Peripheral surgical wounding may induce cognitive impairment through interlukin-6-dependent mechanisms in aged mice

Abstract

Post-operative cognitive dysfunction (POCD) is associated with morbidity, mortality and increased cost of medical care. However, the neuropathogenesis and targeted interventions of POCD remain largely to be determined. We have found that the peripheral surgical wounding induces an age-dependent Aβ accumulation, neuroinflammation and cognitive impairment in aged mice. Pro-inflammatory cytokine interlukin-6 (IL-6) has been reported to be associated with cognitive impairment in rodents and humans. However, the role of IL-6 in the neuropathogenesis of POCD is unknown. We therefore employed pharmacological (IL-6 antibody) and genetic (knockout of IL-6) approach to investigate whether IL-6 contributed to the peripheral surgical wounding-induced cognitive impairment in aged mice. Abdominal surgery under local anesthesia (peripheral surgical wounding) was established in 18-month-old wild-type and IL-6 knockout mice (n = 6 to 10 in each group). Brain level of IL-6 and cognitive function in the mice were determined by western blot, ELISA at the end of procedure, and Fear Conditioning System at 7 days after the procedure. The peripheral surgical wounding increased the level of IL-6 in the hippocampus of aged wild-type, but not IL-6 knockout mice. IL-6 antibody ameliorated the peripheral surgical wounding-induced cognitive impairment in the aged wild-type mice. Finally, the peripheral surgical wounding did not induce cognitive impairment in the aged IL-6 knockout mice. These data suggested that IL-6 would be a required pro-inflammatory cytokine for the peripheral surgical wounding-induced cognitive impairment. Given this, further studies are warranted to investigate the role of IL-6 in the neuropathogenesis and targeted interventions of POCD.

Keywords: cognition; fear conditioning system; interlukin-6; mice; neuroinflammation; peripheral surgical wounding.

Figure 1

Peripheral surgical wounding increased IL-6 levels in the hippocampus of aged mice. Note: (A) Western blot analysis showed that the peripheral surgical wounding (lanes 4 to 6) increased the levels of IL-6 in the hippocampus of 18-month-old mice at 12 hours after the peripheral surgical wounding as compared to sham condition (lanes 1 to 3). There was not significant difference in the β-actin levels between the mice in sham group and in surgery group. (B) Quantification of the western blot showed that the peripheral surgical wounding increased the levels of IL-6 in the hippocampus of 18-month-old mice at 12 hours after the peripheral surgical wounding as compared to sham condition. Data are expressed as the mean ± SD, n = 6 in sham or surgery group. **P < 0.01, vs. sham group (student t-test). IL: Interleukin.

Figure 2

IL-6 antibody attenuated the peripheral surgical wounding-induced cognitive impairment in aged mice. Note: Peripheral surgical wounding without the influence of general anesthesia induced cognitive impairment in the context test (A) and tone test (B) of the fear conditioning system (FCS) at 7 days post-procedure in 18-month-old mice. IL-6 antibody attenuated the peripheral surgical wounding-induced reduction in freezing time of the context test (A) and the tone test (B) of the FCS at 7 days post-procedure. Data are expressed as the mean ± SD, n = 10 in each group. *P < 0.05, vs. sham + saline group; #P < 0.05, vs. saline + surgery group (two-way analysis of variance); †P < 0.05: the interaction between the group and the treatment (two-way analysis of variance). IL: Interleukin.

Figure 3

Peripheral surgical wounding did not increase IL-6 levels in the hippocampus of aged IL-6 knockout (KO) mice. Note: ELISA showed that the peripheral surgical wounding did not increase the levels of IL-6 in the hippocampus of 18-month-old IL-6 KO mice at 12 hours after the peripheral surgical wounding as compared to sham condition. Data are expressed as the mean ± SD, n = 6 in sham or surgery group, and analyzed by student t-test. IL: Interleukin.

Figure 4

Peripheral surgical wounding did not induce cognitive impairment in aged IL-6 knockout (KO) mice. Note: The peripheral surgical wounding without the influence of general anesthesia did not significantly alter the freezing time in the context test (A) and tone test (B) of the Fear Conditioning System at 7 days post-procedure in 18-month-old IL-6 KO mice. Data are expressed as the mean ± SD, n = 10 in each group, and analyzed by two-way analysis of variance. IL: Interleukin.