FTY720 attenuates blood-brain barrier damage and ferroptosis in traumatic brain injury partly by activation of mitophagy

Abstract FTY720, an immunomodulatory agent, reduces lymphocyte egress through activation of the sphingosine-1-phosphate (S1P) receptor. Besides, FTY720 exhibits many pharmacological effects including anti-inflammatory and anti-apoptotic activities in central nervous system (CNS) diseases. Our previous study has demonstrated that FTY720 suppressed apoptosis following traumatic brain injury (TBI). Nevertheless, its influence on TBI-induced blood-brain barrier (BBB) disruption and ferroptosis remained insufficiently understood. We established a mouse TBI model in our study, our data showed that FTY720 (0.5 mg/kg) improved neurological outcomes, reduced cerebral edema, and mitigated brain lesion volume as well as dendritic damage after TBI. Furthermore, FTY720 attenuated BBB disruption and preserved tight junction integrity after injury. In addition, FTY720 inhibited TBI-induced ferroptosis and enhanced PINK1/Parkin-dependent mitophagy. However, the neuroprotective effects of FTY720 were partly abolished when mitophagy was blocked by Mdivi-1 (50 mg/kg). These results provided the first evidence that FTY720 exerts a critical protective effect against TBI by alleviating ferroptosis through the activation of mitophagy.