Radiation-induced brain injury: current concepts and therapeutic strategies targeting neuroinflammation

Abstract

Continued improvements in cancer therapies have increased the number of long-term cancer survivors. Radiation therapy remains one of the primary treatment modalities with about 60% of newly diagnosed cancer patients receiving radiation during the course of their disease. While radiation therapy has dramatically improved patient survival in a number of cancer types, the late effects remain a significant factor affecting the quality of life particularly in pediatric patients. Radiation-induced brain injury can result in cognitive dysfunction, including hippocampal-related learning and memory dysfunction that can escalate to dementia. In this article, we review the current understanding of the mechanisms behind radiation-induced brain injury focusing on the role of neuroinflammation and reduced hippocampal neurogenesis. Approaches to prevent or ameliorate treatment-induced side effects are also discussed along with remaining challenges in the field.

Keywords: astrocytes; cognitive dysfunction; neurotoxicity; radiation-induced brain injury; senescence.

Figure 1.

Mechanisms of radiation-induced brain injury. Vascular changes including blood-brain barrier disruption, vascular hyalinization, endothelial senescence, and fibrinoid necrosis. Other proposed mechanisms include loss of hippocampal neurogenesis, astrocyte senescence resulting in the release of senescence-associated secretory phenotype (SASP) cytokines, and neural progenitor cell death that result in cognitive decline following brain irradiation.

Figure 2.

Schematic of Δ133p53α regulation of astrocyte-mediated neuroprotection and neurotoxicity. The transition from healthy to senescent astrocytes is evidenced in the setting of replicative senescence, radiation-induced brain injury, and neurodegenerative disease accompanied by the loss of Δ133p53α. In the senescent state, astrocytes release SASP cytokines and result in neurotoxicity. Senescent astrocytes can be rescued to a healthy astrocyte phenotype by overexpression of Δ133p53α which results in neuroprotection.