Journal
NEUROCHEMICAL RESEARCH
Volume 43, Issue 4, Pages 848-856Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11064-018-2488-9
Keywords
Lithium; Neurons; GSK3 ss; Na+, K+-ATPase alpha 1; Spinal cord injury
Categories
Funding
- National Natural Science Foundation of China [81200935]
- Natural Science Foundation of the Liaoning Province [20170541030]
- Natural Science Foundation of Liaoning Province [201602834]
- Scientific Research Foundation for Overseas Scholars of Education Ministry of China [[2015]1098]
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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 (GSK3 beta) 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 GSK3 beta activity through two different signaling pathways in spinal cord neurons. In the acute phase, lithium inhibited GSK3 beta activity by stimulating phosphorylation of AKT; in the chronic phase, we first discovered that lithium additionally upregulated the expression of Na+, K+-ATPase alpha 1 (NKA alpha 1), which had an inhibitory effect on GSK3 beta activity by inducing the expression of glucocorticoid inducible kinase 1 (SGK1). SGK1 is well known as a regulator of the GSK3 beta/beta-catenin signaling pathway. Moreover, the suppressed activity of GSK3 beta increased the level of beta-catenin in the cytoplasm, which gave rise to the translocation of the freely stabilized beta-catenin to the nucleus. In addition, the accumulation of beta-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.
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