Targeting sphingosine-1-phosphate receptor-2 attenuates spinal cord injury by preventing neuronal ferroptosis

Abstract

Background and Purpose Spinal cord injury (SCI) imposes severe physiological and psychological burdens on patients. We investigated the role of sphingosine-1-phosphate receptor 2 (S1P2 receptor) in contusive spinal cord injury and evaluated the therapeutic effects of an S1P2 receptor antagonist S118 (C(1)(9)H(1)(4)Cl2FN(7)O) in a rat model of SCI.Experimental Approach The SCI model was established using a 10 g weight dropped onto the T10 vertebrae in female rats. After functional testing, spinal cords were harvested for biochemical and histopathological assays at different time points. Nissl and Prussian blue staining were used to analyse neuronal death. Neuronal ferroptosis in spinal cords was examined using transmission electron microscopy, and lipid peroxidation in the cultured neurones was analysed.Key Results After SCI, S1P (Sphingosine 1-phosphate) was released from crushed spinal cords and subsequently activated the neuronal S1P2 receptor to increase lipid peroxidation, which injured neurones via inducing neuronal ferroptosis through the P-ERK/ERK/ACSL4 pathway, resulting in limb paralysis. S1P2 receptor inhibition significantly blocked S1P2 receptor activation and attenuated neuronal ferroptosis. Thus, S1P2 receptor was a therapeutic target for the treatment of SCI. Systemic administration of the S1P2 receptor antagonist S118 (C(1)(9)H(1)(4)Cl2FN(7)O) effectively promoted locomotor function recovery by attenuating neuronal ferroptosis in rat spinal cords. S118 impeded neuronal ferroptosis by inhibiting lipid peroxidation.Conclusions and Implications Contusive SCI is characterised by neuronal loss due to S1P2 receptor activation in spinal neurones. S1P2 receptor activation increases lipid peroxidation, which induces neuronal ferroptosis. S118 (C(1)(9)H(1)(4)Cl2FN(7)O) improves locomotor functional recovery by preserving the spinal cord structure after SCI.