Lithium chloride protects retinal neurocytes from nutrient deprivation by promoting DNA non-homologous end-joining.
Lithium chloride is a therapeutic agent for treatment of bipolar affective disorders. Increasing numbers of studies have indicated that lithium has neuroprotective effects. However, the molecular mechanisms underlying the actions of lithium have not been fully elucidated. This study aimed to investigate whether lithium chloride produces neuroprotective function by improving DNA repair pathway in retinal neurocyte. In vitro, the primary cultured retinal neurocytes (85.7% are MAP-2 positive cells) were treated with lithium chloride, then cultured with serum-free media to simulate the nutrient deprived state resulting from ischemic insult. The neurite outgrowth of the cultured cells increased significantly in a dose-dependent manner when exposed to different levels of lithium chloride. Genomic DNA electrophoresis demonstrated greater DNA integrity of retinal neurocytes when treated with lithium chloride as compared to the control. Moreover, mRNA and protein levels of Ligase IV (involved in DNA non-homologous end-joining (NHEJ) pathway) in retinal neurocytes increased with lithium chloride. The end joining activity assay was performed to determine the role of lithium on NHEJ in the presence of extract from retinal neurocytes. The rejoining levels in retinal neurocytes treated with lithium were significantly increased as compared to the control. Furthermore, XRCC4, the Ligase IV partner, and the transcriptional factor, CREB and CTCF, were up-regulated in retinal cells after treating with 1.0mM lithium chloride. Therefore, our data suggest that lithium chloride protects the retinal neural cells from nutrient deprivation in vitro, which may be similar to the mechanism of cell death in glaucoma. The improvement in DNA repair pathway involving in Ligase IV might have an important role in lithium neuroprotection. This study provides new insights into the neural protective mechanisms of lithium chloride.
Zhuang
Jing
J
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, #54 S Xianlie Road, Guangzhou, Guangdong 510060, China.
Li
Fan
F
Liu
Xuan
X
Liu
Zhiping
Z
Lin
Jianxian
J
Ge
Yihong
Y
Kaminski
Joseph M
JM
Summers
James Bradley
JB
Wang
Zhichong
Z
Ge
Jian
J
Yu
Keming
K
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D000076246:CCCTC-Binding Factor; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis; D019610:Cytoprotection; D004247:DNA / Q000187:drug effects* / Q000235:genetics; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000096:biosynthesis; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D018021:Lithium Chloride / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011995:Recombination, Genetic / Q000187:drug effects*; D012097:Repressor Proteins / Q000096:biosynthesis; D055351:Retinal Neurons / Q000187:drug effects* / Q000502:physiology
D018692:Antimanic Agents; D000076246:CCCTC-Binding Factor; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; C539916:XRCC4 protein, rat; D004247:DNA; D011088:DNA Ligases; D000072481:DNA Ligase ATP; D018021:Lithium Chloride