Radiation-induced Brain Injury Research Articles

Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence

Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type (Lgmn+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn-/-) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP's involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn+/+ primary neurons with the conditioned media derived from irradiated Lgmn+/+ or Lgmn-/- primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.

Repetitive transcranial magnetic stimulation ameliorates cognitive deficits in mice with radiation-induced brain injury by attenuating microglial pyroptosis and promoting neurogenesis via BDNF pathway

BackgroundRadiation-induced brain injury (RIBI) is a common and severe complication during radiotherapy for head and neck tumor. Repetitive transcranial magnetic stimulation (rTMS) is a novel and non-invasive method of brain stimulation, which has been applied in various neurological diseases. rTMS has been proved to be effective for treatment of RIBI, while its mechanisms have not been well understood.MethodsRIBI mouse model was established by cranial irradiation, K252a was daily injected intraperitoneally to block BDNF pathway. Immunofluorescence staining, immunohistochemistry and western blotting were performed to examine the microglial pyroptosis and hippocampal neurogenesis. Behavioral tests were used to assess the cognitive function and emotionality of mice. Golgi staining was applied to observe the structure of dendritic spine in hippocampus.ResultsrTMS significantly promoted hippocampal neurogenesis and mitigated neuroinflammation, with ameliorating pyroptosis in microglia, as well as downregulation of the protein expression level of NLRP3 inflammasome and key pyroptosis factor Gasdermin D (GSDMD). BDNF signaling pathway might be involved in it. After blocking BDNF pathway by K252a, a specific BDNF pathway inhibitor, the neuroprotective effect of rTMS was markedly reversed. Evaluated by behavioral tests, the cognitive dysfunction and anxiety-like behavior were found aggravated with the comparison of mice in rTMS intervention group. Moreover, the level of hippocampal neurogenesis was found to be attenuated, the pyroptosis of microglia as well as the levels of GSDMD, NLRP3 inflammasome and IL-1β were upregulated.ConclusionOur study indicated that rTMS notably ameliorated RIBI-induced cognitive disorders, by mitigating pyroptosis in microglia and promoting hippocampal neurogenesis via mediating BDNF pathway.

Impact of Radiotherapy on Radiation-Induced Brain Injury in Patients with Nasopharyngeal Carcinoma Using Nano-Magnetic Resonance Imaging

This study investigate the changes of white matter injury induced by radiation after radiotherapy in patients with nasopharyngeal carcinoma (NPC) and its association with cognitive dysfunction using multiple MRI methods. A total of 42 patients with NPC who underwent radiotherapy at xxx Hospital between December 2018 and June 2021 were included. The patients were randomly divided into 4 groups based on the timing of radiotherapy. Superparamagnetic iron oxide nanoparticles were used as MRI contrast agents. DTI and MRS scans were conducted to measure FA, ADC, NAA/Cho, Cho/Cr, and NAA/Cr ratios in the hippocampus of both temporal lobes. A cognitive assessment was performed using the MoCA and MMSE scales. After radiotherapy, patients experienced a decline in cognitive scores, which stabilized after 6 months. White matter changes were observed in the hippocampus, with decreased FA and increased ADC values that gradually returned to normal levels. Cho value increased and NAA value decreased initially but eventually returned to pre-treatment levels. No significant changes occurred in the Cr value. Metabolite ratios decreased within 3 months post-radiotherapy but gradually increased thereafter, remaining lower than pre-treatment levels at 6 months. Higher radiation doses did not significantly affect FA and ADC values but decreased white matter metabolite ratios. In conclusion, we reveal that the dosage and duration of radiotherapy can influence the degree of brain injury in patients with NPC and highlights the cognitive decline, white matter changes, and changes in metabolite ratios after radiotherapy for NPC, providing insights into the effects of radiation on brain structure and function.

Terminally differentiated cytotoxic CD4+ T cells were clonally expanded in the brain lesion of radiation-induced brain injury.

Accumulating evidence supports the involvement of adaptive immunity in the development of radiation-induced brain injury (RIBI). Our previous work has emphasized the cytotoxic function of CD8+ T cells in RIBI. In this study, we aimed to investigate the presence and potential roles of cytotoxic CD4+ T cells (CD4+ CTLs) in RIBI to gain a more comprehensive understanding of adaptive immunity in this context. Utilizing single-cell RNA sequencing (scRNA-seq), we analyzed 3934 CD4+ T cells from the brain lesions of four RIBI patients and identified six subclusters within this population. A notable subset, the cytotoxic CD4+ T cells (CD4+ CTLs), was marked with high expression of cytotoxicity-related genes (NKG7, GZMH, GNLY, FGFBP2, and GZMB) and several chemokine and chemokine receptors (CCL5, CX3CR1, and CCL4L2). Through in-depth pseudotime analysis, which simulates the development of CD4+ T cells, we observed that the CD4+ CTLs exhibited signatures of terminal differentiation. Their functions were enriched in protein serine/threonine kinase activity, GTPase regulator activity, phosphoprotein phosphatase activity, and cysteine-type endopeptidase activity involved in the apoptotic signaling pathway. Correspondingly, mice subjected to gamma knife irradiation on the brain showed a time-dependent infiltration of CD4+ T cells, an increase of MHCII+ cells, and the existence of CD4+ CTLs in lesions, along with an elevation of apoptotic-related proteins. Finally, and most crucially, single-cell T-cell receptor sequencing (scTCR-seq) analysis at the patient level determined a large clonal expansion of CD4+ CTLs in lesion tissues of RIBI. Transcriptional factor-encoding genes TBX21, RORB, and EOMES showed positive correlations with the cytotoxic functions of CD4+ T cells, suggesting their potential to distinguish RIBI-related CD4+ CTLs from other subsets. The present study enrichesthe understanding of the transcriptional landscape of adaptive immune cells in RIBI patients. It provides the first description of a clonally expanded CD4+ CTL subset in RIBI lesions, which may illuminate new mechanisms in the development of RIBI and offer potential biomarkers or therapeutic targets for the disease.

CACNA1B protects naked mole-rat hippocampal neuron from apoptosis via altering the subcellular localization of Nrf2 after 60Co irradiation.

Although radiotherapy is the most effective treatment modality for brain tumors, it always injures the central nervous system, leading to potential sequelae such as cognitive dysfunction. Radiation induces molecular, cellular, and functional changes in neuronal and glial cells. The hippocampus plays a critical role in learning and memory; therefore, concerns about radiation-induced injury are widespread. Multiple studies have focused on this complex problem, but the results have not been fully elucidated. Naked mole rat brains were irradiated with 60Co at a dose of 10 Gy. On 7 days, 14 days, and 28 days after irradiation, hippocampi in the control groups were obtained for next-generation sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were subsequently performed. Venn diagrams revealed 580 differentially expressed genes (DEGs) that were common at different times after irradiation. GO and KEGG analyses revealed that the 580 common DEGs were enriched in molecular transducer activity. In particular, CACNA1B mediated regulatory effects after irradiation. CACNA1B expression increased significantly after irradiation. Downregulation of CACNA1B led to a reduction in apoptosis and reactive oxygen species levels in hippocampal neurons. This was due to the interaction between CACNA1B and Nrf2, which disturbed the normal nuclear localization of Nrf2. In addition, CACNA1B downregulation led to a decrease in the cognitive functions of naked mole rats. These findings reveal the pivotal role of CACNA1B in regulating radiation-induced brain injury and will lead to the development of a novel strategy to prevent brain injury after irradiation.

BMSCs attenuate radiation-induced brain injury induced hippocampal neuronal apoptosis through a PI3K/Akt/Bax/Bcl-2 signaling pathway

BackgroundBone marrow mesenchymal stem cell (BMSCs) -based therapies represent a promising treatment for neurological disorders. However, therapeutic effects and mechanisms of BMSCs transplantation for radiation-induced brain injury (RIBI) have not been fully disclosed. In this article, we explored the functions of BMSCs transplantation on RIBI and investigated the protective effects of BMSCS on hippocampal neurons in RIBI as well as the related molecular mechanisms. Materials and methods6–8 weeks-old rats were used to build a RIBI model. Rats in BMSC group were treated with a 3 × 106 BMSCs injection through the tail vein on the 1st day and 8th day after irradiation; rats in both control and RIBI groups were injected with an equivalent volume of physiological saline for comparisons. The Morris water maze was applied to detect the variations in cognitive function after RIBI. MRS was performed to test changes in NAA/Cr, indicating neuronal apoptosis after RIBI. TUNEL was conducted to detect apoptosis of rat hippocampal neurons, and HE staining was carried out to show pathological variations in the hippocampal region of rats. Protein levels of PI3K, P-PI3K, AKT, P-AKT, Bcl-2, and Bax proteins of rats in the hippocampal area were all determined by Western blot. ResultsCognitive function was reduced and hippocampal neurons underwent apoptosis in the rats of the RIBI group, and cognitive abilities, histopathological alterations, and apoptosis of hippocampal neurons were significantly improved after BMSCs treatment; the expression of PI3K, P-PI3K, AKT, P-AKT, and Bcl-2 proteins, in the hippocampal region of the rat, was up-regulated, and Bax proteins were down-regulated. ConclusionsBMCSs can inhibit hippocampal neuronal apoptosis in RIBI, and the mechanism may be associated with the up-regulation of Bcl-2 and down-regulation of Bax by the PI3K/AKT signaling pathway.

Abstract TP297: Focused Mouse Brain Irradiation Model to Define the Neurovascular Unit

Purpose: This project aimed to develop a stereotactic radiosurgery mouse model of radiation-induced brain injury to study endothelial damage within the neurovascular unit (NVU). Classification of focal endothelial damage and the resulting inflammatory cascade has never been cataloged for assessing intrinsic changes versus extrinsic factors of inflammation at the NVU. The study of endothelial damage with invasive models, such as open transcranial injury or vessel occlusion, introduces multiple variables into the system that our model can help overcome to study secondary or systemic insults of the NVU. Methods: Using an X-ray image-guided radiation therapy system, mice were focally irradiated with 30, 45, and 70 Gy to a 5 mm brain target. Mice were followed up at 2, 4, 6, 12 and 18 weeks after irradiation with contrast-enhanced CT imaging for volumetric quantification of radiation effects. Brains were harvested for characterization by histology and immune-multiplexing of reactionary and inflammatory changes to the NVU. Whole coronal slides were scanned and analyzed using machine learning classifiers to quantify cell types within the NVU in the radiated vs. control hemispheres. Results: Radiation-induced changes such as telangiectasias, vessel hyalinization, and white matter necrosis were observed. An inflammatory response with a predominance of T cells was observed, as well as an increase in microglial cells and reactive astrogliosis. These changes were time and dose-dependent after radiation. Serial CTs allowed for determining the development of radiation damage, and the contrast enhancement was proportional to the degree of radiation-induced changes. Conclusions: This radiation model allows precise image-guided targeting with a steep radiation fall-off into surrounding tissues. The NVU’s response to focal insult of endothelial damage presents a novel method of brain injury to specifically study diseases associated with endothelial dysfunction.

Reprimo (RPRM) mediates neuronal ferroptosis via CREB-Nrf2/SCD1 pathways in radiation-induced brain injury

Neuronal ferroptosis has been found to contribute to degenerative brain disorders and traumatic and hemorrhagic brain injury, but whether radiation-induced brain injury (RIBI), a critical deleterious effect of cranial radiation therapy for primary and metastatic brain tumors, involves neuronal ferroptosis remains unclear. We have recently discovered that deletion of reprimo (RPRM), a tumor suppressor gene, ameliorates RIBI, in which its protective effect on neurons is one of the underlying mechanisms. In this study, we found that whole brain irradiation (WBI) induced ferroptosis in mouse brain, manifesting as alterations in mitochondrial morphology, iron accumulation, lipid peroxidation and a dramatic reduction in glutathione peroxidase 4 (GPX4) level. Moreover, the hippocampal ferroptosis induced by ionizing irradiation (IR) mainly happened in neurons. Intriguingly, RPRM deletion protected the brain and primary neurons against IR-induced ferroptosis. Mechanistically, RPRM deletion prevented iron accumulation by reversing the significant increase in the expression of iron storage protein ferritin heavy chain (Fth), ferritin light chain (Ftl) and iron importer transferrin receptor 1 (Tfr1), as well as enhancing the expression of iron exporter ferroportin (Fpn) after IR. RPRM deletion also inhibited lipid peroxidation by abolishing the reduction of GPX4 and stearoyl coenzyme A desaturase-1 (SCD1) induced by IR. Importantly, RPRM deletion restored or even increased the expression of nuclear factor, erythroid 2 like 2 (Nrf2) in irradiated neurons. On top of that, compromised cyclic AMP response element (CRE)-binding protein (CREB) signaling was found to be responsible for the down-regulation of Nrf2 and SCD1 after irradiation, specifically, RPRM bound to CREB and promoted its degradation after IR, leading to a reduction of CREB protein level, which in turn down-regulated Nrf2 and SCD1. Thus, RPRM deletion recovered Nrf2 and SCD1 through its impact on CREB. Taken together, neuronal ferroptosis is involved in RIBI, RPRM deletion prevents IR-induced neuronal ferroptosis through restoring CREB-Nrf2/SCD1 pathways.

TDP-43 was Involved in Radiation-induced Neuronal Damage and May Not Through the BDNF/TrkB Pathway.

Cognitive dysfunction is the most common form of radiation-induced brain injury. TDP-43 is known to be associated with hippocampal degeneration and cognitive dysfunction, in this study we wanted to know if it also had an effect on radiation-induced hippocampus damage. At first, we found the expression of TDP-43 and p-TDP-43 was increased in the hippocampus of rats with radiation-induced cognitive dysfunction. Single-cell RNA-seq analysis of the rat hippocampus showed that TDP-43 was expressed in all cell types and was significantly upregulated in neuron cells after irradiation. Enrichment analysis of gene ontology (GO) functions and KEGG pathways showed that the differential expression genes in neuron after irradiation may be involved in synaptic plasticity. In vitro, the expression of TDP-43 was also increased in neuron cells after irradiation, while the expression of brain-derived neurotrophic factor (BDNF), TrkB, typical synaptic signature proteins (SYN, GAP43 and PSD95), β-tubulin and dendritic spines were decreased. In the irradiated neurons, the β-tubulin, dendritic and spines typical synaptic signature proteins had more severe damage in pcDNA3.1-TDP-43 plasmid transfections group, however, the damages were alleviated in the siRNA-TDP-43 plasmid transfections group. BDNF was highly expressed in the irradiated pcDNA3.1-TDP-43 plasmid transfections group, while its expression was decreased in the siRNA-TDP-43 group. The TrkB expression was significantly reduced in neurons after exposure to ionizing radiation, however, there was no significant correlation with TDP-43 expression. These data indicate that TDP-43 is involved in radiation-induced neuronal synaptic plasticity decline and developmental damage, furthermore, the BDNF/TrkB signaling pathway may not be involved in this process.

Adding simultaneous integrated boost to whole brain radiation therapy improved intracranial tumour control and minimize radiation-induced brain injury risk for the treatment of brain metastases

BackgroundBrain metastases (BMs) are the most frequent intracranial tumours associated with poor clinical outcomes. Radiotherapy is essential in the treatment of these tumours, although the optimal radiation strategy remains controversial. The present study aimed to assess whether whole brain radiation therapy with a simultaneous integrated boost (WBRT + SIB) provides any therapeutic benefit over WBRT alone.MethodsWe included and retrospectively analysed 82 patients who received WBRT + SIB and 83 who received WBRT alone between January 2012 and June 2021. Intracranial progression-free survival (PFS), local tumour control (LTC), overall survival (OS), and toxicity were compared between the groups.ResultsCompared to WBRT alone, WBRT + SIB improved intracranial LTC and PFS, especially in the lung cancer subgroup. Patients with high graded prognostic assessment score or well-controlled extracranial disease receiving WBRT + SIB had improved intracranial PFS and LTC. Moreover, WBRT + SIB also improved the long-term intracranial tumour control of small cell lung cancer patients. When evaluating toxicity, we found that WBRT + SIB might slightly increase the risk of radiation-induced brain injury, and that the risk increased with increasing dosage. However, low-dose WBRT + SIB had a tolerable radiation-induced brain injury risk, which was lower than that in the high-dose group, while it was comparable to that in the WBRT group.ConclusionsWBRT + SIB can be an efficient therapeutic option for patients with BMs, and is associated with improved intracranial LTC and PFS. Furthermore, low-dose WBRT + SIB (biologically effective dose [BED] ≤ 56 Gy) was recommended, based on the acceptable risk of radiation-induced brain injury and satisfactory tumour control.Trial registrationRetrospectively registered.

Reduction of acute radiation-induced brain injury in rats by anlotinib.

Radiation therapy in the treatment of brain tumors also leads to the occurrence of radiation brain injury (RBI). Anlotinib is a small-molecule inhibitor of multi-receptor tyrosine kinase with high selectivity for vascular endothelial growth factor receptor-2. In this study, we constructed a rat model of RBI and investigated the effect of anlotinib on RBI and its mechanism of action through drug intervention during the acute phase of RBI. Six-week-old male (Sprague-Dawley) rats were used to construct an animal model of RBI to evaluate the protective effect of anlotinib on acute RBI by histopathological staining, brain edema determination, blood-brain barrier integrity evaluation and quick real time-polymerase chain reaction , ELISA detection of inflammation-related indexes, and western-blot detection of related gene protein expression. Anlotinib reduced the degree of edema in the hippocampal region of rats, improved the pathological morphology of neural cells and vascular endothelial cells, and decreased blood-brain barrier permeability. Anlotinib reduced glial fibrillary acidic protein protein expression in the hippocampal region of rat brain tissue and inhibited astrocyte activation. It inhibited the release of inflammatory factors (interleukin [IL]-6, IL-8 and vascular endothelial growth factor) and down-regulated the expression of janus kinase-2/signal transducer and activator of transcription-3 (JAK2/STAT3) signaling pathway-related proteins. This study found that anlotinib has a protective effect against RBI in rats and anlotinib may be a new candidate for the treatment of RBI.

Mitigation of Acute Radiation-Induced Brain Injury by Anlotinib: A Meaningful Study

Mitigation of Acute Radiation-Induced Brain Injury by Anlotinib: A Meaningful Study

A Synthetic Steroid 5α-Androst-3β, 5, 6β-triol Alleviates Radiation-Induced Brain Injury in Mice via Inhibiting GBP5/NF-κB/NLRP3 Signal Axis.

Radiotherapy for head and neck tumors can lead to a severe complication known as radiation-induced brain injury (RIBI). However, the underlying mechanism of RIBI development remains unclear, and limited prevention and treatment options are available. Neuroactive steroids have shown potential in treating neurological disorders. 5α-Androst-3β, 5, 6β-triol (TRIOL), a synthetic neuroprotective steroid, holds promise as a treatment candidate for RIBI patients. However, the neuroprotective effects and underlying mechanism of TRIOL on RIBI treatment are yet to be elucidated. In the present study, our findings demonstrate TRIOL's potential as a neuroprotective agent against RIBI. In gamma knife irradiation mouse model, TRIOL treatment significantly reduced brain necrosis volume, microglial activation, and neuronal loss. RNA-sequencing, immunofluorescence, real-time quantitative polymerase chain reaction, siRNA transfection, and western blotting techniques revealed that TRIOL effectively decreased microglial activation, proinflammatory cytokine release, neuron loss, and guanylate-binding protein 5 (GBP5) expression, along with its downstream signaling pathways NF-κB and NLRP3 activation in vitro. In summary, TRIOL effectively alleviate RIBI by inhibiting the GBP5/NF-κB/NLRP3 signal axis, reducing microglia activation and pro-inflammation cytokines release, rescuing neuron loss. This study highlights the potential of TRIOL as a novel and promising therapy drug for RIBI treatment.

Reprimo (RPRM) as a Potential Preventive and Therapeutic Target for Radiation-Induced Brain Injury via Multiple Mechanisms.

Patients receiving cranial radiotherapy for primary and metastatic brain tumors may experience radiation-induced brain injury (RIBI). Thus far, there has been a lack of effective preventive and therapeutic strategies for RIBI. Due to its complicated underlying pathogenic mechanisms, it is rather difficult to develop a single approach to target them simultaneously. We have recently reported that Reprimo (RPRM), a tumor suppressor gene, is a critical player in DNA damage repair, and RPRM deletion significantly confers radioresistance to mice. Herein, by using an RPRM knockout (KO) mouse model established in our laboratory, we found that RPRM deletion alleviated RIBI in mice via targeting its multiple underlying mechanisms. Specifically, RPRM knockout significantly reduced hippocampal DNA damage and apoptosis shortly after mice were exposed to whole-brain irradiation (WBI). For the late-delayed effect of WBI, RPRM knockout obviously ameliorated a radiation-induced decline in neurocognitive function and dramatically diminished WBI-induced neurogenesis inhibition. Moreover, RPRM KO mice exhibited a significantly lower level of acute and chronic inflammation response and microglial activation than wild-type (WT) mice post-WBI. Finally, we uncovered that RPRM knockout not only protected microglia against radiation-induced damage, thus preventing microglial activation, but also protected neurons and decreased the induction of CCL2 in neurons after irradiation, in turn attenuating the activation of microglial cells nearby through paracrine CCL2. Taken together, our results indicate that RPRM plays a crucial role in the occurrence of RIBI, suggesting that RPRM may serve as a novel potential target for the prevention and treatment of RIBI.

Short report: Plasma based biomarkers detect radiation induced brain injury in cancer patients treated for brain metastasis: A pilot study.

Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.

Enhanced VEGF secretion and blood-brain barrier disruption: Radiation-mediated inhibition of astrocyte autophagy via PI3K-AKT pathway activation.

Radiation-induced damage to the blood-brain barrier (BBB) is the recognized pathological basis of radiation-induced brain injury (RBI), a side effect of head and neck cancer treatments. There is currently a lack of therapeutic approaches for RBI due to the ambiguity of its underlying mechanisms. Therefore, it is essential to identify these mechanisms in order to prevent RBI or provide early interventions. One crucial factor contributing to BBB disruption is the radiation-induced activation of astrocytes and oversecretion of vascular endothelial growth factor (VEGF). Mechanistically, the PI3K-AKT pathway can inhibit cellular autophagy, leading to pathological cell aggregation. Moreover, it acts as an upstream pathway of VEGF. In this study, we observed the upregulation of the PI3K-AKT pathway in irradiated cultured astrocytes through bioinformatics analysis, we then validated these findings in animal brains and in vitro astrocytes following radiation exposure. Additionally, we also found the inhibition of autophagy and the oversecretion of VEGF in irradiated astrocytes. By inhibiting the PI3K-AKT pathway or promoting cellular autophagy, we observed a significant amelioration of the inhibitory effect on autophagy, leading to reductions in VEGF oversecretion and BBB disruption. In conclusion, our study suggests that radiation can inhibit autophagy and promote VEGF oversecretion by upregulating the PI3K-AKT pathway in astrocytes. Blocking the PI3K pathway can alleviate both of these effects, thereby mitigating damage to the BBB in patients undergoing radiation treatment.

Radioprotective effect of Ginkgolide B on brain: the mediating role of DCC/MST1 signaling

Purpose The risk of brain exposure to ionizing radiation increases gradually due to the extensive application of nuclear technology in medical, industrial, and aerospace fields. Radiation-induced brain injury (RBI) is highly likely to cause a wide range of neurological complications, including schizophrenia, Alzheimer’s disease (AD), depression. Ginkgolide B (GB) is one of the effective active components extracted from ginkgo biloba leaves, exerts protective effects on CNS, which is involved in the regulation of the Hippo signaling pathway. MST1, as one of the core kinases of the Hippo pathway, participated in regulating cell proliferation, differentiation, and apoptosis. However, it remains unclear whether GB attenuates radiation brain injury (RBI) and whether the radioprotective effect of GB refers to MST1 signaling. Hence, our study aimed to explore the radiation protection effect and the potential mechanism of GB. Materials and methods C57BL/6 mice were stimulated with an X-ray (20 Gy) to establish an RBI model. Then, morris water maze test (MWM) and step-down passive avoidance test (SDPAT) were used to assess the learning and memory function of mice. The open field test (OFT), tail suspension test (TST), and forced swimming test (FST) were used to assess changes in locomotor activity and hopelessness. Besides, X-ray-stimulated SH-SY5Y cells were used to verify the radioprotective effect of GB. Immunofluorescence double staining, Dihydroethidium (DHE), western blot, and flow cytometry were used to explore the role of DCC/MST1 signaling in RBI. Results In this study, X-ray-treated mice exhibited cognitive impairment and depression-like behavior, which was ameliorated by GB treatment. GB also reduced the ROS production and the number of TUNEL-positive cells in the hippocampus. Moreover, GB increased the protein levels of p-AKT and Bcl2, while decreased the protein levels of MST1, p-p38, p-JNK, cleaved-caspase-3 and Bax both in vivo and in vitro. Additionally, exogenous Netrin-1 alleviated X-ray-induced ROS production and apoptosis, whereas knockout of Netrin-1 receptor DCC abolished the protective effect of GB. Conclusion Oxidative stress and MST1-mediated neuronal apoptosis participated in radiation-induced cognitive impairment and depression-like behaviors, and modulation of DCC by GB was an effective intervention against RBI.

Total-Body Irradiation Alters White Matter Volume and Microstructural Integrity in Rhesus Macaques

Long-term survivors of brain irradiation can suffer from irreversible injury and cognitive impairment. T1-weighted and diffusion tensor magnetic resonance imaging are used to evaluate brain volumes and white matter (WM) microstructure in neurodevelopmental and neurodegenerative conditions. The goal of this study was to evaluate the long-term effects of single-dose total-body irradiation (TBI) or TBI with 5% partial-body sparing on brain volumetrics and WM integrity in macaques. We utilized MRI scans from a cohort of male rhesus macaques (age range: 3.6-22.8 years), to compare global and regional brain volumes and WM diffusion in survivors of TBI (T1w: n=137, DTI: n=121, dose range: 3.5-10 Gy) against unirradiated controls (T1w: n=48, DTI: n=38). In all ROIs, radiation affected the age-related changes in fractional anisotropy (FA); in general, FA increased across age in both groups, but to a lesser extent in the irradiated group (interaction p-values <0.01). Depending on the ROI, mean diffusivity (MD) decreased or remained the same across age in unirradiated animals, while it increased or did not change in irradiated animals. The increases in MD were driven by changes in radial diffusivity (RD) which followed similar trends across age. Axial diffusivity (AD) did not differ by irradiation status. Age-related changes in relative volumes in controls reflected normal trends in humans with increasing WM and decreasing gray matter (GM) until middle age. Cerebrospinal fluid (CSF) volume did not differ across age in controls. WM volume was lower and CSF volume was higher in young, irradiated macaques. WM volume was similar between groups and CSF volume reduced in older irradiated macaques. GM volume was unaffected by radiation. TBI results in delayed WM expansion and long-term disruption of WM integrity. Diffusion changes suggest that myelin injury in WM is a hallmark of late-delayed radiation induced brain injury.

FGIN-1-27 Mitigates Radiation-induced Mitochondrial Hyperfunction and Cellular Hyperactivation in Cultured Astrocytes

Radiation-induced brain injury (RBI) poses a significant challenge in the context of radiotherapy for intracranial tumors, necessitating a comprehensive understanding of the cellular and molecular mechanisms involved. While prior investigations have underscored the role of astrocyte activation and excessive vascular endothelial growth factor production in microvascular damage associated with RBI, there remains a scarcity of studies examining the impact of radiation on astrocytes, particularly regarding organelles such as mitochondria. Thus, our study aimed to elucidate alterations in astrocyte and mitochondrial functionality following radiation exposure, with a specific focus on evaluating the potential ameliorative effects of translocator protein 18 kDa(TSPO) ligands. In this study, cultured astrocytes were subjected to X-ray irradiation, and their cellular states and mitochondrial functions were examined and compared to control cells. Our findings revealed that radiation-induced astrocytic hyperactivation, transforming them into the neurotoxic A1-type, concomitant with reduced cell proliferation. Additionally, radiation triggered mitochondrial hyperfunction, heightened the mitochondrial membrane potential, and increased oxidative metabolite production. However, following treatment with FGIN-1-27, a TSPO ligand, we observed a restoration of mitochondrial function and a reduction in oxidative metabolite production. Moreover, this intervention mitigated astrocyte hyperactivity, decreased the number of A1-type astrocytes, and restored cell proliferative capacity. In conclusion, our study has unveiled additional manifestations of radiation-induced astrocyte dysfunction and validated that TSPO ligands may serve as a promising therapeutic strategy to mitigate this dysfunction. It has potential clinical implications for the treatment of RBI.

A comprehensive predictive model for radiation-induced brain injury in risk stratification and personalized radiotherapy of nasopharyngeal carcinoma

Background and purposeRadiation-induced brain injury (RBI) is a severe radiotoxicity for nasopharyngeal carcinoma (NPC) patients, greatly affecting their long-term life quality and survival. We aim to establish a comprehensive predictive model including clinical factors and newly developed genetic variants to improve the precision of RBI risk stratification. Materials and methodsBy performing a large registry-based retrospective study with magnetic resonance imaging follow-up on RBI development, we conducted a genome-wide association study and developed a polygenic risk score (PRS) for RBI in 1189 NPC patients who underwent intensity-modulated radiotherapy. We proposed a tolerance dose scheme for temporal lobe radiation based on the risk predicted by PRS. Additionally, we established a nomogram by combining PRS and clinical factors for RBI risk prediction. ResultsThe 38-SNP PRS could effectively identify high-risk individuals of RBI (P = 1.42 × 10−34). Based on genetic risk calculation, the recommended tolerance doses of temporal lobes should be 57.6 Gy for individuals in the top 10 % PRS subgroup and 68.1 Gy for individuals in the bottom 50 % PRS. Notably, individuals with high genetic risk (PRS > P50) and receiving high radiation dose in the temporal lobes (D0.5CC > 65 Gy) had an approximate 50-fold risk over individuals with low PRS and receiving low radiation dose (HR = 50.09, 95 %CI = 24.27–103.35), showing an additive joint effect (Pinteraction < 0.001). By combining PRS with clinical factors including age, tumor stage, and radiation dose of temporal lobes, the predictive accuracy was significantly improved with C-index increased from 0.78 to 0.85 (P = 1.63 × 10−2). ConclusionsThe PRS, together with clinical factors, could improve RBI risk stratification and implies personalized radiotherapy.