Pathogenesis Of Radiation-induced Brain Injury Research Articles

The effects of Lactobacillus reuteri microcapsules on radiation-induced brain injury by regulating the gut microenvironment.

A radiation-induced brain injury (RIBI) is a major adverse event following radiotherapy of malignant tumors. RIBI would affect cognitive function, leading to a series of complications and even death. However, the pathogenesis of RIBI is still unclear, and it still lacks specific therapeutic drugs. The gut-brain bidirectional communication may be mediated by various microbiota and metabolites in the gastrointestinal tract. Probiotics are closely related to physiological health. The theory of the gut-brain axis provides us with a new idea to improve the gut microenvironment by supplementing probiotics against RIBI. Here, Lactobacillus reuteri microcapsules (LMCs) were prepared, which were predominantly irregular spheres with a rough surface under a scanning electron microscope and a narrow size distribution ranging from 20 to 700 μm. The transmission electron microscopy images showed that the structure of microcapsules containing Lactobacillus reuteri (L. reuteri) was a core and shell structure. The survival of L. reuteri in microcapsules was significantly more than that of free L. reuteri in the simulated stomach environment of pH 1.2. 16S rDNA sequencing showed that LMCs observably increased the relative abundance of Lactobacillus in RIBI mice. More importantly, compared with the RIBI model mice, the behavior of RIBI mice treated with LMCs was significantly improved. In addition, LMCs greatly alleviated the pathological damage of the hippocampus and intestines in the mice after irradiation and reduced the level of TNF-α and IL-6 in vivo. Generally, LMCs are a promising oral preparation, which provide new ideas and methods for the treatment of RIBI.

Research progress of brain-derived microparticles on microglia polarization in radiation-induced brain injury of head and neck tumors

Radiation brain injury（RBI） is one of the complications of radiotherapy for head and neck malignant tumors, which has a serious impact on the prognosis and quality of life of patients. The existence of radiation-induced brain injury not only limits the radiation therapy dose of head and neck malignant tumors, but also restricts the efficacy of tumor patients, and has a serious impact on the prognosis and quality of life of patients. The pathogenesis of radiation-induced brain injury is not yet completely clear, we use various clinical treatment for radiation brain injury patients to alleviate some clinical symptoms, but it cannot effectively reverse the brain injury process. In recent years, with the further exploration of radiation-induced brain injury and the accumulation of clinical experience, studies have found that microglial polarization plays an important role in radiation-induced brain injury, and brain-derived particles can activate microglia. This article reviews the research progress of brain-derived microparticles on the polarization of microglia in radiation-induced brain injury of head and neck tumors.

Regulatory coupling between long noncoding RNAs and senescence in irradiated microglia

BackgroundMicroglia have been implicated in the pathogenesis of radiation-induced brain injury (RIBI), which severely influences the quality of life during long-term survival. Recently, irradiated microglia were speculated to present an aging-like phenotype. Long noncoding RNAs (lncRNAs) have been recognized to regulate a wide spectrum of biological processes, including senescence; however, their potential role in irradiated microglia remains largely uncharacterized.MethodsWe used bioinformatics and experimental methods to identify and analyze the senescence phenotype of irradiated microglia. Western blotting, enzyme-linked immunosorbent assays, immunofluorescence, and quantitative real-time reverse transcription-polymerase chain reaction were performed to clarify the relationship between the radiation-induced differentially expressed lncRNAs (RILs) and the distinctive molecular features of senescence in irradiated microglia.ResultsWe found that the senescence of microglia could be induced using ionizing radiation (IR). A mutual regulation mode existed between RILs and three main features of the senescence phenotype in irradiated microglia: inflammation, the DNA damage response (DDR), and metabolism. Specifically, for inflammation, the expression of two selected RILs (ENSMUST00000190863 and ENSMUST00000130679) was dependent on the major inflammatory signaling pathways of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). The two RILs modulated the activation of NF-κB/MAPK signaling and subsequent inflammatory cytokine secretion. For the DDR, differential severity of DNA damage altered the expression profiles of RILs. The selected RIL, ENSMUST00000130679, promoted the DDR. For metabolism, blockade of sterol regulatory element-binding protein-mediated lipogenesis attenuated the fold-change of several RILs induced by IR.ConclusionsOur findings revealed that certain RILs interacted with senescence in irradiated microglia. RILs actively participated in the regulation of senescence features, suggesting that RILs could be promising intervention targets to treat RIBI.

Endothelial progenitor cell transplantation restores vascular injury in mice after whole-brain irradiation

Vascular damage plays an important role in the pathogenesis of radiation-induced brain injury (RBI). Endothelial progenitor cells (EPCs) are responsible for maintaining and repairing endothelial function, and have become a promising method for the treatment of cerebrovascular diseases. However, whether EPC transplantation plays a protective role in RBI has not been fully elucidated. Therefore, the present study investigated the effects of bone marrow-derived EPC transplantation in a whole-brain irradiation (WBI) mouse model. Mice were divided into the three groups: control group, irradiation group and EPCs group. Phosphate buffered saline or EPCs were intravenously injected into mice one week after irradiation, and brains were analyzed eight weeks after injection. Flow cytometry demonstrated that irradiation led to a significant reduction in the peripheral blood EPC count; however, EPC transplantation led to a significant increase in the circulating EPCs. Intravital two-photon imaging and western blotting demonstrated that EPC transplantation reversed the effects of irradiation by decreasing blood–brain barrier permeability and increasing the expression of tight junction proteins in the brain. Additionally, immunofluorescence staining revealed that the brain microvascular density was higher in the EPCs group than the irradiation group. Therefore, EPC transplantation may restore damage caused by WBI to the blood–brain barrier, tight junctions, and cerebral capillary density. These results highlight the potential beneficial effects of EPC transplantation on vascular damage induced by RBI.

Ionizing radiation modulates vascular endothelial growth factor expression through STAT3 signaling pathway in rat neonatal primary astrocyte cultures.

Background and PurposeRadiation‐induced brain injury (RBI) usually occurs six months to three years after irradiation, often shows cognitive dysfunction, epilepsy, and other neurological dysfunction. In severe cases, it can cause a wide range of cerebral edema, even herniation. It seriously threatens the survival of patients and their quality of life, and it becomes a key factor in limiting the radiation dose and lowering the therapeutic efficacy in recent years. Therefore, studying the pathogenesis of RBI and exploring new therapeutic targets are of great significance.MethodsIn our study, we observed the activation and secretory function in astrocytes as well as the intracellular signal transducer and activator of transcription 3 (STAT3) signal transduction pathway activation status after exposing different doses of X‐ray irradiation by using MTT, Immunocytologic analysis, and Western blot analysis. Further, we used the same way to explore the role of vascular endothelial growth factor (VEGF) in signal transduction pathways playing in the activation of astrocytes after irradiating through the use of specificInhivascular endothelial growth factorbitors of STAT3.ResultsAst can be directly activated, reactive hyperplasia and hypertrophy, the expression of the activation marker glial fibrillary acidic protein is increased, and the expression of vascular endothelial growth factor (VEGF) in the cells is increased, which may lead to RBI. After the addition of STAT3 pathway inhibitor, most of the Ast radiation activation was suppressed, and the expression of high‐level expression of VEGF decreased after irradiation.ConclusionOur findings demonstrated that X‐ray irradiation directly induced the activation of astrocytes in a persistent manner and X‐ray irradiation activated STAT3 signaling pathway. As the same time, we found that X‐ray irradiation induced the activation of astrocytes and secretion cytokine. The STAT3 signaling pathway may participate in the pathogenesis of radiation‐induced brain injury.

Altered properties of brain white matter structural networks in patients with nasopharyngeal carcinoma after radiotherapy.

Previous neuroimaging studies revealed radiation-induced brain injury in patients with nasopharyngeal carcinoma (NPC) in the years after radiotherapy (RT). These injuries may be associated with structural and functional alterations. However, differences in the brain structural connectivity of NPC patients at different times after RT, especially in the early-delayed period, remain unclear. We acquired diffusion tensor imaging (DTI) data from three groups of NPC patients, 25 in the pre-RT (before RT) group, 22 in the early-delayed (1-6months) period (post-RT-ED) group, and 33 in the late-delayed (>6months) period (post-RT-LD) group. Then, we constructed brain white matter (WM) structural networks and used graph theory to compare their between-group differences. The NPC patients in the post-RT-ED group showed decreased global properties when compared with the pre-RT group. We also detected the nodes with between-group differences in nodal parameters. The nodes that differed between the post-RT-ED and pre-RT groups were mainly located in the default mode (DMN) and central executive networks (CEN); those that differed between the post-RT-LD and pre-RT groups were located in the limbic system; and those that differed between the post-RT-LD and post-RT-ED groups were mainly in the DMN. These findings may indicate that radiation-induced brain injury begins in the early-delayed period and that a reorganization strategy begins in the late-delayed period. Our findings may provide new insight into the pathogenesis of radiation-induced brain injury in normal-appearing brain tissue from the network perspective.

Radiation-induced abnormal cortical thickness in patients with nasopharyngeal carcinoma after radiotherapy

Conventional MRI studies showed that radiation-induced brain necrosis in patients with nasopharyngeal carcinoma (NPC) in years after radiotherapy (RT) could involve brain gray matter (GM) and impair brain function. However, it is still unclear the radiation-induced brain morphological changes in NPC patients with normal-appearing GM in the early period after RT. In this study, we acquired high-resolution brain structural MRI data from three groups of patients, 22 before radiotherapy (pre-RT) NPC patients with newly diagnosed but not yet medically treated, 22 NPC patients in the early-delayed stage after radiotherapy (post-RT-ED), and 20 NPC patients in the late-delayed stage after radiotherapy (post-RT-LD), and then analyzed the radiation-induced cortical thickness alteration in NPC patients after RT. Using a vertex-wise surface-based morphometry (SBM) approach, we detected significantly decreased cortical thickness in the precentral gyrus (PreCG) in the post-RT-ED group compared to the pre-RT group. And the post-RT-LD group showed significantly increased cortical thickness in widespread brain regions, including the bilateral inferior parietal, left isthmus of the cingulate, left bank of the superior temporal sulcus and left lateral occipital regions, compared to the pre-RT group, and in the bilateral PreCG compared to the post-RT-ED group. Similar analysis with ROI-wise SBM method also found the consistent results. These results indicated that radiation-induced brain injury mainly occurred in the post-RT-LD group and the cortical thickness alterations after RT were dynamic in different periods. Our findings may reflect the pathogenesis of radiation-induced brain injury in NPC patients with normal-appearing GM and an early intervention is necessary for protecting GM during RT.

Kukoamine A Prevents Radiation-Induced Neuroinflammation and Preserves Hippocampal Neurogenesis in Rats by Inhibiting Activation of NF-κB and AP-1.

Impaired hippocampal neurogenesis and neuroinflammation are involved in the pathogenesis of radiation-induced brain injury. Kukoamine A (KuA) was demonstrated to have neuroprotective effects through inhibiting oxidative stress and apoptosis after whole-brain irradiation (WBI) in rats. The aim of this study was to investigate whether administration of KuA would prevent radiation-induced neuroinflammation and the detrimental effect on hippocampal neurogenesis. For this study, male Wistar rats received either sham irradiation or WBI (30Gy single dose of X-rays) followed by the immediate injection of either KuA or vehicle intravenously. The dose of KuA was 5, 10, and 20mg/kg, respectively. The levels of pro-inflammatory cytokines were assayed by ELISA kits. The newborn neurons were detected by 5-bromo-2-deoxyuridine (BrdU)/neuronal nuclei (NeuN) double immunofluorescence. Microglial activation was measured by Iba-1 immunofluorescence. The expression of Cox-2 and the activation of nuclear factor κB (NF-κB), activating protein 1(AP-1), and PPARδ were evaluated by western blot. WBI led to a significant increase in the level of TNF-α, IL-1β, and Cox-2, and it was alleviated by KuA administration. KuA attenuated microglial activation in rat hippocampus after WBI. Neurogenesis impairment induced by WBI was ameliorated by KuA. Additionally, KuA alleviated the increased translocation of NF-κB p65 subunit and phosphorylation of c-jun induced by WBI and elevated the expression of PPARδ. These data indicate that KuA could ameliorate the neuroinflammatory response and protect neurogenesis after WBI, partially through regulating the activation of NF-κB, AP-1, and PPARδ.

Correlation between magnetic resonance perfusion weighted imaging of radiation brain injury and pathology.

We used magnetic resonance perfusion weighted imaging and pathological evaluation to examine different stages of radiation-induced brain injury and to investigate the correlation between the relative cerebral blood volume (rCBV) ratio and vascular endothelial growth factor (VEGF). Thirty adult rats were randomly divided into 2 groups: control and radiation group. The control group was not subjected to irradiation. The irradiation group rats were examined by magnetic resonance imaging and magnetic resonance perfusion weighted imaging at 1, 3, 6, 9, and 12 months after radiation treatment. We measured the rCBV, mean transit time, and time to peak. Hematoxylin and eosin staining, immunohistochemical staining, and electron microscopy were performed. VEGF absorbance was evaluated by immunohistochemical staining. Compared with the control group, the differences in rCBV, mean transit time, time to peak, and VEGF absorbance after 3 months were statistically significant (P < 0.05). rCBV was positively correlated with VEGF (r = 0.94, P < 0.05). Magnetic resonance perfusion weighted imaging can reflect pathophysiological changes in brain tissue after irradiation. Decreased expression of VEGF plays a critical role in the pathogenesis of radiation-induced brain injury.

Effect of edaravone on radiation-induced brain necrosis in patients with nasopharyngeal carcinoma after radiotherapy: a randomized controlled trial.

Excessive generation of free radicals plays a critical role in the pathogenesis of radiation-induced brain injury. This study was designed to evaluate the protective effect of edaravone, a free radical scavenger, on radiation-induced brain necrosis in patients with nasopharyngeal carcinoma. Eligible patients were randomized 1:1 to the control group and the edaravone group (intravenous 30 mg twice per day for 2 weeks). Both groups received intravenous conventional steroid therapy and were monitored by brain MRI and LENT/SOMA scales prior to the entry of the trial and at 3-months after completing the trial. The primary end point was a 3-month response rate of the proportional changes determined by MRI. The trial is registered at Clinicaltrials.gov Identifier: NCT01865201. Between 2009 and 2012, we enrolled 154 patients. Of whom 137 were eligible for analysis. The volumes of necrosis estimated on T2-weighted image showed that 55.6 % edaravone-treated patients (40 out of 72) showed edema decreases ≥25 %, which was significantly higher than that in the control group (35.4 %, 23 out of 65, p = 0.025). Forty-four patients treated with edaravone (61.1 %) reported improvement in neurologic symptoms and signs evaluated by LENT/SOMA scales, while the rate was 38.5 % in the control group (p = 0.006). MRI of the edaravone group showed a significant decrease in area of T1-weighted contrast enhancement (1.67 ± 4.69 cm2, p = 0.004) and the T2-weighted edema (5.08 ± 10.32 cm2, p = 0.000). Moreover, compared with those in control group, patients with edaravone exhibited significantly better radiological improvement measured by T2-weighted image (p = 0.042). Administration of edaravone, in adjunct to steroid regimen, might provide a better outcome in patients with radiation-induced brain necrosis.

The PPARδ agonist GW0742 inhibits neuroinflammation, but does not restore neurogenesis or prevent early delayed hippocampal-dependent cognitive impairment after whole-brain irradiation

Brain tumor patients often develop cognitive impairment months to years after partial or fractionated whole-brain irradiation (WBI). Studies suggest that neuroinflammation and decreased hippocampal neurogenesis contribute to the pathogenesis of radiation-induced brain injury. In this study, we determined if the peroxisomal proliferator-activated receptor (PPAR) δ agonist GW0742 can prevent radiation-induced brain injury in C57Bl/6 wild-type (WT) and PPARδ knockout (KO) mice. Dietary GW0742 prevented the acute increase in IL-1β mRNA and ERK phosphorylation measured at 3h after a single 10-Gy dose of WBI; it also prevented the increase in the number of activated hippocampal microglia 1 week after WBI. In contrast, dietary GW074 failed to prevent the radiation-induced decrease in hippocampal neurogenesis determined 2 months after WBI in WT mice or to mitigate their hippocampal-dependent spatial memory impairment measured 3 months after WBI using the Barnes maze task. PPARδ KO mice exhibited defects including decreased numbers of astrocytes in the dentate gyrus/hilus of the hippocampus and a failure to exhibit a radiation-induced increase in activated hippocampal microglia. Interestingly, the number of astrocytes in the dentate gyrus/hilus was reduced in WT mice, but not in PPARδ KO mice 2 months after WBI. These results demonstrate that, although dietary GW0742 prevents the increase in inflammatory markers and hippocampal microglial activation in WT mice after WBI, it does not restore hippocampal neurogenesis or prevent early delayed hippocampal-dependent cognitive impairment after WBI. Thus, the exact relationship between radiation-induced neuroinflammation, neurogenesis, and cognitive impairment remains elusive.

164. Potential utilization of minocycline as a radioprotective agent in the brain

Roughly 50% of adult and 100% of pediatric cancer survivors who receive whole-brain irradiation for metastatic disease will develop cognitive dysfunction. Patients who are subjected to cranial radiotherapy for management of primary and metastatic tumors (∼200,000/year) are at the highest risk for neuropsychological deficits. Radiation induces a neuroinflammatory milieu of reactive oxygen species and pro-inflammatory cytokines such as tumor necrosis factor (TNF)-a and interleukin (IL)-1b, which are responsible for the pathogenesis of radiation-induced brain injury. Minocycline (MC), a second-generation tetracycline derivative, has anti-inflammatory, free radical scavenging and antiapoptotic properties. To characterize the neuroprotective effect of MC on radiation-induced inflammation in the brain, female C57BL/6 mice were treated with MC (i.p.) for 5 days beginning immediately before whole-body irradiation with 3 Gy Co-60 γ-rays. Brains were collected 32 days post-irradiation and analyzed for gene expression and cytokine levels. Although there were few detectable changes in cytokines at the protein level, radiation exposure up-regulated gene expression of the IL-1 family (Il1f6, Il1f8 and Il1f10), TNF super family (Tnfsf11b and Tnfsf12), growth differentiating factors (Gdf1, 2, 10 and 15) and bone morphogenetic proteins (Bmp4, 5, 6, 7 and 10). With MC treatment, the expression of many of these genes was no longer significantly different from 0 Gy controls. This suggests that MC may be useful as a neuroprotective agent and may reduce the risk for neurocognitive deficits.

PPARs and Anticancer Therapies

PPARs and Anticancer Therapies

Role of PPARs in Radiation-Induced Brain Injury.

Whole-brain irradiation (WBI) represents the primary mode of treatment for brain metastases; about 200 000 patients receive WBI each year in the USA. Up to 50% of adult and 100% of pediatric brain cancer patients who survive >6 months post-WBI will suffer from a progressive, cognitive impairment. At present, there are no proven long-term treatments or preventive strategies for this significant radiation-induced late effect. Recent studies suggest that the pathogenesis of radiation-induced brain injury involves WBI-mediated increases in oxidative stress and/or inflammatory responses in the brain. Therefore, anti-inflammatory strategies can be employed to modulate radiation-induced brain injury. Peroxisomal proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the steroid/thyroid hormone nuclear receptor superfamily. Although traditionally known to play a role in metabolism, increasing evidence suggests a role for PPARs in regulating the response to inflammation and oxidative injury. PPAR agonists have been shown to cross the blood-brain barrier and confer neuroprotection in animal models of CNS disorders such as stroke, multiple sclerosis and Parkinson's disease. However, the role of PPARs in radiation-induced brain injury is unclear. In this manuscript, we review the current knowledge and the emerging insights about the role of PPARs in modulating radiation-induced brain injury.