RESUMO
Treatment of malignant childhood posterior fossa tumors (CPFT) often includes surgical resection and craniospinal radiotherapy (CSI). Nasopharyngeal tumors in childhood (CNPHT) are often treated with surgery and radiotherapy (RT), leading to incidental brain irradiation. RT to the developing brain is associated with risks for cognitive impairments. We studied cognitive functioning, health-related quality of life (HRQOL), fatigue, and psychological distress, in adult survivors of CPFT and CNPHT, representing two groups, which had received high and low radiation dose-exposure to the brain, respectively. Cognitive tests were used to compare CPFT (n = 12) and CNPHT (n = 7) survivors to matched healthy controls (n = 28). HRQOL data was compared to the general population (GP) (n = 1415-1459). Average follow-up was 23 (CPFT) and 19 years (CNPHT). CPFT survivors had significant deficits in all cognitive domains. CNPHT survivors showed results below the control group but differed statistically only on one executive test. HRQOL-ratings indicated that both groups had similar self-reported cognitive problems. CPFT survivors reported more emotional problems and fatigue. Anxiety was seen in both CPFT and CNPHT survivors. This study confirmed long-term cognitive sequelae after RT in adult survivors of CPFT,and possible RT-induced cognitive deficits in adult CNPHT survivors.
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Sobreviventes de Câncer , Neoplasias , Adulto , Sobreviventes de Câncer/psicologia , Criança , Fadiga , Seguimentos , Humanos , Neoplasias/psicologia , Testes Neuropsicológicos , Qualidade de Vida/psicologiaRESUMO
Rheumatoid arthritis (RA) is an inflammatory joint disease with a neurological component including depression, cognitive deficits, and pain, which substantially affect patients' quality of daily life. Insulin-like growth factor 1 receptor (IGF1R) signaling is one of the factors in RA pathogenesis as well as a known regulator of adult neurogenesis. The purpose of this study was to investigate the association between IGF1R signaling and the neurological symptoms in RA. In experimental RA, we demonstrated that arthritis induced enrichment of IBA1+ microglia in the hippocampus. This coincided with inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) and up-regulation of IGF1R in the pyramidal cell layer of the cornus ammoni and in the dentate gyrus, reproducing the molecular features of the IGF1/insulin resistance. The aberrant IGF1R signaling was associated with reduced hippocampal neurogenesis, smaller hippocampus, and increased immobility of RA mice. Inhibition of IGF1R in experimental RA led to a reduction of IRS1 inhibition and partial improvement of neurogenesis. Evaluation of physical functioning and brain imaging in RA patients revealed that enhanced functional disability is linked with smaller hippocampus volume and aberrant IGF1R/IRS1 signaling. These results point to abnormal IGF1R signaling in the brain as a mediator of neurological sequelae in RA and provide support for the potentially reversible nature of hippocampal changes.
Assuntos
Artrite Reumatoide/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adulto , Idoso , Animais , Artrite Reumatoide/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Giro Denteado/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Masculino , Camundongos , Pessoa de Meia-Idade , Neurogênese/efeitos dos fármacos , Dor , Medição da Dor , Fosforilação , Receptores de Somatomedina/antagonistas & inibidores , Receptores de Somatomedina/metabolismo , Regulação para Cima , Adulto JovemRESUMO
Dietary fiber is considered a strong intestinal protector, but we do not know whether dietary fiber protects against the long-lasting mucosal damage caused by ionizing radiation. To evaluate whether a fiber-rich diet can ameliorate the long-lasting pathophysiological hallmarks of the irradiated mucosa, C57BL/6J mice on a fiber-rich bioprocessed oat bran diet or a fiber-free diet received 32 Gray in four fractions to the distal colorectum using a linear accelerator and continued on the diets for one, six or 18 weeks. We quantified degenerating crypts, crypt fission, cell proliferation, crypt survival, macrophage density and bacterial infiltration. Crypt loss through crypt degeneration only occurred in the irradiated mice. Initially, it was most frequent in the fiber-deprived group but declined to levels similar to the fiber-consuming group by 18 weeks. The fiber-consuming group had a fast response to irradiation, with crypt fission for growth or healing peaking already at one week post-irradiation, while crypt fission in the fiber-deprived group peaked at six weeks. A fiber-rich diet allowed for a more intense crypt cell proliferation, but the recovery of crypts was eventually lost by 18 weeks. Bacterial infiltration was a late phenomenon, evident in the fiber-deprived animals and intensified manyfold after irradiation. Bacterial infiltration also coincided with a specific pro-inflammatory serum cytokine profile. In contrast, mice on a fiber-rich diet were completely protected from irradiation-induced bacterial infiltration and exhibited a similar serum cytokine profile as sham-irradiated mice on a fiber-rich diet. Our findings provide ample evidence that dietary fiber consumption modifies the onset, timing and intensity of radiation-induced pathophysiological processes in the intestinal mucosa. However, we need more knowledge, not least from clinical studies, before this finding can be introduced to a new and refined clinical practice.
Assuntos
Proliferação de Células/efeitos dos fármacos , Colo , Fibras na Dieta/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Lesões por Radiação/tratamento farmacológico , Animais , Colo/efeitos dos fármacos , Colo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The intermediate filament protein nestin is expressed by neural stem cells, but also by some astrocytes in the neurogenic niche of the hippocampus in the adult rodent brain. We recently reported that nestin-deficient (Nes-/-) mice showed increased adult hippocampal neurogenesis, reduced Notch signaling from Nes-/- astrocytes to the neural stem cells, and impaired long-term memory. Here we assessed learning and memory of Nes-/- mice in a home cage set up using the IntelliCage system, in which the mice learn in which cage corner a nose poke earns access to drinking water. Nes-/- and wildtype mice showed comparable place learning assessed as the incorrect corner visit ratio and the incorrect nose poke ratio. However, during reversal place learning, a more challenging task, Nes-/- mice, compared to wildtype mice, showed improved learning over time demonstrated by the incorrect visit ratio and improved memory extinction over time assessed as nose pokes per visit to the previous drinking corner. In addition, Nes-/- mice showed increased explorative activity as judged by the increased total numbers of corner visits and nose pokes. We conclude that Nes-/- mice exhibit improved reversal place learning and memory extinction, a finding which together with the previous results supports the concept of the dual role of hippocampal neurogenesis in cognitive functions.
Assuntos
Comportamento Exploratório/fisiologia , Memória/fisiologia , Atividade Motora/fisiologia , Nestina/deficiência , Reversão de Aprendizagem/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Intermediate filaments (also termed nanofilaments) are involved in many cellular functions and play important roles in cellular responses to stress. The upregulation of glial fibrillary acidic protein (GFAP) and vimentin (Vim), intermediate filament proteins of astrocytes, is the hallmark of astrocyte activation and reactive gliosis in response to injury, ischemia or neurodegeneration. Reactive gliosis is essential for the protective role of astrocytes at acute stages of neurotrauma or ischemic stroke. However, GFAP and Vim were also linked to neural plasticity and regenerative responses in healthy and injured brain. Mice deficient for GFAP and vimentin (GFAP-/-Vim-/-) exhibit increased post-traumatic synaptic plasticity and increased basal and post-traumatic hippocampal neurogenesis. Here we assessed the locomotor and exploratory behavior of GFAP-/-Vim-/- mice, their learning, memory and memory extinction, by using the open field, object recognition and Morris water maze tests, trace fear conditioning, and by recording reversal learning in IntelliCages. While the locomotion, exploratory behavior and learning of GFAP-/-Vim-/- mice, as assessed by object recognition, the Morris water maze, and trace fear conditioning tests, were comparable to wildtype mice, GFAP-/-Vim-/- mice showed more pronounced memory extinction when tested in IntelliCages, a finding compatible with the scenario of an increased rate of reorganization of the hippocampal circuitry.
Assuntos
Proteína Glial Fibrilar Ácida/fisiologia , Aprendizagem/fisiologia , Memória/fisiologia , Vimentina/fisiologia , Animais , Proteína Glial Fibrilar Ácida/genética , Hipocampo/fisiologia , Filamentos Intermediários/metabolismo , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Knockout , Neurogênese , Vimentina/genéticaRESUMO
BACKGROUND AND PURPOSE: Traditionally, elastase has been used to study exocrine activity of the pancreas in patients with chronic pancreatitis and cystic fibrosis, and calprotectin as a marker for gut-wall inflammation in patients with inflammatory bowel disease. The aim of the study was to find out whether elastase and calprotectin could be used as inflammatory markers for radiation-induced gut wall injury of the distal bowel. MATERIAL AND METHODS: Adult male mice were exposed to two, three, or four fractions of 6 Gy or 8 Gy irradiation to the sigmoid and rectum of the large bowel, using a linear accelerator. Fecal samples were collected from mice at 1, 3, and 6 weeks post-irradiation. The fecal levels of elastase and calprotectin were analyzed using ELISA. RESULTS: Three and 6 weeks after irradiation, we found a dose-effect relationship between dose of ionizing radiation and the fecal level of elastase; that is significantly higher levels of elastase were observed in mice that had received a high irradiation dose. We also found that irradiated mice hosted in the same cage had a comparable level (either high or low) of elastase. No significant differences were observed from the calprotectin data. CONCLUSIONS: We found a clear association between the dose of ionizing radiation to the distal colon and the level of elastase in the fecal samples.
Assuntos
Biomarcadores/análise , Doenças Inflamatórias Intestinais/etiologia , Elastase Pancreática/análise , Radioterapia/efeitos adversos , Animais , Modelos Animais de Doenças , Fracionamento da Dose de Radiação , Fezes , Doenças Inflamatórias Intestinais/patologia , Complexo Antígeno L1 Leucocitário/análise , Masculino , Camundongos Endogâmicos C57BLRESUMO
A deeper understanding of the radiation-induced pathophysiological processes that develop in the gut is imperative to prevent, alleviate, or eliminate cancer survivorship diseases after radiotherapy to the pelvic area. Most rodent models of high-dose gastrointestinal radiation injury are limited by high mortality. We therefore established a model that allows for the delivering of radiation in fractions at high doses while maintaining long-term survival. Adult male C57/BL6 mice were exposed to small-field irradiation, restricted to 1.5 cm of the colorectum using a linear accelerator. Each mouse received 6 or 8 Gy, two times daily in 12-h intervals in two, three, or four fractions. Acute cell death was examined at 4.5 h postirradiation and histological changes at 6 wk postirradiation. Another group was given four fractions of 8 Gy and followed over time for development of visible symptoms. Irradiation caused immediate cell death, mainly limited to the colorectum. At 6 wk postirradiation, several crypts displayed signs of radiation-induced degeneration. The degenerating crypts were seen alongside crypts that appeared perfectly healthy. Crypt survival was reduced after the fourth fraction regardless of dose, whereas the number of macrophages increased. Angiogenesis was induced, likely as a compensatory mechanism for hypoxia. Four months postirradiation, mice began to show radiation-induced symptoms, and histological examination revealed an extensive crypt loss and fibrosis. Our model is uniquely suitable for studying the long-term trajectory and underlying mechanisms of radiation-induced gastrointestinal injury.NEW & NOTEWORTHY A novel mouse model for studying the long-term trajectory of radiation-induced gut injury. The method allows for the use of high doses and multiple fractions, with minor impact on animal health for at least 3 mo. Crypt loss and a slow progression of fibrosis is observed. Crypt degeneration is a process restricted to isolated crypts. Crypt degeneration is presented as a convenient proxy endpoint for long-term radiation-induced gut injury.
Assuntos
Neoplasias Colorretais , Modelos Animais de Doenças , Trato Gastrointestinal , Camundongos , Neoplasias Induzidas por Radiação/patologia , Lesões Experimentais por Radiação/patologia , Animais , Sobrevivência Celular , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Fracionamento da Dose de Radiação , Trato Gastrointestinal/lesões , Trato Gastrointestinal/patologia , Trato Gastrointestinal/efeitos da radiação , Pelve/efeitos da radiação , Radioterapia/efeitos adversos , Radioterapia/métodosRESUMO
OBJECTIVE: Treatment of pediatric brain tumors is associated with potential long-term cognitive sequelae. Patients treated with craniospinal irradiation for posterior fossa tumors are at high risk. New biomarkers that could help to differentiate treatment effects from other causes of cognitive dysfunction would be valuable in tailoring optimal survivorship care. Biomarkers that reflect biological mechanisms behind treatment-associated cognitive decline would also be important in the evaluation of future treatment regimens for pediatric brain or skull base tumors. METHODS: In this biomarker-finding study, 10 adult survivors of pediatric medulloblastoma, skull base tumors, and posterior fossa low-grade glioma underwent study specific lumbar puncture at a minimum of 17 years following treatment. We analyzed cerebrospinal fluid biomarkers reflecting neuron and astrocyte integrity, amyloid metabolism, inflammation, extracellular matrix, synaptic integrity, and blood-brain barrier function. The values were compared with biomarker levels in healthy controls of comparable age. RESULTS: Biomarkers reflecting neuronal injury (neurofilament light chain protein), astrocyte injury or activation (glial fibrillary acidic protein) as well as inflammation (YKL-40) were significantly elevated in cancer survivors compared to controls. Biomarkers reflecting amyloid metabolism showed a pattern of decrease in patients treated for medulloblastoma. INTERPRETATION: The results suggest a potential chronic low-grade neurodegeneration and astrocyte activation in patients treated for pediatric brain or skull base tumors. Protein biomarkers of CNS disease could potentially be used to increase our understanding of the contribution from different tumor treatments with regard to long-term symptoms in cancer patients.
RESUMO
Radiotherapy is an effective treatment strategy in the treatment of brain tumors, but it is also a major cause of long-term complications, especially in survivors of pediatric brain tumors. Cognitive decline caused by cranial radiotherapy is thought, at least partly, to depend on injury to stem and progenitor cells in the dentate gyrus of the hippocampus. This study investigated the effects of lipopolysaccharide (LPS)-induced inflammation at the time of irradiation (IR) in the growing mouse brain. A single injection of LPS (0.3 mg/kg) was administered 24 h prior to cranial IR of 14-day-old male mice. LPS pretreatment increased the levels of the chemokine CCL2 and the cytokine IL-1ß in the brain by 440 and 560%, respectively, compared to IR alone. IR disrupted hippocampal neurogenesis and the growth of the dentate gyrus, and the mice pretreated with LPS displayed an even more pronounced lack of growth than the vehicle-treated group 2 months after IR. The density of microglia was not affected, but LPS-pretreated mice displayed 48% fewer bromodeoxyuridine-positive cells and 43% fewer doublecortin-positive cells in the granule cell layer 2 months after IR compared with the vehicle-treated group. In conclusion, an ongoing inflammation in the brain at the time of IR further enhanced the IR-induced loss of neurogenesis, and may aggravate future cognitive deficits in patients treated with cranial radiotherapy.
Assuntos
Encéfalo/patologia , Inflamação/patologia , Neurogênese/efeitos dos fármacos , Neurônios/patologia , Lesões por Radiação/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Quimiocina CCL2/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/efeitos da radiação , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/patologia , Microglia/efeitos da radiação , Neurogênese/efeitos da radiação , Neurônios/efeitos dos fármacos , Neurônios/efeitos da radiação , Lesões por Radiação/metabolismoRESUMO
BACKGROUND: Radiotherapy is effective in the treatment of cancer but also causes damage to non-cancerous tissue. Pelvic radiotherapy may produce chronic and debilitating bowel symptoms, yet the underlying pathophysiology is still undefined. Most notably, although pelvic radiotherapy causes an acute intestinal inflammation there is no consensus on whether the late-phase pathophysiology contains an inflammatory component or not. To address this knowledge gap, we examined the potential presence of a chronic inflammation in mucosal biopsies from irradiated pelvic cancer survivors. METHODS: We biopsied 24 cancer survivors two to 20 years after pelvic radiotherapy, and four non-irradiated controls. Using tandem mass tag (TMT) mass spectrometry and mRNA sequencing (mRNA-seq), we charted proteomic and transcriptomic profiles of the mucosal tissue previously exposed to a high or a low/no dose of radiation. Changes in the immune cell populations were determined with flow cytometry. The integrity of the protective mucus layers were determined by permeability analysis and 16S rRNA bacterial detection. FINDINGS: 942 proteins were differentially expressed in mucosa previously exposed to a high radiation dose compared to a low radiation dose. The data suggested a chronic low-grade inflammation with neutrophil activity, which was confirmed by mRNA-seq and flow cytometry and further supported by findings of a weakened mucus barrier with bacterial infiltration. INTERPRETATION: Our results challenge the idea that pelvic radiotherapy causes an acute intestinal inflammation that either heals or turns fibrotic without progression to chronic inflammation. This provides a rationale for exploring novel strategies to mitigate chronic bowel symptoms in pelvic cancer survivors. FUNDING: This study was supported by the King Gustav V Jubilee Clinic Cancer Foundation (CB), The Adlerbertska Research Foundation (CB), The Swedish Cancer Society (GS), The Swedish State under the ALF agreement (GS and CB), Mary von Sydow's foundation (MA and VP).
RESUMO
Cranial radiotherapy in the treatment of pediatric malignancies may lead to cognitive deficits, and girls suffer more severe deficits than boys. However, most experimental studies are performed on male animals only. Our aim was to investigate possible long-term gender differences in response to cranial irradiation (IR). Basal neurogenesis in non-irradiated mice was higher in females but this was not apparent until the animals were adult. Male and female C57BL/6J mice received a single dose of 8 Gy to the whole brain on postnatal day 14 and were killed 6 h or 4 months later. Proliferation in the subgranular zone of the dentate gyrus in the hippocampus, as judged by the number of phosphohistone H3-positive cells, was reduced by half 6 h after IR in both males and females. The reduced proliferation was still obvious 4 months after IR. Consequently, the continuous addition of new neurons to the granule cell layer (GCL) during brain growth was reduced in irradiated mice, and the reduction was more pronounced in females. This resulted in hampered growth of the GCL, reduced bromodeoxyuridine incorporation in adulthood, and severely reduced adult neurogenesis, as judged by the number of doublecortin-positive cells in the GCL. In an open-field test, locomotor activity was increased in both males and females after IR and anxiety levels were increased, more so in females. In an IntelliCage test, place learning was impaired by IR in females but not males.
Assuntos
Giro Denteado/efeitos da radiação , Aprendizagem/efeitos da radiação , Atividade Motora/efeitos da radiação , Neurogênese/efeitos da radiação , Fatores Sexuais , Animais , Giro Denteado/crescimento & desenvolvimento , Giro Denteado/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Importance: Acute lymphoblastic leukemia (ALL) constitutes 20% to 30% of all pediatric cancers. The 5-year overall survival among pediatric patients with ALL in high-income countries such as Sweden is currently more than 90%, but long-term unselected nationwide mortality data and mortality data in relation to the general population are lacking. Objective: To compare mortality between pediatric patients with ALL and the general population during a 30-year period in Sweden and to assess the incidence of ALL in Sweden. Design, Setting, and Participants: This cohort study included pediatric patients (aged <18 years) with a morphologically verified ALL diagnosis in the Swedish Cancer Register and/or at least 2 ALL diagnoses in the Swedish National Patient Register between January 1, 1988, and December 31, 2017. Data were cross-linked to the Swedish Cause of Death Register. Data were analyzed from May 2019 to January 2022. Main Outcomes and Measures: The main outcomes were mortality among patients with ALL compared with that in the general population and mortality in different subgroups within the cohort. Standardized mortality ratios (SMRs) were calculated using the general Swedish population as a reference. Within-cohort survival analyses were performed. Results: A total of 2397 patients (1354 [56%] male; mean [SD] age at diagnosis, 6.1 [4.7] years) were included in the study. The mean (SD) incidence of pediatric ALL during the study period was 4.11 (0.60) cases per 100 000 persons per year (females, 3.68 [0.65] cases per 100 000 persons per year; males, 4.52 [0.81] cases per 100 000 persons per year; P < .001). The observed number of deaths among pediatric patients with ALL was 409 vs the 9.5 deaths expected in the general population, resulting in an overall SMR of 43.1 (95% CI, 39.0-47.5); females had a higher SMR than males (57.8 [95% CI, 49.5-67.2] vs 34.5 [95% CI, 32.0-41.4]; P < .001). Analysis within the cohort showed a continued decrease in survival throughout the 30-year follow-up. The association between calendar year of ALL diagnosis, corresponding with different ALL treatment protocols, and mortality showed the lowest survival for the 1988-1991 group and the highest for the 2008-2017 group (χ2 = 20.3; P < .001). Conclusions and Relevance: In this cohort study, a consistently high SMR was seen among pediatric patients with ALL. Within the ALL cohort, survival evolved to a similar extent as in the young general population of Sweden. Furthermore, survival among patients with ALL decreased throughout the whole follow-up period without any trend difference after the 5-year follow-up time point. The changes in ALL treatment protocols were associated with overall improved absolute survival over time.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Feminino , Humanos , Masculino , Criança , Suécia/epidemiologia , Estudos de Coortes , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Causas de Morte , RendaRESUMO
We sought to determine whether radiation to the colorectum had an impact on parameters of hippocampal neurogenesis and, if so, whether it could be modulated by a fiber-rich diet. Male C57BL/6J mice were fed a diet containing bioprocessed oat bran or a fiber-free diet, starting two weeks before colorectal irradiation with 4 fractions of 8 Gray or sham-irradiation. Diets were then continued for 1, 6 or 18 weeks, whereafter parameters of hippocampal neurogenesis were analyzed and correlated to serum cytokine levels. No statistically significant changes in neuronal markers or cell proliferation were found at one week post-irradiation. Six weeks post-irradiation there was a decreased cell proliferation in the subgranular zone that appeared slightly more pronounced in irradiated animals on a fiber-free diet and increased numbers of immature neurons per mm2 dentate gyrus in the irradiated mice, with a statistically significant increase in mice on a fiber-rich diet. Microglial abundancy was similar between all groups. 18 weeks post-irradiation, a fiber-free diet had reduced the number of immature neurons, whereas irradiation resulted in an increase. Despite this, the population of mature neurons was stable. Analysis of serum cytokines revealed a negative correlation between MIP1-α and the number of immature neurons one week after irradiation, regardless of diet. Our findings show that pelvic radiotherapy has the potential to cause a long-lasting impact on hippocampal neurogenesis, and dietary interventions may modulate this impact. More in-depth studies on the relationship between irradiation-induced intestinal injury and brain health are warranted.
Assuntos
Hipocampo , Neurogênese , Animais , Giro Denteado , Fibras na Dieta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NeurôniosRESUMO
Irradiation-induced loss of neural stem and progenitor cells may contribute to cognitive deficits. Furthermore, subsequent inflammation inhibits neural progenitor cell differentiation. Here we have characterized the microglia response after a single dose of 8 Gy to the brains of postnatal day 9 or 21 rats. The number of Iba-1-positive microglia increased 6 h after IR but had decreased 7 days later, below control levels, and this decrease was more pronounced in P9 rats. Active caspase-3 and TUNEL staining revealed irradiation-induced microglia death. This age-dependent IR-induced loss of microglia likely affects both the response to IR and further brain development.
Assuntos
Encéfalo/citologia , Microglia/efeitos da radiação , Radiação , Fatores Etários , Animais , Animais Recém-Nascidos , Encéfalo/crescimento & desenvolvimento , Encéfalo/efeitos da radiação , Proteínas de Ligação ao Cálcio/metabolismo , Contagem de Células/métodos , Feminino , Marcação In Situ das Extremidades Cortadas/métodos , Indóis , Masculino , Proteínas dos Microfilamentos , Ratos , Ratos Wistar , Proteínas Repressoras/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
We characterized the inflammatory response after a single dose of 8 Gy to the brains of postnatal day 9 rats. Affymetrix gene chips revealed activation of multiple inflammatory mechanisms in the acute phase, 6 h after irradiation. In the subacute phase, 7 days after irradiation, genes related to neurogenesis and cell cycle were down-regulated, but glial fibrillary acidic protein (GFAP) was up-regulated. The concentrations of 14 different cytokines and chemokines were measured using a microsphere-based xMAP technology. CCL2, Gro/KC and IL-1alpha were the most strongly up-regulated 6 h after irradiation. CCL2 was expressed in astrocytes and microglia in the dentate gyrus and the subventricular zone (SVZ). Hypertrophy, but not hyperplasia, of astrocytes was demonstrated 7 days after irradiation. In summary, we found transient activation of multiple inflammatory mechanisms in the acute phase (6 h) after irradiation and activation of astrocytes in the subacute phase (7 days) after irradiation. It remains to be elucidated whether these transient changes are involved in the persistent effects of radiation observed on neurogenesis and cognition in rodents.
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Encéfalo/patologia , Encéfalo/efeitos da radiação , Inflamação/metabolismo , Neurogênese , Animais , Apoptose/efeitos da radiação , Astrócitos/metabolismo , Astrócitos/efeitos da radiação , Biomarcadores/metabolismo , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Quimiocina CCL2/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Gliose/patologia , Imunoensaio , Imuno-Histoquímica , Inflamação/patologia , Microglia/metabolismo , Microglia/efeitos da radiação , Análise de Sequência com Séries de Oligonucleotídeos , Estresse Oxidativo/efeitos da radiação , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Better survival rates among pediatric brain tumor patients have resulted in an increased awareness of late side effects that commonly appear following cancer treatment. Radiation-induced changes in hippocampus and white matter are well described, but do not explain the full range of neurological late effects in childhood cancer survivors. The aim of this study was to investigate thalamus following cranial irradiation (CIR) to the developing brain. At postnatal day 14, male mice pups received a single dose of 8 Gy CIR. Cellular effects in thalamus were assessed using immunohistochemistry 4 months after CIR. Interestingly, the density of neurons decreased with 35% (p = 0.0431) and the density of astrocytes increased with 44% (p = 0.011). To investigate thalamic astrocytes, S100ß+ cells were isolated by fluorescence-activated cell sorting and genetically profiled using next-generation sequencing. The phenotypical characterization indicated a disrupted function, such as downregulated microtubules' function, higher metabolic activity, immature phenotype and degraded ECM. The current study provides novel insight into that thalamus, just like hippocampus and white matter, is severely affected by CIR. This knowledge is of importance to understand the late effects seen in pediatric brain tumor survivors and can be used to give them the best suitable care.
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Irradiação Craniana , Radiação Ionizante , Tálamo/efeitos da radiação , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Astrócitos/efeitos da radiação , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos da radiação , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microtúbulos/metabolismo , Fenótipo , Análise de Sequência de DNA , Tálamo/metabolismo , Tálamo/patologiaRESUMO
Chronic intestinal injury after pelvic radiotherapy affects countless cancer survivors worldwide. A comprehensive understanding of the long-term injury dynamics is prevented in available animal models. With linear accelerators that are used to treat cancer in patients, we irradiated a small volume encompassing the colorectum in mice with four fractions of 8 Gy per fraction. We then determined the long-term dynamics of mucosal injury, repair, and the duration of inflammation. We show that crypt fission, not cell proliferation, is the main long-term mechanism for rescuing crypt density after irradiation, and provides a potentially wide window for clinical interventions. Persisting macrophage aggregations indicate a chronic mucosal inflammation. A better understanding as to how crypt fission is triggered and why it fails to repair fully the mucosa may help restore bowel health after pelvic radiotherapy. Moreover, anti-inflammatory interventions, even if implemented long after completed radiotherapy, could promote bowel health in pelvic cancer survivors.
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Mucosa Intestinal/efeitos da radiação , Pelve/efeitos da radiação , Radioterapia/efeitos adversos , Animais , Proliferação de Células/efeitos da radiação , Colo/efeitos da radiação , Modelos Animais de Doenças , Humanos , Inflamação/fisiopatologia , Macrófagos/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Brain tumors are the most common form of solid tumors in children. Due to the increasing number of survivors, it is of importance to prevent long-term treatment-induced side effects. Montelukast, a leukotriene receptor antagonist, may have the desired neuroprotective properties. The aim of the study was to determine whether montelukast could reduce adverse effects of cranial irradiation (CIR) to the young brain. Daily injections of montelukast or vehicle was given to young mice for 4 or 14 days in combination with CIR or under normal conditions. Montelukast treatment for 4 days protected against cell death with 90% more cell death in the vehicle group compared to the montelukast group 24 h after CIR. It also resulted in less microglia activation 6 h after CIR, where montelukast lowered the levels of CD68 compared to the vehicle groups. Interestingly, the animals that received montelukast for 14 days had 50% less proliferating cells in the hippocampus irrespective of receiving CIR or not. Further, the total number of neurons in the granule cell layer was altered during the sub-acute phase. The number of neurons was decreased by montelukast treatment in control animals (15%), but the opposite was seen after CIR, where montelukast treatment increased the number of neurons (15%). The results show beneficial effects by montelukast treatment after CIR in some investigated parameters during both the acute phase and with longer drug treatment. However, it also resulted in lower proliferation in the hippocampus under normal conditions, indicating that the effects of montelukast can be either beneficial or unfavorable, depending on the circumstances.
Assuntos
Acetatos/farmacologia , Antiasmáticos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neurogênese/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Ciclopropanos , Ensaio de Imunoadsorção Enzimática , Feminino , Fluorometria , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica , Camundongos , SulfetosRESUMO
PURPOSE: To unravel the role of the vasculature in radiation-induced brain tissue damage. MATERIALS AND METHODS: Postnatal day 14 mice received a single dose of 10 Gy cranial irradiation and were sacrificed 6 h, 24 h or 7 days post-irradiation. Endothelial cells were isolated from the hippocampus and cerebellum using fluorescence-activated cell sorting, followed by cell cycle analysis and gene expression profiling. RESULTS: Flow cytometric analysis revealed that irradiation increased the percentage of endothelial cells, relative to the whole cell population in both the hippocampus and the cerebellum. This change in cell distribution indicates that other cell types are more susceptible to irradiation-induced cell death, compared to endothelial cells. This was supported by data showing that genes involved in endothelial cell-specific apoptosis (e.g. Smpd1) were not induced at any time point investigated but that genes involved in cell-cycle arrest (e.g. Cdkn1a) were upregulated at all investigated time points, indicating endothelial cell repair. Inflammation-related genes, on the other hand, were strongly induced, such as Ccl2, Ccl11 and Il6. CONCLUSIONS: We conclude that endothelial cells are relatively resistant to ionizing radiation but that they play an active, hitherto unknown, role in the inflammatory response after irradiation. In the current study, this was shown in both the hippocampus, where neurogenesis and extensive cell death after irradiation occurs, and in the cerebellum, where neurogenesis no longer occurs at this developmental age.