Protective Effect of RNase on Unilateral Nephrectomy-Induced Postoperative Cognitive Dysfunction in Aged Mice

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially for elderly patients. Administration of RNase has been reported to exhibit neuroprotective effects in acute stroke. However, the potential role of RNase on POCD is unknown. Therefore, we sought to investigate whether RNase treatment could mitigate unilateral nephrectomy induced-cognitive deficit in aged mice. In the present study, twelve-month-old mice were administered RNase or an equal amount of normal saline perioperatively. All mice underwent Morris Water Maze (MWM) training 3 times per day for 7 days to acclimatize them to the water maze before surgical operation, and testing on days 1, 3 and 7 after surgery. We found that perioperative administration of RNase: 1) attenuated unilateral nephrectomy-induced cognitive impairment at day 3 after surgery; 2) reduced the hippocampal cytokines mRNA production and serum cytokines protein production at day 1 and day 7 (for MCP-1) after surgery, and; 3) inhibited hippocampal apoptosis as indicated by cleaved caspase-3 western blot and TUNEL staining at day 1 after surgery. In addition, a trend decrease of total serum RNA levels was detected in the RNase treated group after surgery compared with the untreated group. Further, our protocol of RNase administration had no impact on the arterial blood gas analysis right after surgery, kidney function and mortality rate at the observed days postoperatively. In conclusion, perioperative RNase treatment attenuated unilateral nephrectomy-induced cognitive impairment in aged mice

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RNase treatment decreased cytokine expression in the hippocampus and serum after unilateral nephrectomy in aged mice.

<p>A, Hippocampal cytokine mRNA. At day 1, day 3 and day 7 after surgery, cytokine mRNA levels were measured using qRT-PCR. B, Serum cytokine protein expression. At day 1, day 3 and day 7 after surgery, cytokine proteins were assayed using Luminex. Data are presented as mean ± SEM (panel A, n = 4 per group; panel B, n = 6 per group). *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001, ****<i>P</i><0.0001. CXCL1, chemokine (C-X-C mortif) ligand 1; MIP-2, macrophage inflammatory protein-2; MCP-1, monocyte chemotactic protein-1; IL, interleukin; TNF, tumor necrosis factor; S-S, sham surgery plus placebo; S-P, surgery plus placebo; S-R, surgery plus RNase.</p

Effect of RNase administration on total serum RNA after unilateral nephrectomy in aged mice.

<p>The concentration of total serum RNA at day 1, day 3 and day 7 after surgery in aged mice from all three groups and the naïve control group were measured. Data are presented as mean ± SEM (n = 5 per group; n = 6 for naïve control group). *<i>P</i><0.05 vs. S-S group. S-S, sham surgery plus placebo; S-P, surgery plus placebo; S-R, surgery plus RNase.</p

RNase treatment reduced cognitive impairment induced by unilateral nephrectomy surgery in aged mice.

<p>The MWM was used for the training of spatial memory formation in aged mice for 7 days before experiments and followed by the postoperative testing of reversal learning for 7 days. A, Escape latency during the experiments. B, Percentage of time spent in the target quadrant during the experiments. C, Swimming path length during the experiments. D, Swimming speed during the experiments. E, The probe trial test at day 3 and day 7 after surgery. F, Representative swim paths for S-R and S-P group at day 3 after surgery. The above data are shown as mean ± SEM; n = 10 for training; n = 8 for testing. *<i>P</i><0.05 v.s. S-S group, #<i>P</i><0.05 v.s. S-R group. S-S, sham surgery plus placebo; S-P, surgery plus placebo; S-R, surgery plus RNase.</p

RNase treatment attenuated hippocampal apoptosis after unilateral nephrectomy in aged mice.

<p>A, TUNEL staining at day 1 after surgery. A-a, S-S group; A-b, S-P group; A-c, S-R group. B, Quantitation of TUNEL staining. C, Quantitation of relative intensity of cleaved caspase-3 bands and a representative blot at day 1 after surgery. Data are presented as mean ± SEM (panel B, n = 6 per group; panel C, n = 3 per group). *<i>P</i><0.05, **<i>P</i><0.01. S-S, sham surgery plus placebo; S-P, surgery plus placebo; S-R, surgery plus RNase.</p