Inhibition of Cytosolic Phospholipase A2Has Neuroprotective Effects on Motoneuron and Muscle Atrophy after Spinal Cord Injury.
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 cytosolic phospholipase A2(PLA2) may play an important role in the pathogenesis of SCI. In the present study, we investigated whether blocking cytosolic PLA2(cPLA2) pharmacologically with arachidonyl trifluoromethyl ketone (ATK) or genetically using cPLA2knockout (KO) mice attenuates motoneuron atrophy after 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, 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 cPLA2in cPLA2KO 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 cPLA2, further supporting a role for cPLA2as a neurotherapeutic target for SCI treatment.
Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery and Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Nai-Kui
NK
Liu
Program in Neuroscience and Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, USA.
James S
JS
Byers
Indiana University School of Medicine, Bloomington, Indiana, USA.
Tom
T
Lam
Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery and Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Qing-Bo
QB
Lu
Program in Neuroscience and Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, USA.
Dale R
DR
Sengelaub
Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery and Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Xiao-Ming
XM
Xu
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000187:drug effects / Q000201:enzymology*; D009133:Muscular Atrophy / Q000201:enzymology* / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D064801:Phospholipase A2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D054510:Phospholipases A2, Cytosolic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000453:epidemiology*
D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D064801:Phospholipase A2 Inhibitors; C081565:arachidonyltrifluoromethane; D054510:Phospholipases A2, Cytosolic
atrophy; cPLA2; dendrites; morphology; neuroprotection