Suppression of Neuroinflammation Attenuates Persistent Cognitive and Neurogenic Deficits in a Rat Model of Cardiopulmonary Bypass

Abstract

Post-operative cognitive dysfunction (POCD) can be a serious surgical complication, and patients undergoing cardiac procedures are at particular risk for POCD. This study examined the effect of blocking neuroinflammation on behavioral and neurogenic deficits produced in a rat model of cardiopulmonary bypass (CPB). Minocycline, a drug with established anti-inflammatory activity, or saline was administered daily for 30 days post-CPB. Treatment with minocycline reduced the number of activated microglia/macrophages observed in the dentate gyrus of the hippocampus at 6 months post-CPB, consistent with an anti-inflammatory action in this CPB model. Behavioral testing was conducted at 6 months post-CPB utilizing a win-shift task on an 8-arm radial maze. Minocycline-treated animals performed significantly better than saline-treated animals on this task after CPB. In addition, the CPB-induced reduction in adult neurogenesis was attenuated in the minocycline-treated animals. Together, these findings indicate that suppressing neuroinflammation during the early post-surgical phase can limit long-term deficits in both behavioral and neurogenic outcomes after CPB.

Keywords: cardiopulmonary bypass; cognitive; microglia; minocycline; neurogenesis; neuroinflammation.

FIGURE 1

The effect of minocycline on neuroinflammation and neurogenesis. (A) Immunohistochemical staining with ED1 in the dentate gyrus. The granule cell layer (G) and hilus (H) of the dentate gyrus are shown in sections from the CPB + Saline and CPB + Minocycline groups. (B) An example of the morphology of an ED1-positive (ED1⁺), activated microglia/macrophage in the dentate gyrus. (C) Unbiased cell counting was performed for ED1-positive cells at 6 months post-CPB. There were significantly fewer ED1-positive cells in the CPB + Minocycline group as compared to the CPB + Saline group. Values shown are Means and SEMs (*p < 0.05; t-test). (D) Immunohistochemical staining for DCX in the dentate gyrus in sections from CPB + Saline and CPB + Minocycline groups. (E) An example of the morphology of a DCX-positive (DCX⁺), immature neuron in the dentate gyrus. (F) Unbiased cell counting was performed for DCX-positive cells at 6 months post-CPB. There were significantly more DCX-positive cells in the CPB + Minocycline group as compared to the CPB + Saline group. Values shown are Means and SEMs (*p < 0.05; t-test).

FIGURE 2

The effect of minocycline on performance on the win-shift task at 6 months post-CPB. Treatment with minocycline improved performance on the task. The number of correct choices on the task was significantly greater in the CPB + Minocycline group at the 3- and 12-h intertrial intervals. Values shown are Means ± SEM (*p < 0.05).