Lithium-mediated protection of hippocampal cells involves enhancement of DNA-PK-dependent repair in mice

J Clin Invest. 2009 May;119(5):1124-35. doi: 10.1172/jci34051.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Cell Line
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / radiation effects
  • Cells, Cultured
  • DNA / radiation effects
  • DNA Breaks, Double-Stranded
  • DNA Repair / drug effects*
  • DNA Repair / physiology
  • DNA-Activated Protein Kinase / antagonists & inhibitors
  • DNA-Activated Protein Kinase / metabolism*
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism*
  • Female
  • Glioma / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / radiation effects*
  • Histones / metabolism
  • Humans
  • Lithium / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Morpholines / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / radiation effects*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Rad51 Recombinase / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / physiology
  • X-Rays


  • 1-(2-hydroxy-4-morpholin-4-ylphenyl)ethanone
  • Acetophenones
  • DNA-Binding Proteins
  • Histones
  • Morpholines
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • gamma-H2AX protein, mouse
  • DNA
  • Lithium
  • DNA-Activated Protein Kinase
  • Prkdc protein, mouse
  • Rad51 Recombinase
  • Rad51 protein, mouse