Lithium Treatment Prevents Neurocognitive Deficit Resulting from Cranial Irradiation

Yazlovitskaya, Eugenia M.; Edwards, E.; Thotala, Dinesh; Fu, Allie; Osusky, K.; Whetsell, William O.; Boone, Braden; Shinohara, Eric T.; Hallahan, Dennis E.

doi:10.1158/0008-5472.can-06-2740

Cited by 166 publications

(157 citation statements)

References 48 publications

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“…Intellectual impairment, reduction in performance IQ, memory loss, and dementia have been reported after exposure of the brain to radiation. Evidence suggests that the cognitive decline seen is due to IR-induced damage to the hippocampus, a critical area of the brain responsible for learning and memory (5)(6)(7). Consistent with these findings, radiation to the hippocampus is associated with more pronounced cognitive deficits compared with radiation to other areas of the brain (8).…”

Section: Introductionmentioning

confidence: 75%

“…One such potential compound is lithium, a drug widely used in the treatment of bipolar mood disorder (21). Evidence suggests that lithium protects the brain against a variety of insults, such as stroke and oxidative stress (6,7,(21)(22)(23)(24)(25). However, the mechanisms of the neuroprotection by lithium are not well defined.…”

Section: Introductionmentioning

confidence: 99%

“…However, the mechanisms of the neuroprotection by lithium are not well defined. Several studies have reported that lithium activates the prosurvival PI3K/Akt signaling pathway, leading to inhibition of the glycogen synthase kinase-3 (GSK-3) pathway (6,26,27). Recently, we have shown that lithium prophylaxis improves cognitive performance in mice exposed to cranial IR and protects irradiated hippocampal neurons from apoptosis (6).…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Wang²,

Jiang³

et al. 2009

J. Clin. Invest.

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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.

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Section: Introductionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Yang

Wang²,

Jiang³

et al. 2009

J. Clin. Invest.

Self Cite

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“…48,70,72 Indeed, the profound impact of brain irradiation on neurogenesis has led to its becoming the gold-standard laboratory technique to abolish neurogenesis in animal models. 4,56,57,83,96 Although the mechanisms are not fully understood, a link between persistent microglial activation and impaired hippocampal neurogenesis has been reported. 57,58 It is now known that although radiation kills rapidly dividing neural progenitor cells, the more quiescent neural stem cells (NSCs) remain viable after brain radiation, albeit in a persistently quiescent state only modestly responsive to proneurogenic stimuli such as voluntary physical exercise and mitogenic stimulation.…”

Section: Impact Of Radiation On Neurogenesis and Neuronal Functionmentioning

confidence: 99%

Radiation-induced brain injury: low-hanging fruit for neuroregeneration

Burns

Awad

et al. 2016

FOC

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Brain radiation is a fundamental tool in neurooncology to improve local tumor control, but it leads to profound and progressive impairments in cognitive function. Increased attention to quality of life in neurooncology has accelerated efforts to understand and ameliorate radiation-induced cognitive sequelae. Such progress has coincided with a new understanding of the role of CNS progenitor cell populations in normal cognition and in their potential utility for the treatment of neurological diseases. The irradiated brain exhibits a host of biochemical and cellular derangements, including loss of endogenous neurogenesis, demyelination, and ablation of endogenous oligodendrocyte progenitor cells. These changes, in combination with a state of chronic neuroinflammation, underlie impairments in memory, attention, executive function, and acquisition of motor and language skills. Animal models of radiation-induced brain injury have demonstrated a robust capacity of both neural stem cells and oligodendrocyte progenitor cells to restore cognitive function after brain irradiation, likely through a combination of cell replacement and trophic effects. Oligodendrocyte progenitor cells exhibit a remarkable capacity to migrate, integrate, and functionally remyelinate damaged white matter tracts in a variety of preclinical models. The authors here critically address the opportunities and challenges in translating regenerative cell therapies from rodents to humans. Although valiant attempts to translate neuroprotective therapies in recent decades have almost uniformly failed, the authors make the case that harnessing human radiation-induced brain injury as a scientific tool represents a unique opportunity to both successfully translate a neuroregenerative therapy and to acquire tools to facilitate future restorative therapies for human traumatic and degenerative diseases of the central nervous system.

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“…Up to now, the preclinical studies using animal models have provided very important insights into potential pathogenesis of radiation-induced cognitive impairment. It is believed that the cognitive impairment post-radiation is caused by radiation-induced impairment in the hippocampusdependent functions involved in learning, memory and spatial information processing [38][39][40][41] . Since the vasculature and the oligodendrocyte lineage were usually believed to be the major radiation targets in central nervous system (CNS), it was hypothesized that radiation-induced cognitive impairment might be ascribed to the DNA damage in vascular endothelial and brain glial cells, thus resulting in irreversible proliferation inhibition of these cells [42,43] .…”

Section: Pathogenesis Of Radiation-induced Cognitive Impairmentmentioning

confidence: 99%

Radiation-induced cognitive impairment

2015

Ther Targets Neurol Dis

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Radiation-induced cognitive impairment is one of the late adverse effects of cranial radiation therapy (CRT) for cancer patients with primary and metastatic brain tumors, head and neck cancers etc. It affects approximately 40-50% patients who survive for >6 months and severely reduces the quality of survivors' life. With the advancement of radiation therapy technology, the survival of brain tumor patients is significantly improved, thus understanding the etiology of CRT-induced cognitive impairment and developing the potential strategies of the management of this side-effect have become more important than ever. Some valuable insights have been obtained through extensive preclinical studies. It is suggested that radiation-induced cognitive impairment is due to the dysfunctions of hippocampus-dependent learning, memory and spatial information processing after radiation exposure. Until now, research results have shown that radiation-induced cognitive impairment and neurodegenerative disorders such as Alzheimer disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and aging-related cognitive decline, share some similar pathogenic factors, including chronic oxidative stress and inflammation, impairment in neurogenesis and angiogenesis. Blockade of these factors by antioxidants, anti-inflammatory drugs, transplant of neural stem cells, systemic hypoxia etc. can significantly ameliorate cognitive decline in cranially irradiated experimental animals. These studies shed the light on the pathogenesis of radiation-induced cognitive impairment and may have important implication in developing novel therapeutic interventions for surviving cancer patients who suffer from cognitive decline after CRT.

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Lithium Treatment Prevents Neurocognitive Deficit Resulting from Cranial Irradiation

Cited by 166 publications

References 48 publications

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

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

Radiation-induced brain injury: low-hanging fruit for neuroregeneration

Radiation-induced cognitive impairment

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