Arachidonyl Trifluoromethyl Ketone Is Neuroprotective after Spinal Cord Injury

Abstract

In spinal cord injury (SCI), neuronal and oligodendroglial loss occurs as a result of the initial trauma and the secondary damage that is triggered by excitotoxicity, free radicals, and inflammation. There is evidence that SCI ellicits increased cytosolic phospholipase A(2) (cPLA(2)) activity. The cleavage of phospholipids by cPLA(2) leads to release of fatty acids, and in particular arachidonic acid (AA), the metabolites of which have been associated with increased inflammation and oxidative stress. The aim of our study was to investigate whether the inhibition of cPLA(2) following SCI leads to tissue protection and an improved functional outcome. Adult rats received compression SCI and 30 min after injury they were treated intravenously with either saline or the cPLA(2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) (7.13 mg/kg). The animals were sacrificed at 7 days post-injury and the lesioned tissue was labeled using markers for neurons, oligodendrocytes, and macrophages/activated microglia. We also assessed locomotor recovery using the Basso-Beattie-Bresnahan (BBB) score. The number of surviving neurons and oligodendrocytes was significantly increased in animals treated with the cPLA(2) inhibitor compared to saline controls. The behavioral analysis mirrored the neuroprotective effects and showed that the inhibitor-treated group had better locomotor recovery compared to saline controls. Our results show that AACOCF3 has neuroprotective potential, and support the idea that cPLA(2) is critically involved in acute spinal injury.

The RNA-binding Protein HuR Stabilizes Cytosolic Phospholipase A2α mRNA under Interleukin-1β Treatment in Non-small Cell Lung Cancer A549 Cells

“…This construct was named as the PLA599 plasmid. Full-length cPLA 2 ␣ 3Ј-UTR was amplified using specific primers and cloned into plasmid pGL 3 promoter vector (Promega) using the XbaI and FseI sites. Various regions of the cPLA 2 ␣ 3Ј-UTR were amplified by PCR and cloned into pGEM-T easy vector (Promega) for in vitro transcription to synthesize probes used in RNA electrophoretic mobility shift assays (EMSAs) and biotin-labeled probe pulldown assays.…”

“…Treatment with the cPLA 2 ␣ inhibitor arachidonyl-trifluoromethyl ketone (AACOCF 3 ) increases the survival of neurons and oligodendrocytes in rats that received compression spinal cord injuries (3). Moreover, it has been shown that reduced cPLA 2 ␣ expression contributes to a remarkable resistance to acute respiratory distress syndrome (ARDS), asthma, and collagen-induced arthritis in the cPLA 2 ␣-deficient mouse model (4 -6).…”

Role of phospholipase A2s and lipid mediators in secondary damage after spinal cord injury

“…Moreover, the role of cPLA 2 GIVA and sPLA 2 GIIA have not been assessed in these in vivo studies (Liu et al 2006;Titsworth et al 2007). Evidence of a detrimental role of intracellular PLA 2 s in SCI was first shown in experiments with arachidonyl trifluoromethyl ketone (AACOCF3; Huang et al 2009). AACOCF3 is a nonselective inhibitor of intracellular PLA 2 s, and in these experiments, its effects in SCI were tested over a short 7-day period after injury (Huang et al 2009).…”

“…Evidence of a detrimental role of intracellular PLA 2 s in SCI was first shown in experiments with arachidonyl trifluoromethyl ketone (AACOCF3; Huang et al 2009). AACOCF3 is a nonselective inhibitor of intracellular PLA 2 s, and in these experiments, its effects in SCI were tested over a short 7-day period after injury (Huang et al 2009). This inhibitor, which blocks both cPLA 2 and iPLA 2 , led to a modest improvement in locomotor recovery and reduction of neuronal and oligodendrocyte loss (Huang et al 2009), but the relative contribution of cPLA 2 and iPLA 2 in SCI still remained to be shown.…”

“…AACOCF3 is a nonselective inhibitor of intracellular PLA 2 s, and in these experiments, its effects in SCI were tested over a short 7-day period after injury (Huang et al 2009). This inhibitor, which blocks both cPLA 2 and iPLA 2 , led to a modest improvement in locomotor recovery and reduction of neuronal and oligodendrocyte loss (Huang et al 2009), but the relative contribution of cPLA 2 and iPLA 2 in SCI still remained to be shown. We have recently dissected out the role of cPLA 2 GIVA, iPLA 2 GVIA, and sPLA 2 GIIA after spinal cord contusion injury in mice .…”