The Molecular Mechanism Of Anti-neuronal Injury Lithium Chloride Inhibit Vascular Smooth Muscle Cell Proliferation And Migration As Well

As one of the lightest solid elements, lithium has been used as a mood stabilizer for more than one century. Studies in recent years have shown that lithium also plays a protective role on the cardiovascular system.The proliferation and migration of vascular smooth muscle cells (VSMCs) is a major pathophysiological process leading to various cardiovascular disorders such as in-stent restenosis. However, previous studies stay in the descriptive stage and the direct molecular target responsible for the beneficial action of lithium in cardiovascular system remains unknown.Peroxisome proliferator-activated receptor coactivator-la (PGC-la) is a transcriptional coactivator intensively involved in the regulation of cellular energy metabolism. Recently, We have noted that PGC-la could negatively regulate the pathological activation of VSMCs and increase of PGC-la expression may have great potentials to treat restenosis.We found that pretreatment of LiCl increased PGC-laprotein expression and nuclear translocation in a dose-dependent manner. MTT and EdU incorporation assays indicated that LiCl inhibited serum-induced VSMC proliferation. Similarly, deceleration of VSMC migration was confirmed by wound healing and transwell assays. LiCl also suppressed serum-induced ROS generation and cell cycle progression. At the molecular level, LiCl reduced the protein which involved in the cell cycle re-entry, adhesion, inflammation and motility. In addition, in vivo administration of LiCl alleviated the pathophysiological changes in balloon injury-induced neointima hyperplasia. More importantly, knockdown of PGC-laby siRNA significantly attenuated the beneficial effects of LiCl on VSMCs both in vitro and in vivo.Local anesthetics (LAs) are necessary for the regional anesthesia, spinal anesthesia, and pain management. However, the application of LAs may cause neurotoxicity and result in postoperative neurological complications. In the second part, we evaluated the effects of LiCl on bupivacaine (a frequently used LAs) induced injury in mouse neuroblastoma neuro2a(N2a) cells. Pretreatment of N2a cells with LiCl significantly attenuated bupivacaine-induced cell injury. LiCl pretreatment completely reversed the suppression of Akt and ERKs signalings and significantly prevented the decline of transmembrane potentialin N2a cells after bupivacaine treatment. More importantly, pharmacological inhibition of Akt and ERKs diminished the protective effect of LiCl against bupivacaine-induced neuronal death.In conclusion, our research shows that LiCl has great potentials on the prevention and treatment of cardiovascular diseases related to VSMC abnormal proliferation and migration. In addition, LiCl increases the phosphorylation of ERKs and Akt. LiCl pretreatment provides a protective effect on bupivacaine induced neuronal cell injury. This action of LiCl is mediated through, at least in part, the activating of Akt-and ERKs-dependent mechanisms.