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.

Spinal cannabinoid receptor 2 activation reduces hypersensitivity associated with bone cancer pain and improves the integrity of the blood–spinal cord barrier

“…Under physiological conditions, the BSCB represents a tight barrier between the blood and CNS. Disruption of the BSCB occurs under various pathological conditions, such as ALS, 24 spinal cord injury 25 and neuropathic pain, 10 leading to increased permeability and subsequent damage. As shown in our previous study, T cells infiltrated into the spinal cord during the maintenance of BCP.…”

Neuroprotective Effect of Subdural Infusion of Serp-1 in Spinal Cord Trauma

“…Anti-inflammatory treatments previously attempted have not benefited from sufficient understanding of the pathogenesis of SCI and high-dose, short-term intravenous infusion of methylprednisolone [ 18 , 19 , 20 , 21 ] has been shown to cause severe side effects [ 3 , 20 , 22 , 23 , 24 ] and has recently been discouraged [ 25 ]. Other compounds including riluzole, glibenclamide and cethrin [ 26 ], and also fumaric acid esters [ 27 ], estrogen [ 28 ], endaravone [ 29 ], mitramycine A [ 30 ], and N -Palmytiolethalonamine-oxazoline [ 31 ] have recently been studied in SCI animal models and clinical trials but only in short term treatments in initial stages of SCI. The effects of these experimental treatments have not been measured in a fashion addressing pathogenesis of SCI leaving a possibility that some of these compounds may potentially be found neuroprotective when tested in properly designed pre-clinical studies.…”

Gallic acid attenuates blood-spinal cord barrier disruption by inhibiting Jmjd3 expression and activation after spinal cord injury

“…For myelin staining, selected slides were incubated in 0.1% Luxol fast blue (Solvent Blue 38; Sigma) in acidified 95% ethanol overnight at 60°C. Differentiation was performed with 0.05% lithium carbonate as previous described (Lee et al, 2018). Digital images of Luxol fast blue-stained tissues were obtained by MetaMorph software (Molecular Devices).…”