Activation of the Mevalonate Pathway in Response to Anti-cancer Treatments Drives Glioblastoma Recurrences Through Activation of Rac-1.

Glioblastoma (GBM) is the deadliest adult brain cancer. Under the current standard of care, almost all patients succumb to the disease and novel treatments are urgently needed. Recognizing that GBMs are addicted to cholesterol, past clinical trials have repurposed statins against GBM but failed. The purpose of this study was to test whether treatments that upregulate the cholesterol biosynthesis pathway in GBM would generate a metabolic vulnerability that can be exploited using statins and to determine the underlying mechanisms.Effects of radiotherapy and temozolomide or dopamine receptor antagonists on the mevalonate pathway in GBM were assessed in vitro and in vivo. The impact of statins on self-renewal of glioma stem cells and median survival was studied. Branches of the mevalonate pathway were probed to identify relevant effector proteins.Cells surviving combination treatments that converge in activating the immediate early response, universally upregulated the mevalonate pathway and increased stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 was inhibited by statins, which led to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.We conclude that a combination of dopamine receptor antagonists and statins could potentially improve radiotherapy outcome and warrants further investigation. SIGNIFICANCE: Combination therapies that activate the mevalonate pathway in GBM cells after sublethal treatment enhance self-renewal and migratory capacity through Rac-1 activation, which creates a metabolic vulnerability that can be further potentially exploited using statins.

Radiation-Induced Cellular Plasticity: A Strategy for Combatting Glioblastoma.

Glioblastoma is the deadliest brain cancer in adults and almost all patients succumb to the tumor. While surgery followed by chemo-radiotherapy significantly delays disease progression, these treatments do not lead to long-term tumor control and targeted therapies or biologics have so far failed to further improve survival. Utilizing a transient radiation-induced state of multipotency we used the adenylcyclase activator forskolin to alter the cellular fate of glioma cells in response to radiation. The combined treatment induced the expression of neuronal markers in glioma cells, reduced proliferation and led to a distinct gene expression profile. scRNAseq revealed that the combined treatment forced glioma cells into a microglia- and neuron-like phenotypes. In vivo this treatment led to a loss of glioma stem cells and prolonged median survival in mouse models of glioblastoma. Collectively, our data suggest that revisiting a differentiation therapy with forskolin in combination with radiation could lead to clinical benefit.

[Impact of the 2020 lockdown on prehospital psychiatric emergencies in a large city]. / Auswirkungen des Lockdowns 2020 auf präklinische psychiatrische Notarzteinsätze in einer Großstadt.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic represented a serious challenge for healthcare systems worldwide. Special psychiatric patients represent a vulnerable group and are particularly affected by lockdown interventions. Knowledge on the possible effects for this group of patients in an emergency physician setting is low. OBJECTIVE: The aim of this paper is to investigate the impact of the first lockdown during the COVID-19 pandemic in 2020 on emergency ambulance services for psychiatric patients in a large German city. MATERIAL AND METHODS: A retrospective analysis was conducted on all prehospital psychiatric emergencies in a large German city during the first pandemic-related lockdown from 22 March 2020 to 4 May 2020, with the same period in 2019 serving as a reference. RESULTS: During the first lockdown there was a significant increase in the number of emergency missions with respect to psychiatric cases. A substantial rise in substance-associated deployments was observed. Moreover, there was an increase in the proportion of psychiatric patients who did not meet emergency criteria. Suicidal tendencies and agitation status played a minor role during the lockdown. CONCLUSION: The lockdown had a notable impact on the frequency and profile of emergency physician calls in the metropolitan area studied. The substantial increase in substance-associated callouts can be interpreted as both a deterioration in access to the healthcare system and an expression of the increased stress faced by the general population and vulnerable groups in particular.

Activation of the mevalonate pathway in response to anti-cancer treatments drives glioblastoma recurrences through activation of Rac-1.

Glioblastoma is the deadliest adult brain cancer. Under the current standard of care almost all patients succumb to the disease and novel treatments are urgently needed. Dopamine receptor antagonists have been shown to target cancer cell plasticity in GBM and repurposing these FDA-approved drugs in combination with radiation improves the efficacy of radiotherapy in glioma models. In cells surviving this combination treatment the mevalonate pathway is upregulated at the transcriptional and functional level. Here we report that glioblastoma treatments that converge in the immediate early response to radiation through activation of the MAPK cascade universally upregulate the mevalonate pathway and increase stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 is inhibited by statins, which leads to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.

Nicotinamide Adenine Dinucleotide Phosphate Oxidase Promotes Glioblastoma Radiation Resistance in a Phosphate and Tensin Homolog-Dependent Manner.

Aims: The goal of this study was to determine whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-produced reactive oxygen species (ROS) enhance brain tumor growth of glioblastoma (GBM) under hypoxic conditions and during radiation treatment. Results: Exogenous ROS promoted brain tumor growth in gliomasphere cultures that expressed functional phosphate and tensin homolog (PTEN), but not in tumors that were PTEN deficient. Hypoxia induced the production of endogenous cytoplasmic ROS and tumor cell growth via activation of NOX. NOX activation resulted in oxidation of PTEN and downstream protein kinase B (Akt) activation. Radiation also promoted ROS production via NOX, which, in turn, resulted in cellular protection that could be abrogated by knockdown of the key NOX component, p22. Knockdown of p22 also inhibited tumor growth and enhanced the efficacy of radiation in PTEN-expressing GBM cells. Innovation: While other studies have implicated NOX function in GBM models, this study demonstrates NOX activation and function under physiological hypoxia and following radiation in GBM, two conditions that are seen in patients. NOX plays an important role in a PTEN-expressing GBM model system, but not in PTEN-nonfunctional systems, and provides a potential, patient-specific therapeutic opportunity. Conclusion: This study provides a strong basis for pursuing NOX inhibition in PTEN-expressing GBM cells as a possible adjunct to radiation therapy. Antioxid. Redox Signal. 39, 890-903.

Effects of Dopamine Receptor Antagonists and Radiation on Mouse Neural Stem/Progenitor Cells.

Background: Dopamine receptor antagonists are psychotropic drugs that have been originally developed against psychiatric disorders. We recently identified dopamine receptor antagonists as potential anti-cancer agents and some have entered clinical trials against glioblastoma. Radiotherapy is known to cause cognitive impairment in patients receiving cranial irradiation through the elimination of neural stem/progenitor cells and subsequent loss of neurogenesis. Methods: Using transgenic mice that report the presence of neural stem/progenitor cells through Nestin promoter-driven expression of enhanced green fluorescent protein, the effects of dopamine receptor antagonists alone or in combination with radiation on murine neural stem/progenitor cells were assessed in sphere-formation assays, flow cytometry and immunofluorescence in vitro and in vivo . Results: We report that several dopamine receptor antagonists show sex-dependent effects on neural stem/progenitor cells both in vitro and in vivo . Hydroxyzine, trifluoperazine, amisulpride, nemonapride or quetiapine alone or in combination with radiation significantly increased the number of neural stem/progenitor cells in female neurospheres but not in male mice. Dopamine receptor antagonists either protected neural stem/progenitor cells from radiation or expanded the stem cell pool, thus indicating that this combination therapy against glioblastoma will not increase radiation-induced cognitive decline through increasing elimination of neural stem/progenitor cells and subsequent loss of neurogenesis. Conclusions: We conclude that a therapeutic window for dopamine receptor antagonists in combination with radiation potentially exist, making it a novel combination therapy against glioblastoma. Normal tissue toxicity of this combination potentially differs depending on age and sex and should be taken into consideration when designing clinical trials. Key Points: - Neural stem/progenitor cells show sex-dependent sensitivity to dopamine receptor antagonists- Dopamine receptor antagonists active against GBM increase Neural stem/progenitor cells counts. Importance of the Study: Combination therapy of dopamine receptor antagonists with radiation have entered clinical trials against glioblastoma but the normal tissue toxicity of this combination has not been fully explored yet. Here we present evidence that some dopamine receptor antagonists show sex-dependent effects on neural stem/progenitor cells either by protecting neural stem/progenitor cells from radiation or inducing an expansion of the stem cell pool, suggesting that this combination therapy against glioblastoma will not increase radiation-induced cognitive decline through increasing elimination of neural stem/progenitor cells and subsequent loss of neurogenesis. Normal tissue toxicity of this combination potentially differs depending on age and sex and should be further explored in clinical trials.

[What Influence did the Lockdown 2020 have on the Use of a Central Emergency Room by Psychiatric Emergency Patients]. / Welchen Einfluss hatte der Lockdown 2020 auf die Inanspruchnahme einer zentralen Notaufnahme durch psychiatrische Notfallpatienten.

OBJECTIVE: The current coronavirus pandemic (Covid-19 disease) poses major challenges to healthcare systems worldwide. The aim of this work was to identify the impact on psychiatric emergency presentations in an ED during the implemented lockdown. METHODS: A retrospective survey of all psychiatric emergency presentations in the ED during the lockdown was conducted. The same period in 2019 served as the reference year. RESULTS: There was a decrease in psychiatric patients. Changes were observed in the age and diagnoses. CONCLUSION: Some clear effects of the lockdown on psychiatric emergencies in an ED setting can be described. However, the changes were smaller than in other countries with other health care systems.

Factors predicting admission of psychiatric emergency contacts after presenting to the emergency department: results of a regression analysis.

BACKGROUND: Psychiatric emergency patients have great relevance in the interdisciplinary emergency department. Emergency physicians in this setting often have to make decisions under time pressure based on incomplete information regarding the patient's further treatment. The aim of this study was to identify possible predictors associated with an increased likelihood of inpatient psychiatric admission. METHODS: A retrospective cross-sectional study of all psychiatric emergency contacts in an interdisciplinary emergency department (ED) of a general hospital in a large German city was conducted for 2015. A binary regression analysis was performed to identify possible predictors. RESULTS: In 2015, a total of 21421 patient contacts were reported in the emergency department, of which 1733 were psychiatric emergencies. Psychiatric emergency was the fourth most common cause presenting to the ED. The most common diagnosis given was mental and behavioral disorders due to the use of psychotropic substances (F1). Factors associated with an increased probability of inpatient psychiatric admission were previously known patients, patients under a legal care order (guardianship), and previous outpatient medical contact. No association for gender or age was found. Data demonstrated a negative relationship between a neurotic, stress-related and somatoform disorder diagnosis and admission. CONCLUSIONS: The present study shows some significant characteristics associated with an increased likelihood of emergency admission. Independent of the health care system, the predictors found seem to be relevant with regard to the probability of admission, when compared internationally. To improve the treatment of patients in emergency units, these factors should be taken into account.

P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells.

Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence.

[Excited Delirium Syndrome (ExDS): emergence and emergency management]. / Erregungssturm ­ Entstehung und Notfallbehandlung.

The Excited Delirium Syndrome (ExDS) is a state of maximum psychophysiological excitation far beyond mental agitation. Patients themselves are at an acute risk and put others at a high risk. We present data from eleven patients and a short literature review. Results: 9 of 11 patients were acutely intoxicated (alcohol, magic mushrooms, THC, ecstacy, or "flakka"). Eight had a history of substance abuse and 4 of other mental illness. None of the patients responded to attempts at verbal de-escalation. Seven had significant injuries at the time of admission to the hospital. The aggressive "psychiatric" presentation of ExDS can lead to vital risks being overlooked (hyperexcitation, acidosis, rhabdomyolysis, hypoxemia, and cardiovascular decompensation), which may even be increased by severe methods of restraint (hogtie; positional asphyxia). Early recognition of ExDS and its risks, comprehensive management and the prevention of inappropriate treatment will help to reduce fatal outcomes.

Effects of the DRD2/3 antagonist ONC201 and radiation in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the deadliest of all brain cancers in adults. The current standard-of-care is surgery followed by radiotherapy and temozolomide, leading to a median survival time of only 15 months. GBM are organized hierarchically with a small number of glioma-initiating cells (GICs), responsible for therapy resistance and tumor recurrence, suggesting that targeting GICs could improve treatment response. ONC201 is a first-in-class anti-tumor agent with clinical efficacy in some forms of high-grade gliomas. Here we test its efficacy against GBM in combination with radiation. METHODS: Using patient-derived GBM lines and mouse models of GBM we test the effects of radiation and ONC201 on GBM self-renewalin vitro and survivalin vivo.A possible resistance mechanism is investigated using RNA-Sequencing. RESULTS: Treatment of GBM cells with ONC201 reduced self-renewal, clonogenicity and cell viabilityin vitro. ONC201 exhibited anti-tumor effects on radioresistant GBM cells indicated by reduced self-renewal in secondary and tertiary glioma spheres. Combined treatment of ONC201 and radiation prolonged survival in syngeneic and patient-derived orthotopic xenograft mouse models of GBM. Subsequent transcriptome analyses after combined treatment revealed shifts in gene expression signatures related to quiescent GBM populations, GBM plasticity, and GBM stem cells. CONCLUSIONS: Our findings suggest that combined treatment with the DRD2/3 antagonist ONC201 and radiation improves the efficacy of radiation against GBMin vitroandin vivothrough suppression of GICs without increasing toxicity in mouse models of GBM. A clinical assessment of this novel combination therapy against GBM is further warranted.

Targeting Glioma Stem Cells.

Only a small fraction of the tumor cell population, glioma-initiating cells (GICs) help glioblastoma propagate, invade, evade immune recognition, repair DNA in response to radiation more efficiently, remodel the microenvironment for optimal growth, and actively pump out chemotherapies. Recent data hint that efforts toward GIC characterization and quantification can help predict patient outcomes, and yet the different subpopulations of GICs remain incompletely understood. A better understanding of GIC subtypes and functions proves critical for engineering targeted therapies. Challenges for doing so are discussed, and dopamine receptor antagonists are introduced as new means to enhance the efficacy of the current standard-of-care against GICs.

Dopamine Receptor Antagonists, Radiation, and Cholesterol Biosynthesis in Mouse Models of Glioblastoma.

BACKGROUND: Glioblastoma is the deadliest brain tumor in adults, and the standard of care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options. METHODS: Using patient-derived HK-157, HK-308, HK-374, and HK-382 glioblastoma lines, the GL261 orthotopic mouse models of glioblastoma, and HK-374 patient-derived orthotopic xenografts, we tested the effect of radiation and the dopamine receptor antagonist quetiapine on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism was investigated using RNA-sequencing. The blood-brain-barrier-penetrating statin atorvastatin was used to overcome this resistance mechanism. All statistical tests were 2-sided. RESULTS: Treatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro, and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing mice. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered GL261 and HK-374 orthotopic tumors vulnerable to simultaneous treatment with atorvastatin and further statistically significantly prolonged the survival of C57BL/6 (n = 10 to 16 mice per group; median survival not reached; log-rank test, P < .001) and NOD Scid gamma mice (n = 8 to 21 mice per group; hazard ratio = 3.96, 95% confidence interval = 0.29 to 12.40; log-rank test, P < .001), respectively. CONCLUSIONS: Our results indicate promising therapeutic efficacy with the triple combination of quetiapine, atorvastatin, and radiation treatment against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use, our study could be rapidly translated into a clinical trial.

Tumor necrosis factor receptor signaling modulates carcinogenesis in a mouse model of breast cancer.

Pro-inflammatory conditions have long been associated with mammary carcinogenesis and breast cancer progression. The underlying mechanisms are incompletely understood but signaling of pro-inflammatory cytokine TNFα through its receptors TNFR1 and TNFR2 is a major mediator of inflammation in both obesity and in the response of tissues to radiation, 2 known risk factors for the development of breast cancer. Here, we demonstrated the loss of one TNFR2 allele led to ductal hyperplasia in the mammary gland with increased numbers of mammary epithelial stem cell and terminal end buds. Furthermore, loss of one TNFR2 allele increased the incidence of breast cancer in MMTV-Wnt1 mice and resulted in tumors with a more aggressive phenotype and metastatic potential. The underlying mechanisms include a preferential activation of canonical NF-κB signaling pathway and autocrine production of TNFα. Analysis of the TCGA dataset indicated inferior overall survival for patients with down-regulated TNFR2 expression. These findings unravel the imbalances in TNFR signaling promote the development and progression of breast cancer, indicating that selective agonists of TNFR2 could potentially modulate the risk for breast cancer in high-risk populations.

[Analysis of the psychiatric emergency inpatients in an ER setting at a general hospital]. / Charakterisierung des stationär aufgenommenen psychiatrischen Notfallpatienten in einer interdisziplinären ZNA.

OBJECTIVES: Evaluation of psychiatric emergency contacts in an interdisciplinary emergency room. METHODS: We conducted a retrospective examination of all psychiatric consultations of 2015. RESULTS: The three most common emergency syndromes could be assigned in descending order to the F1 (32.2%), the F2 (25.9%) and the F3 diagnoses (21.2%). The admission rate was 58.9% and more than half of the patients came to the emergency room on foot (55.7%). Diagnosis-specific differences were found between first-time presenters and patients who had presented previously. CONCLUSION: The psychiatric emergency has high relevance in the emergency room. The majority of the patients admitted to hospital meet the emergency criteria according to the guideline.

[Characterization of Ambulant Emergency Contacts in an Emergency Room at a General Hospital]. / Charakterisierung von ambulanten Notfallkontakten in einer interdisziplinären Notaufnahme.

OBJECTIVE: Scientific interest in emergency psychiatric patients has increased significantly over the last two decades. Nevertheless, current knowledge of this group of patients in the setting of an interdisciplinary emergency department is surprisingly low. METHODS: A retrospective examination of all ambulatory psychiatric emergency contacts in the emergency room of a regional hospital in 2015 took place. RESULTS: Solely F4 diagnoses accounted for 48.1 % of all first-time patients. Female patients younger than 25 years used the ER twice as often as their male control-group. Almost half of all outpatients fulfilled no emergency criteria. CONCLUSION: There are specific age and gender differences. The proportion of patients without any emergency criteria was surprisingly high. More scientific research is needed in order to scrutinize this possible inappropriate use of an ER by psychiatric patients.

The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma.

Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over surgery alone, but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype, and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP causes loss of radiation-induced Nanog mRNA expression, and activation of GSK3 with consecutive posttranslational reduction in p-Akt, Sox2, and ß-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that the combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment-resistant, induced GICs (iGICs).

1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine treatment after brain irradiation preserves cognitive function in mice.

BACKGROUND: Normal tissue toxicity is an inevitable consequence of primary or secondary brain tumor radiotherapy. Cranial irradiation commonly leads to neurocognitive deficits that manifest months or years after treatment. Mechanistically, radiation-induced loss of neural stem/progenitor cells, neuroinflammation, and demyelination are contributing factors that lead to progressive cognitive decline. METHODS: The effects of 1-[(4-nitrophenyl)sulfonyl]-4-phenylpiperazine (NSPP) on irradiated murine neurospheres, microglia cells, and patient-derived gliomaspheres were assessed by sphere-formation assays, flow cytometry, and interleukin (IL)-6 enzyme-linked immunosorbent assay. Activation of the hedgehog pathway was studied by quantitative reverse transcription PCR. The in vivo effects of NSPP were analyzed using flow cytometry, sphere-formation assays, immunohistochemistry, behavioral testing, and an intracranial mouse model of glioblastoma. RESULTS: We report that NSPP mitigates radiation-induced normal tissue toxicity in the brains of mice. NSPP treatment significantly increased the number of neural stem/progenitor cells after brain irradiation in female animals, and inhibited radiation-induced microglia activation and expression of the pro-inflammatory cytokine IL-6. Behavioral testing revealed that treatment with NSPP after radiotherapy was able to successfully mitigate radiation-induced decline in memory function of the brain. In mouse models of glioblastoma, NSPP showed no toxicity and did not interfere with the growth-delaying effects of radiation. CONCLUSIONS: We conclude that NSPP has the potential to mitigate cognitive decline in patients undergoing partial or whole brain irradiation without promoting tumor growth and that the use of this compound as a radiation mitigator of radiation late effects on the central nervous system warrants further investigation.

Radiation mitigation of the intestinal acute radiation injury in mice by 1-[(4-nitrophenyl)sulfonyl]-4-phenylpiperazine.

The objective of the study was to identify the mechanism of action for a radiation mitigator of the gastrointestinal (GI) acute radiation syndrome (ARS), identified in an unbiased high-throughput screen. We used mice irradiated with a lethal dose of radiation and treated with daily injections of the radiation mitigator 1-[(4-nitrophenyl)sulfonyl]-4-phenylpiperazine to study its effects on key pathways involved in intestinal stem cell (ISC) maintenance. RNASeq, quantitative reverse transcriptase-polymerase chain reaction, and immunohistochemistry were performed to identify pathways engaged after drug treatment. Target validation was performed with competition assays, reporter cells, and in silico docking. 1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine activates Hedgehog signaling by binding to the transmembrane domain of Smoothened, thereby expanding the ISC pool, increasing the number of regenerating crypts and preventing the GI-ARS. We conclude that Smoothened is a target for radiation mitigation in the small intestine that could be explored for use in radiation accidents as well as to mitigate normal tissue toxicity during and after radiotherapy of the abdomen.

Effects of Brain Irradiation in Immune-Competent and Immune-Compromised Mouse Models.

Patient-derived orthotopic xenografts (PDOXs) closely recapitulate primary human glioblastoma (GBM) tumors in terms of histology and genotype. Compared to other mouse strains, NOD-scid IL2Rgammanull (NSG) mice show excellent tumor take rates, which makes them an ideal host for PDOXs. However, NSG mice harbor a mutation in the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), which renders them relatively radiosensitive. This has been a frequently voiced concern in studies involving ionizing radiation. In this study, we assessed brain toxicity in NSG mice compared to three other different mouse strains frequently used in radiation studies at radiation doses commonly used in experimental combination therapy studies. C3H/Sed/Kam, C57Bl/6, nude and NOD-scid IL2Rgammanull mice received a single dose of 4 Gy to the right brain hemispheres using an image-guided small animal irradiator. Brains were stained using H&E, luxol fast blue, and antibodies against IBA1 and GFAP one, two, four or six months postirradiation. Additional animals of all four strains were exposed to five daily fractions of 2 Gy (5 × 2 Gy), and tissue sections were stained 72 h later against gH2AX, NeuN, GFAP and IBA1. None of the mouse strains displayed radiation-induced toxicity at any of the time points tested. Radiation doses relevant for testing combination therapies can be safely applied to the brains of NSG mice without the occurrence of radiation-induced normal tissue toxicity.