12255 Brain GFRAL Signaling Mediates Chemotherapy-Induced Fatigue And Cognitive Impairment In Mice

Abstract

Abstract Disclosure: R. Dantzer: None. Brain GFRAL Signaling Mediates Chemotherapy-Induced Fatigue and Cognitive Impairment in Mice Brandon Chelette, PhD, Anand Singh, PhD, Robert Dantzer, DVM, PhDDept. of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA Fatigue and cognitive impairments are commonly reported by cancer patients undergoing chemotherapy. The mechanisms of these neurotoxicities are still obscure. We hypothesize that they are mediated by mitokines that are released by cells undergoing mitochondrial stress in response to chemotherapy. For the present study, we have focused on growth differentiation factor 15 (GDF15) which acts in the brain by activating its receptor, GDNF family receptor alpha-like (GFRAL). Chemotherapy-induced fatigue was assessed by reduced voluntary wheel running. Cognitive impairment was assessed by altered performance in the Puzzle Box Test that measures executive function. We first checked whether commonly used chemotherapeutic drugs can induce GDF15. Mice were injected with cisplatin, paclitaxel, or bortezomib, and their effects on plasma levels of GDF15 were measured 24 h after (ELISA). Cisplatin was used in the following experiments in the form of one or two cycles of daily injections for five days with a rest of five days between cycles. To determine whether GFRAL mediates the effects of cisplatin on wheel running and performance in the puzzle box, mice were injected with a neutralizing antibody targeted to GFRAL (GFRALna) during or after cisplatin treatment. All studies were carried out in male and female C57BL/6 J mice using a 2 (+ chemotherapy) x 2 (+ GFRALna) factorial design with a minimum of 6 mice/group. Mitochondrial dysfunction was measured via Seahorse XF Analyzer Mito Stress Test. To determine whether activation of the GDF15/GFRAL axis recruits a central GDF15 compartment, Gdf15 mRNA was measured by qRT-PCR in the brain parenchyma, meninges, and choroid plexus. All the chemotherapeutic agents we tested induced statistically significant increases in circulating GDF15. GFRALna administered during cisplatin treatment (prevention) or after completion of cisplatin treatment (cure) abrogated cisplatin-induced decrease in wheel running and the deficit displayed by cisplatin-treated mice in the first hard trial run in the puzzle box. GFRALna also blocked the decrease in maximal oxygen consumption rate of mitochondrial in synaptosomes from cisplatin-treated mice. Cisplatin did not induce Gdf15 mRNA in the brain parenchyma but increased its expression in the meninges and choroid plexus. Although the role of this GDF15 brain compartment in the neurotoxicity of cisplatin remains to be determined, the present findings can be interpreted to suggest that GDF15-GFRAL signaling represents a new target for the treatment of chemotherapy-induced fatigue and cognitive impairment. Count: 2,246 characters Presentation: 6/1/2024