Water-soluble fullerene derivatives mitigate cranial radiation-induced neuroinflammation and cognitive dysfunction

Radiotherapy is widely used to treat malignant and benign brain tumors. A major constraint, however, is the low tolerance of normal brain tissue to radiation. Cranial irradiation-induced injury manifests as inflammatory responses and neurodegeneration, which jointly contribute to progressive cognitive decline. These complications can restrict the delivery of optimal therapeutic doses, cause persistent neurological symptoms, and ultimately compromise quality of life. Thus, neuroprotective agents have emerged as a strategy to safeguard normal tissues from radiation-induced neurotoxicity. This study investigated the efficacy of a highly soluble [60]fullerene (C₆₀) derivative, C₆₀-ser, a carbon-based nanomaterial, to mitigate radiation-induced brain injury. Oral administration of C₆₀-ser 24 h after cranial irradiation of male C57BL/6 mice restored spatial working memory, as evidenced by significantly improved performance in the Y-maze test conducted 45 days after irradiation. At the cellular level, immunohistochemical analysis revealed that irradiation alone activated microglia for up to 84 days after exposure, indicative of generating a sustained pro-inflammatory microenvironment. Critically, this activation was markedly alleviated in mice treated with C₆₀-ser; CD68 reactivity was restored to levels similar to unirradiated mice. Together, these behavioral and molecular findings suggest that C₆₀-ser can mitigate radiation-induced neurotoxicity by suppressing neuroinflammatory responses when administered 24 h after cranial irradiation.