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Published on: November 20, 2015
Sevoflurane exposure in postnatal rats induced long-term cognitive impairment through upregulating
Yunzhi Ling1, Xiaohong Li1, Li Yu2
1Department of Anesthesiology, First Affiliated Hospital of Bengbu Medical College, Anhui, Hefei 233004, P.R. China.
Insights
Sevoflurane anesthesia in infant rats impairs working memory in adulthood. This cognitive decline is linked to increased caspase-3 (CASP3) gene expression in the hippocampus, suggesting a potential mechanism for anesthetic-induced neurotoxicity.
Area of Science:
- Neuroscience
- Anesthesiology
- Molecular Biology
Background:
- Anesthetic exposure in early life is linked to long-term neurological deficits.
- The molecular mechanisms underlying these cognitive impairments remain largely unknown.
Purpose of the Study:
- To identify gene expression changes associated with long-term cognitive impairment from postnatal sevoflurane exposure.
- To investigate the role of caspase-3 (CASP3) in sevoflurane-induced cognitive deficits.
Main Methods:
- Wistar rats exposed to sevoflurane at postnatal day 7 (P7).
- Behavioral tests (Y-maze) to assess working memory in adult rats.
- Transcriptome profiling and quantitative polymerase chain reaction (qPCR) of hippocampal tissues.
- Immunohistochemical analysis for caspase-3 and cleaved-poly (ADP-ribose) polymerase (PARP).
Main Results:
- Sevoflurane exposure for 4-6 hours significantly impaired working memory in adult rats.
- 264 genes were aberrantly expressed in the hippocampus, with caspase-3 (CASP3) showing the most significant upregulation.
- Increased CASP3 expression correlated negatively with spatial working memory performance.
- Elevated levels of cleaved-PARP, a caspase-3 substrate, were observed.
Conclusions:
- Upregulation of caspase-3/cleaved-PARP pathway is implicated in long-term cognitive impairment following early-life sevoflurane exposure.
- This finding may inform clinical strategies for preventing anesthetic-induced cognitive deficits in children.
Abstract:
The association of anesthetic exposure in infants or young children with the long-term impairment of neurologic functions has been reported previously; however, the underlying mechanisms remain largely unknown. In order to identify dysregulated gene expression underlying long-term cognitive impairment caused by sevoflurane exposure at the postnatal stage, the present study initially performed behavioral tests on adult Wistar rats, which received 3% sevoflurane at postnatal day 7 (P7) for different time course. Subsequently, transcriptome profiling of hippocampal tissues from experimental and control rats was performed. Significant impairment of the working memory was observed in adult rats with sevoflurane exposure for 4-6 h, when compared with the control rats. The results indicated that a total of 264 genes were aberrantly expressed (51 downregulated and 213 upregulated; fold change >2.0; P<0.05; false discovery rate <0.05) in the hippocampus of experimental adult rats compared with those from control rats. Particularly, the expression of caspase-3 gene (CASP3), encoding caspase-3 protein, presented the most significant upregulation, which was further validated by quantitative polymerase chain reaction and immunohistochemical analysis. Further analysis revealed that CASP3 expression level was negatively correlated with the rats' spatial working memory performance, as indicated by the Y-maze test. The level of cleaved-poly (ADP-ribose) polymerase (PARP), a substrate of caspase-3, was also increased in the hippocampus of experimental adult rats. Thus, the present study revealed that upregulation of caspase-3/cleaved-PARP may be involved in long-term cognitive impairment caused by sevoflurane exposure in infants, which may be useful for the clinical prevention of cognitive impairment.
