Abstract
l-3-n-Butylphthalide (l-NBP) exerts neuroprotective effects in animal models of cerebral ischemia, but its potential benefits in repeated cerebral ischemia–reperfusion (RCIR) injury remain unknown. We investigated the effect of l-NBP on cognitive impairment induced by RCIR in mice. Male C57Bl/6 mice received sham surgery or bilateral common carotid artery occlusion (3 times, 20 min each) and were orally administered preoperative l-NBP (30 mg/kg/day, 7 days), postoperative l-NBP (30 or 60 mg/kg/day, 28 days) or postoperative vehicle (28 days). Learning and memory were assessed by the Morris water maze task and step-down passive avoidance test. Nissl staining was used to identify pathologic changes in the hippocampal CA1 region. The expressions of proteins associated with signaling, apoptosis and autophagy were assessed by quantitative PCR and western blot. RCIR induced deficits in learning and memory that were alleviated by preoperative or postoperative l-NBP administration. Pathologic lesions in the hippocampal CA1 region induced by RCIR were less severe in mice treated with l-NBP. Preoperative or postoperative l-NBP administration in mice receiving RCIR promoted hippocampal expression of phospho-Akt and phospho-mTOR (suggesting activation of Akt/mTOR signaling), increased the Bcl-2/Bax ratio (indicating suppression of apoptosis) and reduced the LC3-II/LC3-I ratio (implying inhibition of autophagy). Preoperative or postoperative l-NBP administration also depressed hippocampal levels of beclin-1 mRNA (indicating suppression of autophagy). These findings suggest that the effect of l-NBP to alleviate learning and memory deficits in mice following RCIR may involve activation of Akt/mTOR signaling and regulation of the expressions of proteins related to apoptosis and autophagy.
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Acknowledgements
This study was supported by the Hebei Province Major Medical Research Project of China (zd2013005) and the Hebei Province Natural Science Foundation of China (H2013307046).
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This study was supported by the Hebei Province Major Medical Research Project of China (zd2013005) and the Hebei Province Natural Science Foundation of China (H2013307046).
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Animal care and the experimental protocol were conducted in strict accordance with the regulations of laboratory animal management promulgated by the Ministry of Science and Technology of the People’s Republic of China [1988] no. 134, which conforms to the internationally recognized National Institutes of Health guidance for care and use of laboratory animals. All animal studies were approved by the Animal Care and Use Committee of Hebei General Hospital, Shijiazhuang, China and performed in accordance with ethical standards.
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Xu, J., Huai, Y., Meng, N. et al. l-3-n-Butylphthalide Activates Akt/mTOR Signaling, Inhibits Neuronal Apoptosis and Autophagy and Improves Cognitive Impairment in Mice with Repeated Cerebral Ischemia–Reperfusion Injury. Neurochem Res 42, 2968–2981 (2017). https://doi.org/10.1007/s11064-017-2328-3
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DOI: https://doi.org/10.1007/s11064-017-2328-3