C5aR1 Inhibition Alleviates Cranial Radiation-Induced Cognitive Decline.

ABSTRACT: Cranial radiotherapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive decline (RICD) is a particularly pressing problem for brain cancer survivors who live long after RT. Radiation-induced neuroinflammation and gliosis lead to excessive loss of synaptic integrity and cognitive dysfunction. Using intact and brain cancer-bearing mouse models, we show here that inhibiting anaphylatoxin complement C5a receptor (C5aR1) signaling is neuroprotective against RICD. Both genetic loss in a C5ar1 knockout mouse and pharmacologic inhibition using the orally active, brain-penetrant C5aR1 antagonist PMX205 reversed RICD, leading to neurocognitive improvements in object recognition memory and memory consolidation tasks.

SUBMITTER: Krattli RP 

PROVIDER: S-EPMC12818912 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature