Abstract
Fasting has emerged as a promising therapeutic strategy for neurological disorders, offering protection against insults such as ionizing radiation (IR), which can cause irreversible brain damage. Intermittent fasting (IF), including alternate-day fasting (ADF) and time-restricted feeding (TRF), is being explored for its neuroprotective effects with potential involvement of key signaling pathways such as IRS-1/PI3K/AKT and BDNF/TrkB. Thirty-six male Wistar albino rats were randomly divided into six groups: normal feeding (NF, ad libitum feeding), ADF, TRF (6-h feeding window), NF plus radiation (NF-irradiated, 20-Gy cranial exposure), ADF plus radiation (ADF-irradiated), and TRF plus radiation (TRF-irradiated). Oxidative stress markers, antioxidant enzymes, liver and kidney function parameters, and gene/protein expression levels (IRS1, AKT1, PI3K, GFAP, 8-OHdG, BDNF, TrkB) were evaluated using enzyme-linked immunosorbent assay (ELISA) and RT-PCR, complemented by histopathological analysis. IR significantly impaired antioxidant defenses (GSH, GST, CAT), suppressed IRS-1/PI3K/AKT and BDNF/TrkB signaling, and elevated oxidative damage markers (MDA, ROS, 8-OHdG), inflammation (GFAP), and markers of organ dysfunction (ALT, AST, GGT, urea, creatinine). Both IF regimens mitigated these effects; however, TRF demonstrated greater efficacy than ADF. TRF more effectively reduced oxidative stress, improved antioxidant enzyme activity, and more robustly restored metabolic and neurotrophic signaling pathways. Both ADF and TRF provided neuroprotection against radiation-induced brain injury, but TRF exhibited superior outcomes in reducing oxidative stress and preserving neuronal integrity. These findings highlight TRF as a potentially more effective dietary strategy for mitigating radiation-induced neurotoxicity, with possible contributions from the modulation of IRS-1/PI3K/AKT and BDNF/TrkB pathways.