Mithramycin A Improves Functional Recovery by Inhibiting BSCB Disruption and Hemorrhage after Spinal Cord Injury.

Abstract

After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption and progressive hemorrhage lead to secondary injury, subsequent apoptosis and/or necrosis of neurons and glia, causing permanent neurological deficits. Growing evidence indicates that mithramycin A (MA), an anti-cancer drug, has neuroprotective effects in ischemic brain injury and Huntington's disease (HD). However, the precise mechanism underlying its protective effects is largely unknown. Here, we examined the effect of MA on BSCB breakdown and hemorrhage as well as subsequent inflammation after SCI. After moderate spinal cord contusion injury at T9, MA (150 μg/kg) was immediately injected intraperitoneally (i.p.) and further injected once a day for 5 days. Our data show that MA attenuated BSCB disruption and hemorrhage, and inhibited the infiltration of neutrophils and macrophages after SCI. Consistent with these findings, the expression of inflammatory mediators was significantly alleviated by MA. MA also inhibited the expression and activation of matrix metalloprotease-9 (MMP-9) after injury, which is known to disrupt BSCB and the degradation of tight junction (TJ) proteins. In addition, the expression of sulfonylurea receptor 1 (SUR1) and transient receptor potential melastatin 4 (TRPM4), which are known to mediate hemorrhage at an early stage after SCI, was significantly blocked by MA treatment. Finally, MA inhibited apoptotic cell death and improved functional recovery after injury. Thus, our results demonstrated that MA improves functional recovery by attenuating BSCB disruption and hemorrhage through the downregulation of SUR1/TRPM4 and MMP-9 after SCI.