Pathophysiological Responses in Rat and Mouse Models of Radiation-Induced Brain Injury

Yang, Liguo; Yang, Jianhua; Li, Guoqian; Li, Yi; Wu, Rong; Cheng, Jinping; Tang, Yamei

doi:10.1007/s12035-015-9628-x

Cited by 99 publications

(91 citation statements)

References 106 publications

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“…Exocytosis and vesicle secretion can further facilitate release of purinergic nucleotides, inflammatory molecules, enzymes, and ROS into the extracellular milieu, which collectively can alter the TME to become pro-tumorigenic (60,68,(80)(81)(82) [ Figure 5B]. The dose and time-dependence of radiation exposure can significantly alter the impact of RT on tumor microenvironment by affecting tumor or stromal cell behavior, migration, and treatment response (26,28,29,(83)(84)(85)(86)(87)(88)(89)(90). High-dose irradiation effects include hemorrhage, cognitive decline, neurodegeneration, and premature senescence, which can progress over time (91,92).…”

Section: Discussionmentioning

confidence: 99%

“…Metabolic alterations may be pro-tumorigenic, promoting glioma initiation and progression (21)(22)(23)(24). RT-induced metabolic changes in GBM depend on tumor volume, location, and dose-time regime of RT-administration, all of which can vary treatment response (8,(25)(26)(27)(28)(29). While differential metabolism of glioma tumor cells can be targeted to regress tumor growth, understanding the impact of radiation-induced metabolic alterations in GBM microenvironment can provide new avenues to maximize long term benefits of RT in GBM care.…”

Section: Introductionmentioning

confidence: 99%

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Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Gupta

Vučković

Zhang

et al. 2020

Preprint

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AbstractGlioblastoma (GBM) is uniformly fatal with a one year median survival rate, despite the best available treatment, including radiotherapy (RT). Impacts of prior RT on tumor recurrence are poorly understood but may increase tumor aggressiveness. Metabolic changes have been investigated in radiation-induced brain injury; however, the tumor-promoting effect following prior radiation is lacking. Since RT is vital to GBM management, we quantified the tumor-promoting effects of prior radiotherapy (RT) on patient-derived intracranial GBM xenografts and characterized the metabolic alterations associated with the protumorigenic microenvironment. Human xenografts (GBM143) were implanted into nude mice 24h following 20Gy cranial radiation vs. sham animals. Tumors in pre-radiated mice were more proliferative and more infiltrative, yielding faster mortality (p<0.0001). Histologic evaluation of tumor associated macrophage/microglia (TAMs) revealed cells with a more fully activated ameboid morphology in pre-radiated animals. Microdialyzates from the radiated brain at the margin of tumor infiltration contralateral to the site of implantation were analyzed by unsupervised liquid chromatography-mass spectrometry (LC-MS). In pre-radiated animals, metabolites known to be associated with tumor progression (like, modified nucleotides and polyols) were identified. Whole-tissue metabolomic analysis of the pre-radiated brain microenvironment for metabolic alterations in a separate cohort of nude mice using 1H-NMR revealed significant decrease in levels of antioxidants (glutathione (GSH) and ascorbate (ASC)), NAD+, TCA intermediates, and increased ATP and GTP. Glutathione and ASC showed highest VIPpred (1.65) in OPLS-DA analysis. Involvement of ASC catabolism was further confirmed by GC-MS. To assess longevity of radiation effects, we compared survival with implantation occuring 2 months vs. 24h following radiation, finding worse survival in animals implanted at 2 months. These radiation-induced alterations are consistent with a chronic disease-like microenvironment characterized by reduced levels of antioxidants and NAD+, as well as elevated extracellular ATP and GTP serving as chemoattractants, promoting cell motility and vesicular secretion with decreased levels of GSH and ASC exacerbating oxidative stress. Taken together, these data suggest that IR induces tumor-permissive changes in the microenvironment with metabolomic alterations that may facilitate tumor aggressiveness with important implications for recurrent glioblastoma. Harnessing these metabolomic insights may provide opportunities to attenuate RT-associated aggressiveness of recurrent GBM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Gupta

Vučković

Zhang

et al. 2020

Preprint

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“…Rodents, including mice and rats, are the most commonly utilized animal models in medical research given their genetic background, anatomical structure, operability, and relatively low cost of use [11]. Experimental data indicated that rodents showed similar anatomical …”

Section: The Establishment Of Rodent Modelsmentioning

confidence: 99%

“…In addition, mice are too fragile to undergo repeated anesthesia when long-term observation periods are required. Therefore, rats are utilized more frequently than mice in radiation-based studies [11]. Nonetheless, no abundant research has compared the difference of radiation-induced cognitive dysfunction between different species and strains of rodents.…”

Section: Introductionmentioning

confidence: 99%

The Current Utilization of Cognitive Tests in the Research of Radiation-Induced Cognitive Dysfunction in Rodent Models

Li¹,

Chen²,

Zhang³

2017

Brain Disord Ther

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Recent clinical studies suggest that radiation-induced damage to the hippocampus plays a considerable role in the cognitive dysfunction of patients after cranial irradiation. In particular, deficits in learning, memory, and spatial processing observed in patients who received WBI are thought to be related to hippocampal injury [7]. The mechanisms of radiation-induced cognitive dysfunction are not yet fully understood. According to the available knowledge, radiation-induced cognitive dysfunction is hypothesized to result from dynamic interactions between multiple cell types: vascular and glial clonogens, neurogenesis, neural function and neuroinflammation [8][9][10]. Therefore, studies into the mechanisms and preventive measures of radiation-induced cognitive dysfunction are of paramount importance to decrease the side effects of WBI and increase the quality of life of patients. To achieve this goal, widely acknowledged animal models and universally utilized cognitive tests are the prerequisite and foundation. The Establishment of Rodent ModelsRodents, including mice and rats, are the most commonly utilized animal models in medical research given their genetic background, anatomical structure, operability, and relatively low cost of use [11]. Experimental data indicated that rodents showed similar anatomical AbstractWhole brain irradiation using low LET rays has remained the mainstay to treat some primary and metastatic brain tumors. Radiation-induced cognitive dysfunction is a progressive and irreversible late side effect after whole brain irradiation and inevitably decreases the quality of life of cancer survivors. To address this negative issue, many studies have been performed to explore the mechanisms of radiation-induced cognitive dysfunction and to develop efficacious preventive and treating measures. The prerequisite and foundation of implementing a persuasive and profound study to investigate radiation-induced cognitive dysfunction is the utilization of widely acknowledged animal models and universally applied cognitive tests. In this review, articles studying radiation-induced cognitive dysfunction from 2011 to 2016 were collected. The establishment of animal models and detailed utilization of cognitive tests were analyzed and summarized. This review summarized the general range of irradiation doses and time intervals utilized and the effects of these two factors on the results of cognitive tests. changes and physiopathological mechanisms to human beings after cranial irradiation [12]. In addition, the effects of radiation on rodents could be assessed over relatively short time periods-weeks to months rather than years to decades. Anatomical and functional changes of rodents after cranial irradiation are dependent on age, dose, and sex, which are compatible with the risk factors in human patients [13]. Given that these observations are representative of the effects seen in patients, the rodent model would enable the efficient study of mechanisms and treatments.

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“…Moreover, radiation‐induced brain injury is the most common dose‐limiting complication of patients receiving radiotherapy for malignant brain and neck tumors or lung cancer‐derived brain metastases (Yang et al. ). Radiation‐induced brain injury is a dynamic complex process, which includes acute, early delayed and late delayed damage based on the time course and clinical manifestations (Béhin & Delattre, ).…”

Section: Introductionmentioning

confidence: 99%

Early metabolic characterization of brain tissues after whole body radiation based on gas chromatography–mass spectrometry in a rat model

Yao

Cao

et al. 2018

Biomedical Chromatography

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Radiation-induced brain injury involves acute, early delayed and late delayed damage based on the time-course and clinical manifestations. The acute symptoms are mostly transient and reversible, whereas the late delayed radiation-induced changes are progressive and irreversible. Therefore, evaluation of the organ-specific early response to ionizing radiation exposure is necessary for improving treatment strategies and minimizing possible damage at an early stage after radiation exposure. In the current study, the gas chromatography-mass spectrometry technique based on metabolomics coupled with metabolic correlation network was applied to investigate the early metabolic characterization of rat brain tissues following irradiation. Our findings showed that the metabolic response to irradiation was not just limited to the variations of individual metabolite levels, but also accompanied by alterations of network correlations among various metabolites. Metabolite clustering indicated that energy metabolism disorder and inflammation response were induced following radiation exposure. The correlation networks revealed that the strong positive correlations of differential metabolites were highly reduced and significant negative linkages were highlighted in irradiated groups even without statistical changes in metabolic levels. Our findings provided new insights into our understanding of the radiation-induced acute brain injury mechanism and clues as to the therapy target for clinical applications.

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Pathophysiological Responses in Rat and Mouse Models of Radiation-Induced Brain Injury

Cited by 99 publications

References 106 publications

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

The Current Utilization of Cognitive Tests in the Research of Radiation-Induced Cognitive Dysfunction in Rodent Models

Early metabolic characterization of brain tissues after whole body radiation based on gas chromatography–mass spectrometry in a rat model

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