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Dexmedetomidine attenuates the propofol-induced long-term neurotoxicity in the developing brain of rats by enhancing the PI3K/Akt signaling pathway

Authors Xiao Y, Zhou L, Tu Y, Li Y, Liang Y, Zhang X, Lv J, Zhong Y, Xie Y

Received 23 March 2018

Accepted for publication 24 May 2018

Published 28 August 2018 Volume 2018:14 Pages 2191—2206


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Wai Kwong Tang

Yong Xiao,1,* Lifang Zhou,2,* Youbing Tu,1 Yuantao Li,3 Yubing Liang,4 Xu Zhang,1 Jing Lv,1 Yu Zhong,1 Yubo Xie1

1Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 2Department of Anesthesiology, Institute of Cardiovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 3Department of Anesthesiology, Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, People’s Republic of China; 4Department of Anesthesiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of China

*These authors contributed equally to this work

Background: Propofol induces short- and long-term neurotoxicity. Our previous study showed that dexmedetomidine (Dex) can attenuate the propofol-induced acute neurotoxicity in rodents by enhancing the PI3K/Akt signaling. However, whether treatment of young rats with Dex could protect them from long-term neurotoxicity induced by propofol is unclear.
Materials and methods: Seven-day-old male Sprague Dawley rats were randomized and injected intraperitoneally with saline (100 µL, NS), propofol (100 mg/kg), Dex (75 µg/kg), propofol (100 mg/kg) plus Dex (25, 50 or 75 µg/kg), 10% dimethyl sulfoxide (DMSO, 100 µL) or TDZD-8 (a GSK3β inhibitor, 1 mg/kg), or intracerebroventricularly with DMSO (5 µL) or LY294002 (a PI3K inhibitor, 25 µg/5 µL DMSO). Other rats in the experimental group were injected with the same doses of propofol, Dex and LY294002 or TDZD-8. All the rats were monitored until they were 9 weeks old. Their spatial learning and memory were tested by Morris water maze. The neuronal apoptosis, expression of PSD95, expression and phosphorylation of Akt and GSK3β and synaptic ultrastructures were determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, immunohistochemistry, Western blot and transmission electron microscopy assays, respectively.
Results: Compared with the NS control group, young rats injected with intralipid, Dex, TDZD-8, LY294002 or DMSO alone did not show any significant change as they aged. Propofol significantly increased the escape latency time, hippocampal neuroapoptosis and synaptic ultrastructural changes but decreased the relative levels of PSD95 expression, and Akt and GSK3β phosphorylation in the developing hippocampus of the rats. The neuronal toxic effects of propofol were significantly mitigated by the pretreatment with a higher dose of Dex. The neuroprotective effect of Dex was enhanced by the treatment with TDZD-8, but was completely abrogated by the treatment with LY294002.
Conclusion: Our results indicated that the pretreatment of young rats with Dex attenuated the propofol-induced long-term neurotoxicity in their developing hippocampus by enhancing the PI3K/Akt signaling.

Keywords: propofol, dexmedetomidine, long-term neurotoxicity, PI3K, hippocampus

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