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. 2020 Nov;10(11):e01810.
doi: 10.1002/brb3.1810. Epub 2020 Sep 1.

Propofol inhibits the expression of Abelson nonreceptor tyrosine kinase without affecting learning or memory function in neonatal rats

Long Feng  1   2 , Zhi-Gao Sun  2 , Qiang-Wei Liu  1 , Tao Ma  3 , Zhi-Peng Xu  1 , Ze-Guo Feng  1 , Wei-Xiu Yuan  2 , Hong Zhang  1 , Long-He Xu  1   2
Affiliations

Propofol inhibits the expression of Abelson nonreceptor tyrosine kinase without affecting learning or memory function in neonatal rats

Long Feng et al. Brain Behav. 2020 Nov.

Abstract

Objective: Propofol is one of the most commonly used intravenous drugs to induce and maintain general anesthesia. In vivo and in vitro studies have shown that propofol can affect neuronal growth, leading to apoptosis and impairing cognitive function. The Abelson nonreceptor tyrosine kinase (c-Abl) is associated with both neuritic plaques and neurofibrillary tangles in the brains of patients with Alzheimer's disease and other neurodegenerative diseases. This study aimed to explore the effect of propofol on apoptosis and neurocognition through its regulation of c-Abl expression in vivo and in vitro.

Materials and methods: In this study, primary hippocampal neurons were cultured and exposed to propofol at different concentrations. Protein expression was measured by Western blotting and coimmunoprecipitation. The c-Abl transcription level was verified by fluorescence quantitative PCR. Reactive oxygen species (ROS) levels were detected by flow cytometry. In addition, an animal experiment was conducted to assess neuronal apoptosis by immunofluorescence staining for caspase-3 and to evaluate behavioral changes by the Morris water maze (MWM) test.

Results: The in vitro experiment showed that propofol significantly decreased c-Abl expression and ROS levels. In addition, propofol has no cytotoxic effect and does not affect cell activity. Moreover, in the animal experiment, intraperitoneal injection of 50 mg/kg propofol for 5 days obviously decreased the expression of c-Abl in the neonatal rat brain (p < .05) but did not significantly increase the number of caspase-3-positive cells. Propofol treatment did not significantly reduce the number of platform crossings (p > .05) or prolong the escape latency of neonatal rats (p > .05) in the MWM test.

Conclusions: The present data suggest that reduced expression of this nonreceptor tyrosine kinase through consecutive daily administration of propofol did not impair learning or memory function in neonatal rats.

Keywords: ROS; abelson nonreceptor tyrosine kinase; apoptosis; neonatal rat; neurocognitive dysfunction; propofol.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Propofol reduced c‐Abl protein expression and transcription levels. (a) Immunoblotting to detect the expression of target protein c‐Abl. (b) The relative expression level of c‐Abl. (c) The level of mRNA transcription of c‐Abl in nerve cells changed after drug treatment. All data are presented as the x¯ ± s (*p < .05 vs. the control group; **p < .01 vs. the control group;## p < .01 vs. the propofol group). All quantitative data are represented as the Mean ± SD of three independent experiments
Figure 2
Figure 2
Propofol enhances c‐Abl activity, significantly increases its ubiquitination level, and decreases the ROS level. (a) Target protein c‐Abl, Myc, and pTyr bands. (b) The relative activity of c‐Abl. (c) Ub and c‐Abl expression bands, and the base standard β‐Actin expression bands. (d) Neuronal ROS levels changed after drug treatment. All data are presented as the x¯ ± s (*p < .05 vs. the control group; **p < .01 vs. the control group). All quantitative data are represented as the Mean ± SD of three independent experiments
Figure 3
Figure 3
The effect of propofol on primary hippocampal neuronal cells after 24 hr on apoptosis and activity. (a) Immunofluorescence staining of TUNEL and DAPI of nerve cells in each group. The blue fluorescence is the nucleus of nerve cells stained by DAPI, and the green fluorescence shows TUNEL‐stained nerve cells. (b) The number of TUNEL staining‐positive cells in each group. (c) Bcl‐2 and Bax protein bands and β‐Actin bands of nerve cells. (d) Relative Bcl‐2/Bax ratio. (e) The relative activity changes of nerve cells in different drug treatment groups. The results are presented as x¯ ± s (n = 3). *p < .05 versus the control group; **p < .01 versus the control group; One hundred neurons in each immunofluorescence staining were counted, after which the number of TUNEL‐positive cells was determined
Figure 4
Figure 4
Propofol treatment significantly decreased c‐Abl expression but did not affect caspase‐3‐positive cell numbers in the hippocampus of neonatal rats. (a) Band indicating c‐Abl and β‐Actin expression in the hippocampus of neonatal rats. (b) Relative expression of c‐Abl in the hippocampus of neonatal rats. The results are presented as x¯ ± s (n = 3). **p < .01 versus the control group; ## p < .01 versus the propofol group. All quantitative data are represented as the mean ± SD of three independent experiments. (c) Immunofluorescence staining results of the hippocampus in the acute phase of different drug treatment groups after administration, in which blue is the nerve cell nucleus stained by DAPI and red is the positive nerve cell stained by caspase‐3. (d) The number of caspase‐3‐positive neurons stained between different groups. Scale bar: 100 µm. The results are presented as x¯ ± s (n = 6). *p < .05 versus the control group. One hundred neurons in each immunofluorescence staining film were counted, after which the number of caspase‐3‐positive cells was determined
Figure 5
Figure 5
Effect of five consecutive days of propofol injection on learning and memory function of neonatal rats. (a) The escape latency of the water maze; (b) the number of times the water maze crosses the target quadrant. The results are presented as x¯ ± s (n = 6). *p < .05 versus the control group
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