The Construction of a Radiation-Induced Brain Injury Model and Preliminary Study on the Effect of Human Recombinant Endostatin in Treating Radiation-Induced Brain Injury

Zhou, Juying; Xu, Ximing; Wang, Lili; Qin, Songbin; Hu, Chao; Nie, Liangqin; Yu, Ting

doi:10.12659/msm.917537

Cited by 9 publications

(5 citation statements)

References 33 publications

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“…Consequently, pathological levels of VEGF inevitably result in vasogenic cerebral edema (44), which was consistent with our data in the anlotinib treated groups. Also, Ma et al (45) showed that thrombosis could be observed from 3 to 7 days after irradiation, while thrombus recanalization is first achieved at 14 days. In combination with the histological results, they believed that the sharp increase in BWC at 14 days after irradiation not only results from the over-expression of VEGF, but also with thrombus recanalization.…”

Section: Discussionmentioning

confidence: 99%

Mitigation of acute radiation-induced brain injury in a mouse model using anlotinib

Gao

Zheng

et al. 2021

Ann Palliat Med

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Background: With the development of radiological technologies, radiotherapy has been gradually widely used in the clinic to intracranial tumours and become standardised. However, the related central nervous system disorders are still the most obvious complications after radiotherapy. This study aims to quantify the effectiveness of anlotinib, a small molecule inhibitor of multiple receptor tyrosine kinases, in mitigating acute phase of radiation-induced brain injury (RBI) in a mouse model. Methods:The onset and progression of RBI were investigated in vivo. All mice, (except for the sham group) were irradiated at a single-fraction of 20 Gy and treated with different doses of anlotinib (0, 0.2 and 0.8 mg/kg, respectively). The expression levels of glial fibrillary acidic protein (GFAP), hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and phosphorylated vascular endothelial growth factor receptor-2 (p-VEGFR2) were assessed by western blot. Histological changes were identified by luxol fast blue (LFB) staining. Results:The expression levels of GFAP, HIF-1α, and VEGF were downregulated following treatment with anlotinib. However, anlotinib failed to inhibit the development of demyelination. Cerebral edema [as measured by brain water content (BWC)] was also mitigated following treatment with anlotinib.Conclusions: In summary, treatment with anlotinib significantly mitigated the adverse effects of acute RBI in a dose-dependent manner by downregulating the activation of astrocytes, improving brain hypoxia, and alleviating cerebral edema.

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Section: Discussionmentioning

confidence: 99%

Mitigation of acute radiation-induced brain injury in a mouse model using anlotinib

Gao

Zheng

et al. 2021

Ann Palliat Med

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“…This response was inhibited by GABAa antagonist bicuculline [29]. Therefore, declining the GABAergic neurotransmission in the hypothalamus could be contributing to the decreased appetite and weight loss observed after WBI [11,[30][31][32]. Hypothalamic GABA neurons are also known to regulate several physiological and behavioral responses associated with anxiety and stress.…”

Section: Discussionmentioning

confidence: 99%

Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex

Franco-Pérez

Montes

Sánchez-Hernández

et al. 2020

Preprint

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Background: Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are both highly connected to the hypothalamus and its regulatory processes. Methods: Male Wistar rats were exposed to whole-brain irradiation with 11 Gy (BED= 72Gy). After one month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, glutamine, in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the relative expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann-Whitney U test (p<0.05). Results: Whole-brain irradiation with 11Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus, one month after exposure. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significantly increased levels of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation. Conclusions: Our findings confirm that whole-brain irradiation can affect rat brain regions differently and opens new avenues for study. After one month, WBI decreases inhibitory neurotransmission in the hypothalamus and, conversely, increases excitatory neurotransmission in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex both indicate a modified neurochemical balance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.

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“…This response was inhibited by GABAa antagonist bicuculline [34]. Therefore, declining the GABAergic neurotransmission in the hypothalamus could be contributing to the decreased appetite and weight loss observed after WBI [11,[35][36][37]. Hypothalamic GABA neurons are also known to regulate several physiological and behavioral responses associated with anxiety and stress.…”

Section: Discussionmentioning

confidence: 99%

Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex.

PEREZ

Montes

Sánchez-Hernández

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation (WBI) in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are highly connected to the hypothalamus and its regulatory processes.Methods: Male Wistar rats were exposed to WBI with 11 Gy (Biologically Equivalent Dose= 72Gy). After one month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, and glutamine in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann-Whitney U test (p<0.05).Results: WBI with 11Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significant increases of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation.Conclusion: Our findings confirm that WBI can affect rat brain regions differently and opens new avenues for study. After one month, WBI decreases inhibitory neurotransmission in the hypothalamus and, conversely, increases excitatory neurotransmission in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex indicate a neurochemical imbalance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.

show abstract

The Construction of a Radiation-Induced Brain Injury Model and Preliminary Study on the Effect of Human Recombinant Endostatin in Treating Radiation-Induced Brain Injury

Cited by 9 publications

References 33 publications

Mitigation of acute radiation-induced brain injury in a mouse model using anlotinib

Mitigation of acute radiation-induced brain injury in a mouse model using anlotinib

Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex

Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex.

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