Role of Antioxidants in Modulating BDNF Signaling and Oxidative Stress in Glioblastoma: Current Evidence and Therapeutic Perspectives

Glioblastoma (GBM) remains one of the most aggressive and lethal brain tumors, with limited treatment success despite standard multimodal therapy. Oxidative stress and dysregulated brain-derived neurotrophic factor (BDNF) signaling contribute to GBM progression, therapeutic resistance, and treatment-related neurotoxicity. Therefore, this review aims to examine the complex interplay among antioxidants, BDNF/TrkB signaling, and redox imbalance in GBM, focusing on the potential biological activities of natural antioxidants, particularly polyphenols such as curcumin, resveratrol, and epigallocatechin-3-gallate (EGCG). Preclinical studies suggest that these compounds may modulate oxidative stress, influence glioma cell survival, and alter signaling pathways associated with chemoradiotherapy sensitivity and neuronal protection. Nevertheless, direct evidence that BDNF/TrkB signaling mediates the antitumor effects of these antioxidant compounds in glioblastoma remains insufficient, and observations from non-GBM models should be regarded as mechanistic hypotheses rather than validated therapeutic mechanisms. However, clinical evidence supporting their efficacy in patients with GBM remains limited and inconclusive. Human findings from observational cohorts and clinical trials involving non-GBM populations provide indirect insights into antioxidant-related cognitive and redox outcomes but cannot establish therapeutic benefits in glioblastoma. Furthermore, the dual role of BDNF/TrkB signaling in neuronal protection and tumor progression raises concerns regarding generalized BDNF enhancement. Challenges involving bioavailability, optimal dosing, tumor-specific effects, and potential interactions with conventional treatments further limit clinical translation. Future research should prioritize GBM-specific randomized controlled trials, biomarker-guided strategies, and the simultaneous evaluation of neuroprotective and oncological outcomes. Targeting the antioxidant-BDNF-redox axis remains an experimental therapeutic approach that requires rigorous validation before clinical implementation.