Inhibition of Cytosolic Phospholipase A₂Has Neuroprotective Effects on Motoneuron and Muscle Atrophy after Spinal Cord Injury

Abstract

Surviving motoneurons undergo dendritic atrophy after spinal cord injury (SCI), suggesting an important therapeutic target for neuroprotective strategies to improve recovery of function after SCI. Our previous studies showed that phospholipase A 2 (PLA 2 ) may play an important role in the pathogenesis of SCI. In the present study, we investigated whether blocking cPLA 2 pharmacologically with arachidonyl trifluoromethyl ketone (ATK) or genetically using cPLA 2 knockout (KO) mice attenuates motoneuron atrophy following SCI. C57BL/6 mice received either sham or contusive SCI at the T10 level. At 30 min after SCI, mice were treated with ATK or vehicle. Four weeks later, motoneurons innervating the vastus lateralis muscle of the quadriceps were labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed in three dimensions. Soma volume, motoneuron number, lesion volume, and tissue sparing were also assessed, as were muscle weight, fiber cross-sectional area, and motor endplate size and density. ATK administration reduced percent lesion volume and increased percent volume of spared white matter compared to the vehicle-treated control animals. SCI with or without ATK treatment had no effect on the number or soma volume of quadriceps motoneurons. However, SCI resulted in a decrease in dendritic length of quadriceps motoneurons in untreated animals, and this decrease was completely prevented by treatment with ATK. Similarly, the vastus lateralis muscle weights of untreated SCI animals were smaller than those of sham-surgery controls, and these reductions were prevented by ATK treatment. No effects on fiber cross-sectional areas, motor endplate area or density were observed across treatment groups. Remarkably, genetically deleting cPLA 2 in cPLA 2 KO mice attenuated dendritic atrophy after SCI. These findings suggest that after SCI, cord tissue damage and regressive changes in motoneuron and muscle morphology can be reduced by inhibition of cPLA 2 , further supporting a role for cPLA 2 as a neurotherapeutic target for SCI treatment.

Reaching and Grasping Training Improves Functional Recovery After Chronic Cervical Spinal Cord Injury

“…Rehabilitation may also prevent synaptic stripping in motor neurons after SCI. Previous studies show that SCI causes profound dendritic atrophy and synaptic stripping in the motor neurons caudal to the lesion, which are not directly injured by the trauma (Liu et al, 2014;Wang et al, 2015). Importantly, treadmill training is able to prevent these degenerative changes in motor neurons (Wang et al, 2015).…”

Neuroprotective Effects on the Morphology of Somatic Motoneurons Following the Death of Neighboring Motoneurons: A Role for Microglia?

“…Importantly, after such insults surviving motoneurons also show a variety of morphological and functional changes. For example, motoneurons undergo dendritic retraction and atrophy after injury (e.g., after spinal cord injury; Byers et al ., ; Liu et al ., ; ). Similarly, after peripheral axotomy motoneurons show functional and biochemical changes (e.g., Titmus and Faber, ; Bisby and Tetzlaff, ) as well as dendritic atrophy (e.g., Sumner and Watson, ; O'Hanlon and Lowrie, ; Yang et al ., ).…”

Cervical Cord Neurodegeneration in Traumatic and Non-Traumatic Spinal Cord Injury

“…Pre-clinical studies have highlighted that a range of common primary injury mechanisms are involved in both tSCI 4 and DCM patients, 15 which include apoptosis of cells, inflammation, and vascular changes resulting in cell death at the focal injury site. 5,15,39,40 Secondary injury-induced changes evolve over time and include anterograde and retrograde axonal degeneration of spinal pathyways, 5,14,41,42 remodulation of neuronal spinal circuits, 43 dysregulation of growth factors, 39 shrinkage of the neuron soma size 44 due to a reduction in muscle activity of the upper extremity, and remodeling of microvasculature configuration. 40…”