Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates

Andrews, Rachel N.; Metheny-Barlow, Linda J.; Peiffer, Ann M.; Hanbury, David B.; Tooze, Janet A.; Bourland, J. Daniel; Hampson, Robert E.; Deadwyler, Samuel A.; Cline, J. Mark

doi:10.1667/rr14616.1

Cited by 49 publications

(41 citation statements)

References 89 publications

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“…CD68 was recognized as microglial phagocytosis marker, 35,36 and increased microglia activity and neuroinflammation may contribute to gamma ray-induced brain lesion. 37 Indeed, several proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α, appear to be involved in the brain's response to irradiation. 38 We found these proinflammatory cytokines were upregulated in the irradiated hemisphere of thalamus and cortex as early as 1-week postirradiation, a time point that was weeks before the onset of detectable brain lesion in MRI images.…”

Section: F I G U R Ementioning

confidence: 99%

Gamma ray‐induced glial activation and neuronal loss occur before the delayed onset of brain necrosis

Wang

et al. 2020

FASEB j.

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Radiotherapy is one of the most effective treatments for head and neck tumors. However, delayed radiation‐induced brain necrosis (RN) remains a serious issue due to the lack of satisfying prevention and effective treatment. The pathological role of radiation in the delayed onset of brain necrosis is still largely unknown, and the traditional animal model of whole brain irradiation, although being widely used, does not produce reliable and localized brain necrosis mimicking clinical features of RN. In this study, we demonstrated a successful RN mouse model using optimized gamma knife irradiation in male C57BL/6 mice. On the premise that brain necrosis started to appear at 6 weeks postirradiation in our RN model, as confirmed by both MRI and histopathological examinations, we systematically examined different time points before the onset of RN for the histopathological changes and biochemical indicators. Our initial results demonstrated that in the ipsilateral hemisphere of the irradiated brains, a significant decrease in neuronal numbers that occurred at 4 weeks and a sustained increase in TNF‐α, iNOS, and other inflammatory cytokines beginning at 1‐week postirradiation. Changes of cell morphology and cell numbers of both microglia and astrocytes occurred as early as 1‐week postirradiation, and intervention by bevacizumab administration resulted in reduced microglia activation and reduction of radiation‐induced lesion volume, indicating that chronic glial activation may result in subsequent elevation of inflammatory factors, which led to the delayed onset of neuronal loss and brain necrosis. Since C57BL/6 is the most widely used strain of genetic engineered mouse model, our data provide an invaluable platform for the mechanistic study of RN pathogenesis, identification of potential imaging and biological biomarkers, and the development of therapeutic treatment for the disease.

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Section: F I G U R Ementioning

confidence: 99%

Gamma ray‐induced glial activation and neuronal loss occur before the delayed onset of brain necrosis

Wang

et al. 2020

FASEB j.

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“…Traditionally, white matter and vascular endothelium have been regarded as the core brain structures damaged by irradiation [33]. White matter is recognized as the most vulnerable structure in the brain's response to irradiation [34] in clinical evaluation because of myelination.…”

Section: Tablementioning

confidence: 99%

Temporal lobe microstructural abnormalities in patients with nasopharyngeal carcinoma quantitatively evaluated by high-resolution DWI and DKI after concurrent chemoradiotherapy

Balasubramanian

et al. 2020

Clinical and Translational Radiation Oncology

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To investigate temporal lobe microstructural abnormalities and neurocognitive function impairment after concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma (NPC). Methods: NPC patients who underwent CCRT were enrolled. High-resolution diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) and diffusion-kurtosis imaging (DKI) MRI, were performed 5 times per patient (once pre-CCRT, 1 week post-CCRT, 3 months post-CCRT, 6 months post-CCRT, and 12 months post-CCRT). Neurocognitive function was evaluated by Montreal Neurocognitive Assessment (MoCA) twice per patient, once pre-CCRT, and once 12-months after CCRT. Results: Of 111 patients, 56 completed the entire protocol. The MRI derived apparent diffusion coefficient (ADC), mean of diffusion coefficient (Dmean) and fractional anisotropy (FA) values were significantly decreased (p < 0.05) over the 0-3 month period following CCRT and significantly increased (p < 0.05) over the 3-12 month period following CCRT. The mean of kurtosis coefficient (Kmean) continued to decline over a year post-CCRT. All parameters reveal more pronounced changes in white matter (WM) than in grey matter (GM). MoCA also declined after CCRT (p < 0.001). MoCA showed significant positive correlation with Kmean-WM-6 m, Kmean-WM-12 m and DKmean-WM. Conclusions: High-resolution DWI and DKI should be considered as a promising method for the investigation of temporal lobe microstructural change in NPC patients after CCRT.

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“…Long-term effects (6 months) of irradiation of the whole brain of Rhesus macaques (age 6–11 years), which had received 40 Gy (8 fractions of 5 Gy each, twice per week), increased expression of fibronectin 1 (FN1) in brain tissue at mRNA level ( 32 ) and protein content of fibronectin and collagen I (COL1), whereas collagen IV (COL4) protein level was not affected ( 33 ).…”

Section: Glycoproteinsmentioning

confidence: 99%

Radiation Effects on Brain Extracellular Matrix

Grigorieva

2020

Front. Oncol.

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Radiotherapy is an important therapeutic approach to treating malignant tumors of different localization, including brain cancer. Glioblastoma multiforme (GBM) represents the most aggressive brain tumor, which develops relapsed disease during the 1st year after the surgical removal of the primary node, in spite of active adjuvant radiochemotherapy. More and more evidence suggests that the treatment's success might be determined by the balance of expected antitumor effects of the treatment and its non-targeted side effects on the surrounding brain tissue. Radiation-induced damage of the GBM microenvironment might create tumor-susceptible niche facilitating proliferation and invasion of the residual glioma cells and the disease relapse. Understanding of molecular mechanisms of radiation-induced changes in brain ECM might help to reconsider and improve conventional anti-glioblastoma radiotherapy, taking into account the balance between its antitumor and ECM-destructing activities. Although little is currently known about the radiation-induced changes in brain ECM, this review summarizes current knowledge about irradiation effects onto the main components of brain ECM such as proteoglycans, glycosaminoglycans, glycoproteins, and the enzymes responsible for their modification and degradation.

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Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates

Cited by 49 publications

References 89 publications

Gamma ray‐induced glial activation and neuronal loss occur before the delayed onset of brain necrosis

Gamma ray‐induced glial activation and neuronal loss occur before the delayed onset of brain necrosis

Temporal lobe microstructural abnormalities in patients with nasopharyngeal carcinoma quantitatively evaluated by high-resolution DWI and DKI after concurrent chemoradiotherapy

Radiation Effects on Brain Extracellular Matrix

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