Lithium-mediated protection of hippocampal cells involves enhancement  of DNA-PK-dependent repair in mice.
Long-term neurological deficiencies resulting from hippocampal cytotoxicity induced by cranial irradiation (IR) present a challenge in the treatment of primary and metastatic brain cancers, especially in children. Previously, we showed that lithium protected hippocampal neurons from IR-induced apoptosis and improved neurocognitive function in treated mice. Here, we demonstrate accelerated repair of IR-induced chromosomal double-strand breaks (DSBs) in lithium-treated neurons. Lithium treatment not only increased IR-induced DNA-dependent protein kinase (DNA-PK) threonine 2609 foci, a surrogate marker for activated nonhomologous end-joining (NHEJ) repair, but also enhanced double-strand DNA end-rejoining activity in hippocampal neurons. The increased NHEJ repair coincided with reduced numbers of IR-induced gamma-H2AX foci, well-characterized in situ markers of DSBs. These findings were confirmed in vivo in irradiated mice. Consistent with a role of NHEJ repair in lithium-mediated neuroprotection, attenuation of IR-induced apoptosis of hippocampal neurons by lithium was dramatically abrogated when DNA-PK function was abolished genetically in SCID mice or inhibited biochemically by the DNA-PK inhibitor IC86621. Importantly, none of these findings were evident in glioma cancer cells. These results support our hypothesis that lithium protects hippocampal neurons by promoting the NHEJ repair-mediated DNA repair pathway and warrant future investigation of lithium-mediated neuroprotection during cranial IR, especially in the pediatric population.
Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Eddy S
ES
Yang
Hong
H
Wang
Guochun
G
Jiang
Somaira
S
Nowsheen
Allie
A
Fu
Dennis E
DE
Hallahan
Fen
F
Xia
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004247:DNA / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects* / Q000502:physiology; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014965:X-Rays
C487214:1-(2-hydroxy-4-morpholin-4-ylphenyl)ethanone; D000098:Acetophenones; D004268:DNA-Binding Proteins; D006657:Histones; D009025:Morpholines; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; C475961:gamma-H2AX protein, mouse; D004247:DNA; D008094:Lithium; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse