rats until postoperative day 3 | Surgery and anesthesia, but not anesthesia alone, caused impairments in latency and distance in all rats on postoperative day 1, and in aged rats until postoperative day 3 |
| He et al. (56) | 22–23 month old Sprague-Dawley rats | Splenectomy under general anesthesia vs. 2 h isoflurane anesthesia vs. naïve control | Reversal learning version of Morris water maze | Upregulation of HMGB1 and RAGE levels in surgical group BBB disruption (by TEM) in surgical group | Surgery and anesthesia, but not anesthesia alone, caused cognitive impairments from surgery to postoperative day 3 |
| Qian et al. (139) | 20–22 month old BALB/c mice | Splenectomy with isoflurane vs. isoflurane alone vs. control | Y-maze testing | Splenectomy increased hippocampal expression of IL-1β and TNFα | Splenectomy with anesthesia and anesthesia alone both impaired cognitive testing on postoperative days 1 and 3 |
| Tasbihgou et al. (138) | Adult male Wistar rats | Deep vs. light propofol anesthesia, with and without subsequent exposure to hypoxia | Novel object recognition test | Light anesthesia group with hypoxia had lower neurogenesis, but higher BDNF and microglia-ramification | No impairment in cognitive function in either deep or light anesthesia |
| Walters et al. (136) | Adult Sprague-Dawley rats | Four exposures to isoflurane anesthesia (2, 2, 4, and 6 h) over 7 weeks | Fixed consecutive number, incremental repeated acquisition, progressive ratio tasks† | none | No deficits in any cognitive tasks after single or repeat anesthetic exposure |
| Wang et al. (135) | 6–8 month old male C57BL/6 mice; 14 month old male C57BL/6 mice | Isoflurane vs. no anesthetic exposure | Morris water maze | Older but not younger mice had increased hippocampal expression of NLRP3‡ | Older but not younger mice had cognitive impairment after isoflurane anesthesia compared to no anesthetic exposure |
| Xu et al. (71) | 9 and 18 month old female C57BL/6J mice | Laparotomy under local anesthesia (no sedation) vs. sham procedure (no incision) | Fear conditioning system | Surgery increased hippocampal levels of IL-6 and TNFα in all mice, with larger increases in older mice | Cognitive deficits with surgery alone in both young and older mice |
| Zhang et al. (63) | 4 month old male Fischer 344 rats | Right carotid exploration with propofol and buprenorphine anesthesia vs. anesthesia alone | Barnes maze Fear conditioning system | Surgery decreased cytoplasmic hippocampal NF-κB, increased IL-1β, IL-6, MMP-9 | Surgery and anesthesia, but not anesthesia alone caused impairments in cognitive metrics |
| Zhang et al. (131) | 20 month old male Fischer 344 rats | Right carotid exploration with propofol-buprenorphine anesthesia vs. isoflurane-buprenorphine anesthesia | Barnes maze Fear conditioning system | No difference in hippocampal TNFα and IL-1β expression in propofol vs. isoflurane anesthesia | Surgery caused impairments in cognitive metrics independent of anesthetic type |
| Zhu et al. (137) | Adult male Wistar rats | Transient coronary artery occlusion with and without sevoflurane preconditioning vs. sham operation | N/A | Coronary occlusion increased hippocampal TNFα and IL-1β mRNA expression 1–3 days postoperatively; cytokine levels attenuated by sevoflurane | Coronary occlusion inhibited LTP compared to sham operation; sevoflurane preconditioning reversed this effect on postoperative days 1 and 3 |
BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; HMGB1, high mobility group box-1 protein; IL-1β, interleukin-1 beta; IL-6, interleukin 6; LTP, long-term potentiation; MMP-9, matrix metalloproteinase 9; N/A, non-applicable; NF-κB, nuclear factor-kappa B; NLRP3, NOD-like receptor protein 3 inflammasome; RAGE, receptor for advanced glycosylation end products; TEM, transmission electron microscopy; TNFα, tumor necrosis factor alpha.
†
Rats were trained to perform these tasks for at least 15 months prior to anesthetic exposure.
‡
NLRP3 causes maturation and secretion of cytokines IL-1β and IL-18.