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

Abstract

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.

Pregabalin mitigates microglial activation and neuronal injury by inhibiting HMGB1 signaling pathway in radiation-induced brain injury

“…Therefore, targeting radiation-induced neuroinflammation has been considered as a therapeutic strategy to treat RIBI [ 47 ]. Although traditional medicine like corticosteroids and bevacizumab can both alleviate the symptoms of RIBI to a certain extent, their effects on the improvement of neuroinflammation and microglia activation are not significant [ 4 , 8 ]. Notably, our previous study demonstrated that pregabalin could alleviate radiotherapy-related neuropathic pain in the patients with RIBI [ 24 ].…”

“…Apoptotic cells were detected by DeadEnd Fluorometric TUNEL System (Promega, G3250) according to the manufacturer’s instructions, as previously described [ 4 ]. Briefly, the slices were permeated in 20 g/ml protease K solution for 20 min and blocked in 5% BSA for 1 h. After washing 3 times with PBS, slices were soaked in equilibrium buffer for 10 min, and then incubated with TDT reaction mixture in the dark at 37 ℃ for 1 h. Finally, DAPI was stained to label the nucleus.…”

“…However, radiotherapy also causes damage to the adjacent normal brain tissue and leads to central nervous system (CNS) complications [ 2 , 3 ]. The clinical symptoms of radiation-induced brain injury (RIBI) include cognitive impairment and necrosis of brain tissues, which seriously affects the quality of life of patients [ 3 , 4 ]. Due to lack of understanding to the pathogenesis of RIBI, limited options are available for clinical treatment of patients with RIBI [ 5 ].…”

Activation of LRP1 Ameliorates Cerebral Ischemia/Reperfusion Injury and Cognitive Decline by Suppressing Neuroinflammation and Oxidative Stress through TXNIP/NLRP3 Signaling Pathway in Mice

“…Activated microglia causes endocytosis of cell debris and participates in tissue repair in the early stage of cerebral I/R. However, overactivated brain microglia release inflammatory factors, such as TNF- α and IL-6, and participate in chronic inflammation, causing delayed neuronal death, brain edema, and neurological deficits [ 40 , 41 ]. In this study, the results of double immunofluorescence staining showed that the LRP1 was colocalized with microglia, neurons, and astrocytes in the CA1 subregion of the hippocampus at 72 h after cerebral I/R.…”

Mortality of early treatment for radiation-induced brain necrosis in head and neck cancer survivors: A multicentre, retrospective, registry-based cohort study

“…The mechanisms underlying RN involve blood-brain barrier dysfunction, leakage of intravascular inflammatory cytokines, microglia overreaction and subsequent cellular damage 6 , 23 , 24 , 25 ; thus RN on brain MRI typically presents as a contrast-material enhanced white matter lesion with adjacent cerebral parenchymal edema, which if untreated would ultimately lead to cyst formation or even cerebral hernia. 10 , 18 Although some RN could be asymptomatic with mild brain edema at the early stage, the majority of them would progress and eventually become irreversible without effective interventions.…”