WS635 Attenuates the Anesthesia/Surgery-Induced Cognitive Impairment in Mice

Abstract

Anesthesia/surgery has been reported to be associated with perioperative neurocognitive disorder (PND) in patients and induces cognitive impairment in mice. Previous studies demonstrate cyclosporine A (CsA) attenuates the anesthesia/surgery-induced cognitive impairment in mice. However, CsA has immunosuppressive effects and may not be routinely used to prevent or treat PND in patients. WS635 is a nonimmunosuppressive CsA analog. We, therefore, set out to determine whether WS635 could mitigate the anesthesia/surgery-induced cognitive impairment in mice. We performed abdominal surgery under 1.4% isoflurane anesthesia (anesthesia/surgery) for 2 h in 9 month-old wild-type (WT) mice. We treated the mice with CsA (10 mg/kg) or different doses (13.2 mg/kg, 26.4 mg/kg and 52.8 mg/kg) of WS635 before and after the anesthesia/surgery. Barnes maze and fear conditioning system (FCS) were employed to evaluate the cognitive function in mice. We measured the amounts of postsynaptic density (PSD)-95, synaptophysin, and ATP in the hippocampus and cortex of the mice using western blot and ATP Colorimetric/Fluorometric Assay, respectively. We found that the treatment with 52.8 mg/kg, but not 13.2 mg/kg or 26.4 mg/kg, of WS635 attenuated the anesthesia/surgery-induced cognitive impairment in mice and the reductions in the amounts of PSD-95, synaptophysin, and ATP in the mice brain tissues. These results have established a system to study WS635 further and suggest that we need to perform more experiments to determine whether WS635 can ultimately be used as one of the interventions for PND in patients.

Keywords: ATP; WS635; anesthesia/surgery; cognitive impairment; synapse.

Figure 1

Effects of WS635 on the anesthetic-induced loss of righting reflex in mice. Effects of WS635 and control condition on the presence of loss of righting reflex of mice following different concentrations of isoflurane (A), sevoflurane (B), and desflurane (C). N = 6 mice in each group.

Figure 2

Effects of WS635 on nociception threshold in mice after the anesthesia/surgery. Effects of WS635 and vehicle (corn oil) on the nociception threshold in the wound area (A) and non-wound area (B) in the mice following the anesthesia/surgery. WS635 did not significantly alter the nociception threshold compared to the vehicle in the mice following the anesthesia/surgery. N = 4 mice in each group.

Figure 3

Effects of WS635, CsA, and the anesthesia/surgery on locomotor activity in mice. Effects of WS365 with 13.2 mg/kg and 26.4 mg/kg (A–C) and effects of WS365 with 52.8 mg/kg and CsA with 10 mg/kg (B–D) on escape speed of Barnes maze on training days (7–10 days after the anesthesia/surgery) in mice following control condition or anesthesia/surgery. N = 14–18 mice in each group.

Figure 4

Effects of WS635, CsA, and the anesthesia/surgery on cognitive function in mice detected in Barnes maze. (A) The effects of WS635 with 13.2 mg/kg and 26.4 mg/kg on the anesthesia/surgery-induced changes in Barnes maze’s escape latency at testing day (11 days after the anesthesia/surgery) in mice. (B) The effects of WS635 with 52.8 mg/kg and CsA on the anesthesia/surgery-induced changes in Barnes maze’s escape latency at testing day (11 days after the anesthesia/surgery) in mice. N = 14–17 mice in each group. Two-way ANOVA with the post hoc Bonferroni correction was used. *P < 0.05. P values refer to the difference among different conditions on the escape latency. CsA, cyclosporine A.

Figure 5

Effects of WS635 on the anesthesia/surgery-induced changes in the cognitive function in mice detected in fear conditioning system (FCS). Effects of WS365 (52.8 mg/kg) and vehicle (DMSO) on the anesthesia/surgery-induced changes in the freezing time on the context (A) and tone (B) test of FCS on 8 days after the anesthesia/surgery; and on the context (C) and tone (D) test of FCS on 13 days after the anesthesia/surgery. N = 14–18 mice in each group. Two-way ANOVA with the post hoc Bonferroni correction was used. * or ^#P < 0.05; ** or ^##P < 0.01. P values refer to the difference among different conditions on the freezing time of the FCS. DMSO, dimethyl sulfoxide; FCS, fear conditioning system.

Figure 6

Effects of WS635 on the anesthesia/surgery-induced changes in the amounts of postsynaptic density (PSD)-95 and synaptophysin in the hippocampus and cortex of mice. Effects of WS365 (52.8 mg/kg) and vehicle (DMSO) on the anesthesia/surgery-induced changes in the amounts of PSD-95 in the hippocampus (A,B) and cortex (C,D) of the mice on day 13 after the anesthesia/surgery. Effects of WS365 (52.8 mg/kg) and vehicle (DMSO) on the anesthesia/surgery-induced changes in the amounts of synaptophysin in the hippocampus (E,F) and cortex (G,H) of the mice on day 13 after the anesthesia/surgery. N = 6 mice in each group, * or ^#P < 0.05; ** or ^##P < 0.01; *** P < 0.001. Two-way ANOVA with the post hoc test (Bonferroni correction) was used. P values refer to the difference among different conditions on the amounts of the PSD-95 and synaptophysin. DMSO, dimethyl sulfoxide.

Figure 7

Effects of WS635 on the anesthesia/surgery-induced changes in ATP amounts in the hippocampus and cortex of mice. Effects of WS365 (52.8 mg/kg) and vehicle (DMSO) on the anesthesia/surgery-induced changes in the amounts of ATP in the hippocampus (A) and cortex (B) of the mice immediately after the anesthesia/surgery. N = 6 mice in each group, * P < 0.05; ** P < 0.01. Two-way ANOVA with the post hoc test (Bonferroni correction) was used. P values refer to the difference among different conditions on the amounts of ATP. DMSO, dimethyl sulfoxide.