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Lithium-mediated protection of hippocampal cells involves enhancement of DNA-PK–dependent repair in mice
Eddy S. Yang, … , Dennis E. Hallahan, Fen Xia
Eddy S. Yang, … , Dennis E. Hallahan, Fen Xia
Published April 1, 2009
Citation Information: J Clin Invest. 2009;119(5):1124-1135. https://doi.org/10.1172/JCI34051.
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Research Article Neuroscience Article has an altmetric score of 6

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

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Abstract

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 γ-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.

Authors

Eddy S. Yang, Hong Wang, Guochun Jiang, Somaira Nowsheen, Allie Fu, Dennis E. Hallahan, Fen Xia

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Figure 1

Lithium enhances repair of IR-induced DSBs in hippocampal neurons.

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Lithium enhances repair of IR-induced DSBs in hippocampal neurons.
HT-22...
HT-22 neurons were treated with 3 mM lithium or vehicle for 7 days. Following the treatment period, cells were exposed to 3 Gy IR and incubated for the indicated times. Cells were then prepared and subjected to neutral comet assay as described in Methods. At least 75 comet images were analyzed. (A) Representative control and irradiated cells with or without lithium prophylaxis with and without tails. Original magnification, ×400. (B) Mean percent of cells with comet tail, indicative of DSBs, after IR at various time points. (C) Mean tail moment in control and irradiated cells with and without lithium prophylaxis at various time points after IR. Error bars represent SEM. **P < 0.01, ***P < 0.001 versus control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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