Abstract
Sevoflurane (Sev) might cause neurotoxicity in elderly rats. However, the role of Lin28A in Sev-induced neurotoxicity remains unclear in elderly rats. In this study, elderly rats were used to construct an Sev-induced nerve injury model. Learning and memory abilities were assessed by Morris water maze (MWM) trainings; pathological alterations in hippocampal region were assessed by HE staining; neuronal apoptosis was assessed by TUNEL; related protein expression was analyzed by immunofluorescence, immunohistochemistry, and Western blotting. Results of this study showed that Sev treatment caused nerve injury and cognitive dysfunction in elderly rats, with increased neuronal apoptosis and decreased Lin28A levels. Pathological impairment and learning and memory abilities of elderly rats were significantly improved after forced overexpression of Lin28A using AAV, accompanied by decreased expression of CD68, Iba-1, and GFAP. TUNEL analysis showed that Lin28A overexpression significantly reversed Sev-induced neuronal apoptosis. Further mechanistic analysis showed that Lin28A significantly promoted SIRT1 expression, which further reversed Sev-induced Tau acetylation at lysine 280 and 686 and Tau hyperphosphorylation, thereby alleviating nerve injury and cognitive dysfunction in elderly rats. The introduction of SIRT1 inhibitor EX527 further confirmed the involvement of SIRT1 in the regulation of Lin28A in elderly rats. In conclusion, our findings demonstrated that Lin28A reduced sevoflurane-induced nerve injury and cognitive dysfunction by inhibiting Tau acetylation and phosphorylation via activating SIRT1 in elderly rats.
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All authors contributed to the study conception and design. Material preparation and the experiments were performed by Yingjun Zhu. Data collection and analysis were performed by Min Zhang and Jiayu Wang. The first draft of the manuscript was written by Qingxiu Wang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Ethical approval was obtained from the Ethics Committee of The affiliated Huai’an No.1 People’s Hospital of Nanjing Medical University. The animal experiment complies with the ARRIVE guidelines and in accordance with the National Institutes of Health guide for the care and use of Laboratory animals (Approval No. TJBB03121202).
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Zhu, Y., Zhang, M., Wang, J. et al. Lin28A Reduced Sevoflurane-Induced Nerve Injury and Cognitive Dysfunction by Inhibiting Tau Acetylation and Phosphorylation via Activating SIRT1 in Elderly Rats. Neurotox Res 40, 1913–1923 (2022). https://doi.org/10.1007/s12640-022-00594-4
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DOI: https://doi.org/10.1007/s12640-022-00594-4