Brain irradiation leads to persistent neuroinflammation and long-term neurocognitive dysfunction in a region-specific manner

Constanzo, Julie; Midavaine, Élora; Fouquet, Jérémie P.; Lepage, Martin; Descoteaux, Maxime; Kirby, Karyn; Tremblay, Luc; Masson-Côté, Laurence; Geha, Sameh; Longpré, Jean‐Michel; Paquette, Benoît; Sarret, Philippe

doi:10.1016/j.pnpbp.2020.109954

Cited by 43 publications

(17 citation statements)

References 62 publications

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“…Accumulating evidence in animal models suggest that radiation-induced cognitive decline involves damage in multiple neural cell types, causing structural and functional alterations in the brain-blood barrier and in glial cell populations, reducing neurogenesis in the hippocampus, altering neuronal function, and increasing neuroinflammation [18,19,44,45].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Effects of Ionizing Radiation on the Hippocampus: Linking Effects of the Sonic Hedgehog Pathway Activation with Radiation Response

Antonelli

Casciati

Bellés

et al. 2021

IJMS

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Radiation therapy represents one of the primary treatment modalities for primary and metastatic brain tumors. Although recent advances in radiation techniques, that allow the delivery of higher radiation doses to the target volume, reduce the toxicity to normal tissues, long-term neurocognitive decline is still a detrimental factor significantly affecting quality of life, particularly in pediatric patients. This imposes the need for the development of prevention strategies. Based on recent evidence, showing that manipulation of the Shh pathway carries therapeutic potential for brain repair and functional recovery after injury, here we evaluate how radiation-induced hippocampal alterations are modulated by the constitutive activation of the Shh signaling pathway in Patched 1 heterozygous mice (Ptch1+/−). Our results show, for the first time, an overall protective effect of constitutive Shh pathway activation on hippocampal radiation injury. This activation, through modulation of the proneural gene network, leads to a long-term reduction of hippocampal deficits in the stem cell and new neuron compartments and to the mitigation of radio-induced astrogliosis, despite some behavioral alterations still being detected in Ptch1+/− mice. A better understanding of the pathogenic mechanisms responsible for the neural decline following irradiation is essential for identifying prevention measures to contain the harmful consequences of irradiation. Our data have important translational implications as they suggest a role for Shh pathway manipulation to provide the therapeutic possibility of improving brain repair and functional recovery after radio-induced injury.

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Section: Discussionmentioning

confidence: 99%

Long-Term Effects of Ionizing Radiation on the Hippocampus: Linking Effects of the Sonic Hedgehog Pathway Activation with Radiation Response

Antonelli

Casciati

Bellés

et al. 2021

IJMS

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“…Cranial irradiation activates astrocytes and microglia leading to neuroinflammation and reactive gliosis (71). Upregulation of proinflammatory chemokines, including CCL2, IL-6, IL-18, IL-1a, TNF-a; reactive oxygen species; and nitric oxide, in response to cranial irradiation play a major role in activation of these CNS cell types (72)(73)(74).…”

Section: Neuroinflammationmentioning

confidence: 99%

The Cognitive Effects of Radiotherapy for Brain Metastases

et al. 2022

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Brain metastases are the most common intracranial neoplasm and are seen in upwards of 10-30% of patients with cancer. For decades, whole brain radiation therapy (WBRT) was the mainstay of treatment in these patients. While WBRT is associated with excellent rates of intracranial tumor control, studies have demonstrated a lack of survival benefit, and WBRT is associated with higher rates of cognitive deterioration and detrimental effects on quality of life. In recent years, strategies to mitigate this risk, such as the incorporation of memantine and hippocampal avoidance have been employed with improved results. Furthermore, stereotactic radiosurgery (SRS) has emerged as an appealing treatment option over the last decade in the management of brain metastases and is associated with superior cognitive preservation and quality of life when compared to WBRT. This review article evaluates the pathogenesis and impact of cranial irradiation on cognition in patients with brain metastases, as well as current and future risk mitigation techniques.

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“…A preclinical study in normal rats whose brain was exposed to a single radiation dose (37 Gy at 30% using a Gamma Knife © device) found vascular disorders and neovascularization (43) with no detectable behavior changes at day 54 post-irradiation. At day 110, rats exhibited large RN surrounded by an increasing gradient (distal to proximal from the RN) of microglia that accumulated near newly sprouted blood vessels, upregulation of Iba1 + CD68 + macrophages, and infiltrating CD3 + T cells (44). These effects were accompanied by irreversible neuroinflammation, memory loss and a decrease in anxietylike behavior (44).…”

Section: Rt Modalities and Differential Effects On Tissuesmentioning

confidence: 99%

“…At day 110, rats exhibited large RN surrounded by an increasing gradient (distal to proximal from the RN) of microglia that accumulated near newly sprouted blood vessels, upregulation of Iba1 + CD68 + macrophages, and infiltrating CD3 + T cells (44). These effects were accompanied by irreversible neuroinflammation, memory loss and a decrease in anxietylike behavior (44). In the context of brain RN pathophysiology, there are two main theories whether it is likely that the true cause is multifactorial: i) the vascular injury theory and ii) the glial cell theory.…”

Section: Rt Modalities and Differential Effects On Tissuesmentioning

confidence: 99%

Radiation-Induced Immunity and Toxicities: The Versatility of the cGAS-STING Pathway

et al. 2021

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In the past decade, radiation therapy (RT) entered the era of personalized medicine, following the striking improvements in radiation delivery and treatment planning optimization, and in the understanding of the cancer response, including the immunological response. The next challenge is to identify the optimal radiation regimen(s) to induce a clinically relevant anti-tumor immunity response. Organs at risks and the tumor microenvironment (e.g. endothelial cells, macrophages and fibroblasts) often limit the radiation regimen effects due to adverse toxicities. Here, we reviewed how RT can modulate the immune response involved in the tumor control and side effects associated with inflammatory processes. Moreover, we discussed the versatile roles of tumor microenvironment components during RT, how the innate immune sensing of RT-induced genotoxicity, through the cGAS-STING pathway, might link the anti-tumor immune response, radiation-induced necrosis and radiation-induced fibrosis, and how a better understanding of the switch between favorable and deleterious events might help to define innovative approaches to increase RT benefits in patients with cancer.

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Brain irradiation leads to persistent neuroinflammation and long-term neurocognitive dysfunction in a region-specific manner

Cited by 43 publications

References 62 publications

Long-Term Effects of Ionizing Radiation on the Hippocampus: Linking Effects of the Sonic Hedgehog Pathway Activation with Radiation Response

Long-Term Effects of Ionizing Radiation on the Hippocampus: Linking Effects of the Sonic Hedgehog Pathway Activation with Radiation Response

The Cognitive Effects of Radiotherapy for Brain Metastases

Radiation-Induced Immunity and Toxicities: The Versatility of the cGAS-STING Pathway

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