Oral administration of cytosolic PLA2 inhibitor arachidonyl trifluoromethyl ketone ameliorates cauda equina compression injury in rats

BackgroundPhospholipase A2 (PLA2)-derived proinflammatory lipid mediators such as prostaglandin E2 (PGE2), leukotrienes B4 (LTB4), lysophosphatidylcholine (LPC), and free fatty acids (FFA) are implicated in spinal cord injury (SCI) pathologies. Reducing the levels of these injurious bioactive lipid mediators is reported to ameliorate SCI. However, the specific role of the group IVA isoform of PLA2 cytosolic PLA2 (cPLA2) in lumbar spinal canal stenosis (LSS) due to cauda equina compression (CEC) injury is not clear. In this study, we investigated the role of cPLA2 in a rat model of CEC using a non-toxic cPLA2-preferential inhibitor, arachidonyl trifluoromethyl ketone (ATK).MethodsLSS was induced in adult female rats by CEC procedure using silicone blocks within the epidural spaces of L4 to L6 vertebrae. cPLA2 inhibitor ATK (7.5 mg/kg) was administered by oral gavage at 2 h following the CEC. cPLA2-derived injurious lipid mediators and the expression/activity of cPLA2, 5-lipoxygenase (5-LOX), and cyclooxygenase-2 (COX-2) were assessed. ATK-treated (CEC + ATK) were compared with vehicle-treated (CEC + VEH) animals in terms of myelin levels, pain threshold, and motor function.ResultsATK treatment of CEC animals reduced the phosphorylation of cPLA2 (pcPLA2) determined by Western blot, improved locomotor function evaluated by rotarod task, and reduced pain threshold evaluated by mechanical hyperalgesia method. Levels of FFA and LPC, along with PGE2 and LTB4, were reduced in CEC + ATK compared with CEC + VEH group. However, ATK treatment reduced neither the activity/expression of 5-LOX nor the expression of COX-2 in CEC + VEH animals. Increased cPLA2 activity in the spinal cord from CEC + VEH animals correlated well with decreased spinal cord as well as cauda equina fiber myelin levels, which were restored after ATK treatment.ConclusionThe data indicate that cPLA2 activity plays a significant role in tissue injury and pain after LSS. Reducing the levels of proinflammatory and tissue damaging eicosanoids and the deleterious lipid mediator LPC shows therapeutic potential. ATK inhibits cPLA2 activity, thereby decreasing the levels of injurious lipid mediators, reducing pain, improving functional deficits, and conferring protection against LSS injury. Thus, it shows potential for preclinical evaluation in LSS.

• Publication year

  2015

• Venue

  Journal of Neuroinflammation

• Publication date

  2015-05-15

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1186/s12974-015-0311-yPMID 25971887PMCID 4436116
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• The inhibitor did not reduce 5-lipoxygenase activity or expression, nor cyclooxygenase-2 expression, in cauda equina compression animals.

  Confidence 0.92

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• Increased cPLA2 activity in the spinal cord was associated with lower myelin levels, and inhibitor treatment restored myelin in spinal cord and cauda equina fibers.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• Arachidonyl trifluoromethyl ketone lowered spinal cord and cauda equina levels of free fatty acids, lysophosphatidylcholine, prostaglandin E2, and leukotriene B4 in the cauda equina compression model.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• Oral arachidonyl trifluoromethyl ketone at 7.5 mg/kg given 2 hours after cauda equina compression reduced cPLA2 phosphorylation and improved locomotor and mechanical pain outcomes in rats.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review

• 5-lipoxygenase

  enzyme, protein

  An enzyme involved in leukotriene synthesis that was assayed for activity and expression in the injured spinal cord.

  Aliases: 5-LOX

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• arachidonyl trifluoromethyl ketone

  inhibitor, compound

  A non-toxic cPLA2-preferential inhibitor administered by oral gavage after cauda equina compression.

  Aliases: ATK

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• cauda equina compression

  injury model, condition

  The rat spinal canal stenosis injury model created by silicone blocks placed in the epidural space from L4 to L6.

  Aliases: CEC, LSS due to cauda equina compression

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• cpla2

  enzyme, protein

  The group IVA cytosolic phospholipase A2 enzyme measured by phosphorylation and activity in spinal cord tissue.

  Aliases: cytosolic PLA2, group IVA phospholipase A2

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• cyclooxygenase-2

  enzyme, protein

  An inducible enzyme involved in prostaglandin synthesis that was measured by expression in the injured spinal cord.

  Aliases: COX-2

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• free fatty acids

  lipid mediator, metabolite

  Lipid metabolites measured in spinal cord tissue as part of the cPLA2-derived injury-associated lipid pool.

  Aliases: FFA

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• leukotriene b4

  lipid mediator, eicosanoid

  An inflammatory eicosanoid measured in spinal cord tissue after cauda equina compression.

  Aliases: LTB4

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• lysophosphatidylcholine

  lipid mediator, metabolite

  A cPLA2-linked lipid mediator measured in spinal cord tissue after cauda equina compression.

  Aliases: LPC

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• mechanical hyperalgesia

  outcome, measurement

  A pain sensitivity outcome assessed as pain threshold in the cauda equina compression model.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• myelin

  tissue component, outcome

  The myelin content of spinal cord and cauda equina fibers assessed as a tissue integrity marker.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• prostaglandin e2

  lipid mediator, eicosanoid

  An inflammatory eicosanoid measured in spinal cord tissue after cauda equina compression.

  Aliases: PGE2

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review
• rotarod task

  behavioral test, assessment method

  A behavioral test used to evaluate locomotor function in the injured rats.

  Aliases: rotarod

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAnonymous (12632b8b5f) review

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