Abstract Cranial radiation therapy (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 post-RT lives. Radiation-induced neuroinflammation and gliosis lead to excessive loss of synaptic integrity and cognitive dysfunction. Using intact and brain cancer-bearing mouse models, we showed here that inhibiting anaphylatoxin complement C5a receptor (C5aR1) signaling is neuroprotective against RICD. Both genetic loss in a C5ar1 knockout mouse and pharmacological inhibition using the orally active, brain-penetrant C5aR1 antagonist PMX205 reversed RICD, leading to neurocognitive improvements in object recognition memory and memory consolidation tasks. Inhibiting the C5a/C5aR1 axis reduced microglial activation, astrogliosis, and synaptic loss in the irradiated brain. Importantly, C5aR1 blockade in two syngeneic, orthotopic glioblastoma-bearing mouse models protected against RICD and elevated gene signatures associated with neuroprotection without interfering with the therapeutic efficacy of RT in reducing tumor volume in vivo. As PMX205 has been found to be safe in clinical trials with healthy individuals, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need.
Krattli et al. (Tue,) studied this question.