Deletion of mammalian sterile 20-like kinase 1 attenuates neuronal loss and improves locomotor function in a mouse model of spinal cord trauma

Abstract

Neuronal cell death following spinal cord injury (SCI) is an important contributor to neurological deficits. The purpose of our work was to delineate the function of mammalian sterile 20-like kinase 1 (Mst1), a pro-apoptotic kinase and key mediator of apoptotic signaling, in the pathogenesis of an experimental mouse model of SCI. Male mice received a mid-thoracic spinal contusion injury, and it was found that phosphorylation of Mst1 at the injured site was enhanced significantly following SCI. Furthermore, when compared to the wild-type controls, Mst1-deficient mice displayed improved locomotor function by increased Basso mouse scale score. Deletion of Mst1 in mice attenuated loss of motor neurons and suppressed microglial and glial activation following SCI. Deletion of Mst1 in mice reduced apoptosis via suppressing cytochrome c release and caspase-3 activation following SCI. Deletion of Mst1 attenuated mitochondrial dysfunction and increased ATP formation following SCI. Deletion of Mst1 in mice inhibited local inflammation following SCI, evidenced by reduced activities of myeloperoxidase and protein levels of TNF-α, IL-1β, and IL-6. In conclusion, the present study demonstrated that deletion of Mst1 attenuated neuronal loss and improved locomotor function in a mouse model of SCI, via preserving mitochondrial function, attenuating mitochondria-mediated apoptotic pathway, and suppressing inflammation, at least in part.

Hyperbaric oxygen improves functional recovery of rats after spinal cord injury via activating stromal cell-derived factor-1/CXC chemokine receptor 4 axis and promoting brain-derived neurothrophic factor expression

“…Most of them enhanced inflammation and functional recovery [34] . Neuronal cell death following SCI was an important contributor to neurologic deficits [35] . It might be an effective way to improve recovery by promoting neuronal survival via attenuating inflammation after SCI [36] .…”

MST1 Suppression Reduces Early Brain Injury by Inhibiting the NF-κB/MMP-9 Pathway after Subarachnoid Hemorrhage in Mice

“…Previous studies have suggested that MST1 activation contributes to neuronal apoptosis and inflammation. Genetic deletion of MST1 may reduce the inflammation and microglial activation after spinal cord injury and ischemic stroke [ 13 , 14 ]. Consistent with these reports, we determined that pharmacological inhibition of MST1 or its knockdown alleviated the neurological deficits, brain edema, and BBB disruption induced by SAH.…”

“…In addition, MST1 exhibits fundamental functions in various central nervous system diseases, including vascular dementia, Alzheimer's disease, amyotrophic lateral sclerosis, and cerebral cavernous malformation [ 9 – 12 ]. Furthermore, genetic deletion of MST1 provides neuroprotection against ischemic stroke and spinal cord injury by attenuating neuronal apoptosis and the inflammatory response [ 13 , 14 ].…”

Dopamine Reduced Pyroptosis and Improved Functional Recovery After Spinal Cord Injury 

“…Mounting evidence suggests that, among these, neuronal loss [10] and excessive in ammatory response [7] are especially grievous, by causing persistent damage and progressive degeneration of the spinal cord. Attenuation of secondary neuronal death [11], neuroin ammation [12], and demyelination [8] may contribute to the recovery of locomotor function.…”