Ulinastatin Alleviates Repetitive Ketamine Exposure-Evoked Cognitive Impairment in Adolescent Mice

Abstract

Ketamine (KET) is widely used for induction and maintenance of anesthesia, and long-term use is required for treatment of depression patients. Repeated use of KET is associated with mood and memory disorders. Ulinastatin (UTI), a urinary trypsin inhibitor, has been widely undertaken as an anti-inflammatory drug and proved to have neuroprotective effects. The aim of this work was to determine whether prophylactic use of UTI could attenuate KET-induced cognitive impairment. It was found that repetitive KET anesthesia cause cognitive and emotional disorders in adolescent mice in WMZ and OFT test, while UTI pretreatment reversed the poor performance compared to the AK group, and the platform finding time and center crossing time were obviously short in the CK+UTI group (P < 0.05). Our ELISA experiment results discovered that UTI pretreatment reduced the expression levels of IL-1β and IL-6 induced by CK anesthesia compared to AK (P < 0.05). In addition, UTI pretreatment protected the cognitive function by restraining the expression levels of Tau protein, Tau phospho-396 protein, and Aβ protein in the CK group compared to the AK group in Western blotting (P < 0.05). The results suggested that UTI could act as a new strategy to prevent the neurotoxicity of KET, revealing a significant neuroprotective effect of UTI.

Figure 1

A brief schematic representation of experimental protocols.

Figure 2

Repetitive KET-induced learning and memory impairment. (a) and (b) demonstrated the sailing time; (c) and (d) showed the platform-crossing times. All consequences were expressed as mean ± SD (n = 12). ^∗∗P < 0.01, and ^##P < 0.01.

Figure 3

Repetitive KET treatment in mice evoked anxiety-like behaviors. (a) and (b) showed the center duration time. All result data were expressed as mean ± SD (n = 12). ^#P < 0.05, ^∗∗P < 0.01, and ^##P < 0.01.

Figure 4

Repetitive KET-induced neuroinflammation can be alleviated by UTI. All result data were reported as mean ± SD (n = 6). ^∗ and ^# meant P < 0.05 and P < 0.01, respectively.

Figure 5

(a) and (b) showed the Western blotting results of Tau pS396, Tau protein, and Aβ protein. (c) illustrated the statistical value of each protein. ^∗P < 0.05, ^∗∗P < 0.01, and ^#P < 0.01.