RAGE Inhibition Reduces Surgery-Induced Cerebral Edema After Glioma Resection

Cerebral edema (CE) is a common contributor to neurological decline after brain tumor resection. While corticosteroids are effective in managing CE perioperatively, their use is associated with significant side effects and potential interference with immunotherapeutic efficacy in patients with malignant brain tumors. This study aimed to evaluate the anti-inflammatory effects of 2 inhibitors of the receptor for advanced glycation end products (RAGE)-TTP488 and FPS-ZM1-on CE development after glioma resection in murine models.

Mice bearing orthotopic CT-2A gliomas were randomized into 4 treatment groups before undergoing fluorescence-guided microsurgical tumor resection. The groups received perioperative administration (from day -4 to day +7) of TTP488, FPS-ZM1, dexamethasone, or vehicle. Postoperative CE was assessed using serial brain MRI over a 7-day period and quantified using manual segmentation. Neurological function, wound healing, and response to anti-PD-1 immunotherapy were also evaluated. Bulk RNA sequencing was performed to analyze differential gene expression associated with RAGE inhibition.

Across all groups, CE peaked on postoperative day 2 and subsided by day 7. On postoperative day 1, both TTP488 and FPS-ZM1 significantly reduced CE compared with vehicle (P = .03 for TTP488; P = .03 for FPS-ZM1). Notably, unlike dexamethasone, neither RAGE inhibitor impaired the efficacy of anti-PD-1 immunotherapy. FPS-ZM1 treatment was also associated with improved neurological recovery, enhanced wound healing, and potentiated anti-PD-1 therapy at higher doses.

RAGE inhibitors effectively reduced postoperative CE to a degree comparable with dexamethasone, without compromising the efficacy of immunotherapy or wound healing. These findings suggest that RAGE inhibition may offer a promising steroid-sparing strategy for perioperative management of CE in patients with brain tumor undergoing immunotherapy.