Targeted versus whole-brain radiotherapy: systematic multiparametric and longitudinal investigations in the adult rat

Although radiotherapy improves the prognosis of patients with brain cancer, it induces cognitive deficits. Animal models have been used to address the underlying mechanisms of these radiation-induced deficits. Nonetheless, in most of the animal studies, whole-brain irradiation has been applied, deviating from the clinical practice, where the goal is to reduce the exposure of healthy brain tissue to radiation. Here we analyzed in rats the evolution of brain tissue injury and cognitive impairments induced by irradiation restricted to only one cerebral hemisphere and systematically compared these effects with those observed after whole-brain irradiation. Rats were divided into control, whole-brain-irradiated (WBI) and hemispheric-irradiated (HBI) groups. Multiparametric magnetic resonance imaging, behavioral tests and immunohistology were performed up to 6 months following the irradiation (3 × 10 Gy). Relative to WBI, more restricted irradiation did not induce significant locomotion impairment nor anxiety-like behavior; cognitive deficits and brain atrophy were also reduced after HBI compared with WBI. Magnetic resonance imaging revealed major alterations in the microstructure and the vasculature of brain tissue only in WBI rats. However, immunohistological analyses indicated that HBI induced persistent neuroinflammation confined to the irradiated hemisphere, which appeared more pronounced than that observed after WBI. Overall, the data highlight that restricted brain irradiation mitigates brain damage and induces less cognitive deficits compared with whole-brain irradiation. In the future, refining animal models with targeted cerebral irradiation will be essential for evaluating neuroprotective strategies.