Lithium protects hippocampal progenitors, cognitive performance and hypothalamus-pituitary function after irradiation to the juvenile rat brain

Zhou, Kai; Xie, Cuicui; Wickström, Malin; Dolga, Amalia M.; Zhang, Yaodong; Li, Tao; Xu, Yiran; Culmsee, Carsten; Kogner, Per; Zhu, Changlian; Blomgren, Klas

doi:10.18632/oncotarget.16292

Cited by 25 publications

(33 citation statements)

References 62 publications

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“…Thus we used female rats as the irradiation animal model, and in this study we found that brain irradiation in juvenile female rats led to greater weight gain with age, particularly from 15 weeks after irradiation. Such a greater weight gain did not occur in our previous irradiation studies with male rats [4, 24]. With the aim of further characterizing the weight changes, we evaluated the BMI and abdominal circumference, and these two indicators also increased significantly with age in female rats after juvenile brain irradiation.…”

Section: Discussionmentioning

confidence: 84%

“…However, radiotherapy has both acute and long-lasting adverse effects that can result not only in intellectual impairment [3, 4], but also in endocrine and metabolic sequelae such as growth retardation and metabolic syndrome [5, 6]. Metabolic dysfunction is an increasingly recognized complication of childhood cancer treatments, and childhood cancer survivors are twice as likely as their siblings to be diagnosed with type 2 diabetes mellitus, hypertension, and dyslipidemia, and they have a 4-fold increase in mortality from cardiovascular disease as they enter adolescence and adulthood [7, 8].…”

Section: Introductionmentioning

confidence: 99%

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Cranial Irradiation Induces Hypothalamic Injury and Late-Onset Metabolic Disturbances in Juvenile Female Rats

Sun

Zhou

et al. 2018

Dev Neurosci

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Cranial radiotherapy is one of the most effective tools for treating children with brain tumors. However, radiotherapy-induced late-onset side effects have a significant impact on patients’ quality of life. The purpose of this study was to investigate the effects of irradiation on metabolism and the possible molecular and cellular mechanisms behind such effects. Female Wistar rats were subjected to a single dose of 6-Gy whole-brain irradiation on postnatal day 11. The animals were sacrificed 6 h or 20 weeks after irradiation. Cell death and proliferation, microglial activation, and inflammation were analyzed and RNA sequencing was performed. We found that irradiation led to a significantly increased body weight from 15 weeks (p < 0.05) along with white adipose tissue accumulation and adipocyte hypertrophy at 20 weeks, and these changes were accompanied by glucose and lipid metabolic disturbances as indicated by reduced glucose tolerance, increased insulin resistance, increased serum triglycerides, and an increased leptin/adiponectin ratio. Furthermore, irradiation induced cell death, microglial activation, inflammation, and persistent astrocyte reactivity in the hypothalamus. Hypothalamic transcriptome analysis showed that 865 genes were downregulated and 290 genes were upregulated in the irradiated group 20 weeks after irradiation, and further pathway analysis showed that the insulin resistance-related PI3K-Akt signaling pathway and the energy expenditure-related adipocytokine signaling pathway were downregulated. Gene Ontology enrichment analysis showed that the expression of fatty acid metabolism-related proteins and effector proteins was significantly different in the irradiation group. This study demonstrates that ionizing radiation to the juvenile female brain induces hypothalamic damage that is likely to be associated with delayed metabolic abnormalities, and this critical vulnerability of the hypothalamus to irradiation should be taken into consideration in the development of future protective strategies for radiotherapy.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Cranial Irradiation Induces Hypothalamic Injury and Late-Onset Metabolic Disturbances in Juvenile Female Rats

Sun

Zhou

et al. 2018

Dev Neurosci

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“…The level of radiation-related cognitive impairment is influenced by multiple factors, such as the patient's age and the irradiated brain region may be the most important factors [22]. There is a large body of data showing that age is a risk factor for side effects of RT [30], and the effect on the developing adolescent brain is even more pronounced [31]. In addition, other studies have shown that exposure to different areas of the brain is not equally likely to cause the radiation-related cognitive impairment.…”

Section: Factors Influencing Radiation-related Cognitive Impairmentmentioning

confidence: 99%

Research on the Mechanism of Radiation-Related Cognitive Impairment—A Review

Zuo¹,

Huang²

2019

JCT

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Radiotherapy (RT) remains a kind of front-line treatment for the control of tumor growth, especially for brain cancer. It is well known that cognitive impairment is mainly caused by cerebral RT, but the mechanisms underlying radiation-induced cognitive impairment remain unclear. There are different views on the cognitive dysfunction caused by RT in different studies. The recently research evidences about this topic are reviewed in present work. We found a few of factors including brain injury directly caused by radiation, cerebral tissue ischemia and necrosis caused by cerebrovascular injury, oxidative stress and brain injury mediated by inflammation, etc. which play a crucial role in the cognitive dysfunction caused by radiotherapy. These have all been widely recognized, and recently evidences have also shown that potential therapeutic interventions can effectively prevent cognitive impairment.

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“…Lithium, commonly used in the treatment of bipolar disorder, has been shown to exert neuroprotective and regenerative effects in a variety of neurological insults (Shorter 2009). In preclinical studies lithium protected the neonatal brain against the neurodegenerative effects of hypoxia-ischemia (HI) (Xie et al 2014) and rescued cognitive loss in adult as well as in young mice after cranial irradiation (Yazlovitskaya et al 2006) (Huo et al 2012;Zhou et al 2017). The neuroprotective effects of lithium after cranial radiation are attributable to enhanced hippocampal neurogenesis and decreased apoptosis in young rats and mice (Yazlovitskaya et al 2006) (Huo et al 2012).…”

Section: Introductionmentioning

confidence: 99%

“…These complications include late-occurring cognitive impairments, and a negative impact on social competence (Armstrong et al 2010;Georg Kuhn and Blomgren 2011). It has been demonstrated in animal models that preserving or promoting neurogenesis helps attenuate the cognitive deficits observed in irradiated mice and rats (Naylor et al 2008a;Zhou et al 2017). Progress has been made in identifying mechanisms underlying the neuroprotective effects of lithium in rodent models of brain injury, including anti-apoptotic effects (H. Li et al 2011) (Huo et al 2012) (Omata et al 2008;Q.…”

Section: Lithium Is Effective Even When Introduced Long After the Injurymentioning

confidence: 99%

Lithium treatment reverses irradiation-induced changes in rodent neural progenitors

Zanni

Goto

Gaudenzi

et al. 2019

Preprint

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Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context, and we previously showed that voluntary running introduced long after irradiation rescued hippocampal neurogenesis in young mice (Naylor et al. 2008a). Lithium, a well-known mood stabilizer, has both neuroprotective, proneurogenic as well as anti-tumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation, analogous to the voluntary running study. Female mice received a single 4 Gy whole-brain irradiation dose at postnatal day (PND) 21 and were randomized to 0.24% Li 2 CO 3 chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed at PND 77, 91 and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors and promoted neuronal integration upon its discontinuation. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with proliferation, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced impairment of hippocampal neurogenesis even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.

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Lithium protects hippocampal progenitors, cognitive performance and hypothalamus-pituitary function after irradiation to the juvenile rat brain

Cited by 25 publications

References 62 publications

Cranial Irradiation Induces Hypothalamic Injury and Late-Onset Metabolic Disturbances in Juvenile Female Rats

Cranial Irradiation Induces Hypothalamic Injury and Late-Onset Metabolic Disturbances in Juvenile Female Rats

Research on the Mechanism of Radiation-Related Cognitive Impairment—A Review

Lithium treatment reverses irradiation-induced changes in rodent neural progenitors

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