Lithium Inhibits GSK3β Activity via Two Different Signaling Pathways in Neurons After Spinal Cord Injury
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Spinal cord injury (SCI) is a type of long-term disability with a high morbidity rate in clinical settings for which there is no effective clinical treatment to date. Usually, lithium is used as a popular mood stabilizer. Recently, growing evidence has shown that lithium has clear neuroprotective effects after SCI, and the administration of lithium can effectively improve locomotor recovery. However, the exact neuroprotective mechanism of lithium is still not understood. Glycogen synthase kinase-3 beta (GSK3β) is a serine/threonine kinase that plays an important role in the neuroprotective effects of lithium both in vivo and in vitro. In this study, we discovered that lithium inhibits GSK3β activity through two different signaling pathways in spinal cord neurons. In the acute phase, lithium inhibited GSK3β activity by stimulating phosphorylation of AKT; in the chronic phase, we first discovered that lithium additionally upregulated the expression of Na+, K+-ATPase α1 (NKA α1), which had an inhibitory effect on GSK3β activity by inducing the expression of glucocorticoid inducible kinase 1 (SGK1). SGK1 is well known as a regulator of the GSK3β/β-catenin signaling pathway. Moreover, the suppressed activity of GSK3β increased the level of β-catenin in the cytoplasm, which gave rise to the translocation of the freely stabilized β-catenin to the nucleus. In addition, the accumulation of β-catenin in the nucleus had the benefits of neuronal survival. Hopefully our findings from this study are beneficial in revealing the neuroprotective mechanism of lithium and in offering novel targets for the development of new SCI therapeutic drugs.
KeywordsLithium Neurons GSK3β Na+, K+-ATPase α1 Spinal cord injury
This study was supported by Grant No. 81200935 received by MX from the National Natural Science Foundation of China, Grant No. 20170541030 received by MX from the Natural Science Foundation of the Liaoning Province, Grant No. 201602834 received by BL from the Natural Science Foundation of Liaoning Province and Grant No. 1098 received by BL from the Scientific Research Foundation for Overseas Scholars of Education Ministry of China.
Compliance with Ethical Standards
Conflict of interest
The authors have no conflicts of interest to declare.
All experiments were carried out in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80–23) revised in 1978, and all experimental protocols were approved by the Institutional Animal Care and Use Committee of China Medical University.
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