FTY720, Sphingosine 1-Phosphate Receptor Modulator, Attenuates Radiation-Induced Neurocognitive Deficits in Young Mice

Abstract

Cranial irradiation is an effective treatment modality for both primary and metastatic brain tumors, yet it induces cognitive decline in a substantial number of patients. Recent investigations have revealed a link between radiation-induced cognitive dysfunction and the loss of neural stem cells (NSCs) in the hippocampus. Previously, we showed that FTY720, an agent recently approved by the FDA for treatment of multiple sclerosis, provided radioprotection for NSCs but not tumor cells in vitro. We now examined the ability of fingolimod to mitigate neurocognitive deficits, induced by whole brain irradiation (WBI), in a mouse model. Six-week-old C57/Bl/6J mice were randomized to four experimental groups: (1) WBI + FTY720, (2) WBI + drug vehicle control, (3) sham irradiation + FTY720, and (4) sham irradiation + vehicle. There were 12 mice in each group. Following a single dose of radiation, 7 Gy or 0 Gy (sham), FTY720 or vehicle was given to mice via i.p. injections three times a week for six weeks. Spatial memory was tested using Morris water maze studies. The mice were trained to locate a submerged hidden platform in daily sessions for five days; this was followed by a single probe trial with no platform. The average latency time (length of time to find the platform in water) was calculated for each animal in each trial. Additional behavioral studies included open field, elevated plus maze, and cued fear conditioning studies, testing locomotor activity, anxiety, and amygdala-driven cued response respectively. All data were analyzed using STATA statistical software. In irradiated mice (WBI + vehicle), spatial memory deficits were manifested by significantly longer latency times compared to the non-irradiated controls (sham + vehicle), p < 0.05. Administration of FTY720 fully attenuated radiation-induced memory dysfunction: latency times of irradiated mice treated with FTY720 (WBI + FTY720) were not significantly different from those of non-irradiated controls (sham + vehicle). The latency times of non-irradiated mice treated with FTY720 (sham + FTY720) were equal to those of the non-irradiated vehicle controls (sham + vehicle) as well as of the irradiated FTY720-treated group (WBI + FTY720). There were no statistically significant differences between any of the groups in the open field, elevated plus maze, or fear conditioning studies. We found FTY720 to attenuate radiation-induced spatial memory dysfunction in vivo. Combined with our previous data demonstrating the radioprotective effects of FTY720 on hippocampal neural precursor cells but not tumor cells in vitro, these results provide a strong rationale for testing the efficacy of this FDA-approved agent as a neuroprotector in patients undergoing whole brain radiation therapy.