PURPOSE: A comprehensive literature review was undertaken to understand the effects and underlying mechanisms of cranial radiotherapy (RT) on the hippocampus and hippocampal neurogenesis as well as to explore protective factors and treatments that might mitigate these effects in preclinical studies. METHODS: PubMed/MEDLINE, Web of Science, and Embase were queried for studies involving the effects of radiation on the hippocampus and hippocampal neurogenesis. Data extraction followed the Animal Research Reporting of In Vivo Experiments (ARRIVE) guidelines, and a risk of bias assessment was conducted for the included animal studies using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias tool. RESULTS: Ninety studies were included, with 48 assessing radiation-induced changes and 42 examining possible interventions. The majority of studies (97.8%) used experimental animal models. Studies demonstrated that cranial irradiation reduces hippocampal neurogenesis, particularly in the neurogenic niches of the dentate gyrus
causes alterations in gene expression and enzymatic activity
induces inflammation
promotes apoptosis
and often results in cognitive impairment. Potential protective strategies include pharmacological agents like metformin and peroxisome proliferator-activated receptor-α (PPAR-α) agonists or behavioral interventions like voluntary running. In a risk of bias assessment, many studies were rated as having an unclear risk of bias. CONCLUSION: Radiotherapy, while essential for managing brain tumors, can have adverse effects on hippocampal function and structure in animal models. These effects manifest in reduced neurogenesis, molecular alterations, and increased inflammation, leading to cognitive deficits. Further research is needed to identify and improve interventions and develop comprehensive therapeutic approaches that balance effective tumor control with the preservation of cognitive health.