The role of orexin in brain radiation-induced fatigue

Purpose/Objectives Fatigue, the most common toxicity of whole brain radiation therapy (WBRT), significantly decreases quality of life (QOL) for patients, abrogating the benefit afforded by improved tumor control. The objective of this study is to evaluate the role of diminished orexin neuron activity in the pathogenesis of fatigue induced by clinically significant WBRT fractionation. Materials/Methods Adult male Sprague-Dawley rats received WBRT, 4 Gy in 5 fractions or sham irradiation. Home cage locomotor activity (LMA) was monitored using a photobeam system. Cerebrospinal fluid and brain sections were collected at fatigue onset, nadir, and recovery. CSF orexin concentration was measured using radioimmunoassay. Inflammatory and oxidative expression patterns were evaluated by qPCR. Data were analyzed by t -test or 2-way ANOVA with Bonferroni correction. Significance was set at P Results LMA was decreased in WBRT-treated rats starting following the first fraction and continued to decrease until reaching a nadir following the final fraction, then recovering to a new baseline ∼10% lower than sham- irradiated rats. Food intake and weight gain were reduced in WBRT-treated rats, leading to persistent growth suppression. WBRT induced inflammatory gene expression. CSF orexin concentration will be reported. Conclusions WBRT-induced fatigue can be modeled using home cage LMA. Rats exhibit an activity nadir following final fraction and never fully recover. The role of orexin and inflammation in fatigue will be discussed as potential targets for therapeutic intervention.