FTY720 attenuates iron deposition and glial responses in improving delayed lesion and long-term outcomes of collagenase-induced intracerebral hemorrhage

•Astrocytosis left around delayed lesion without TNFα secretion after ICH.•FTY720 lessened delayed lesion including delayed WMI and neuron loss.•FTY720 inhibited glial responses and TNFα secretion of microglia after ICH.•FTY720 reduced iron content in delayed lesion without affecting volume of hematoma and initial lesion after ICH.•FTY720 improved the long-term outcome including depressive-like behavior and recognition memory impairment without affecting grip motor function recovery after ICH. Most intracerebral hemorrhage (ICH) survivors have poor long-term outcomes, such as cognitive deficits and depression. Delayed lesions of ICH include neuron loss and white matter injury and the pathology of the lesions involves iron deposition and glial responses, which contribute to depressive-like behavior and cognitive impairment in animals. This study aimed to investigate the effects of FTY720 (0.3 mg/kg/day for 4 weeks) on iron deposition, glial responses, histological abnormalities and behavioral dysfunction in mice with ICH. The primary adverse long-term outcomes in our study of ICH mice were depressive-like behavior and impaired recognition memory. We found that FTY720 safely ameliorated depressive-like behavior and impaired recognition without affecting recovery of grip function and locomotor activity 28 days post-ICH. Moreover, we measured neuron loss, white matter lesions, lesion volume and iron deposition at day 28, which were attenuated in the FTY720-treated group compared to the ICH-control group, without changing initial hematoma volume on day 1 post-ICH. Long-term elevation of glial responses, including microglia activity and astrogliosis with tumor necrosis factor alpha (TNFα) expression was demonstrated by Western blot and immunofluorescence staining, which we found was attenuated by FTY720 treatment. Hence, FTY720 could become a novel therapeutic agent for improving long-term outcomes after ICH.