A novel role of phospholipase A<sub>2</sub> in mediating spinal cord secondary injury

Liu, Nai Kui; Zhang, Yi Ping; Titsworth, W. Lee; Jiang, Xiaoyan; Han, Shu; Lu, Pei-Hua; Shields, Christopher B.; Xu, Xiao–Ming

doi:10.1002/ana.20798

Cited by 143 publications

(155 citation statements)

References 42 publications

(67 reference statements)

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“…cPLA 2 is an 85kDa protein enzyme that preferentially produces arachidonic acid (AA) by hydrolyzing the sn-2 position of glycerophospholipids [49]. Our lab has previously shown that cPLA 2 activation increased as early as 8 hours and peaked at 7 days post-SCI [22,21]. Activation of cPLA 2 by its activator, ceramide-1-phosphate or A23187, is sufficient to induce neuronal death, whereas cPLA 2 inhibition reduces cell loss in vitro [22].…”

Section: Discussionmentioning

confidence: 99%

“…Our prior research has demonstrated significant increases of PLA 2 activity and cPLA 2 expression following SCI [21,22]. cPLA 2 is highly expressed in neurons, axons and glial cells and peaked at day 1 in axons, day 3 in glial cells, and day 7 in neurons after SCI [21]. Activation of cPLA 2 is sufficient to induce spinal cord neuronal death in vitro.…”

Section: Introductionmentioning

confidence: 86%

“…A main product of cPLA 2 is arachidonic acid (AA) [19], which can give rise to eicosanoids that mediate inflammation, necrosis and apoptosis [19,20]. Our prior research has demonstrated significant increases of PLA 2 activity and cPLA 2 expression following SCI [21,22]. cPLA 2 is highly expressed in neurons, axons and glial cells and peaked at day 1 in axons, day 3 in glial cells, and day 7 in neurons after SCI [21].…”

Section: Introductionmentioning

confidence: 99%

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RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Walker

et al. 2016

Mol Neurobiol

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Activation of RhoA/Rho kinase leads to growth cone collapse and neurite retraction. Although RhoA/Rho kinase inhibition has been shown to improve axon regeneration, remyelination and functional recovery, its role in neuronal cell death remains unclear. To determine whether RhoA/Rho kinase played a role in neuronal death after injury, we investigated the relationship between RhoA/Rho kinase and cytosolic phospholipase A 2 (cPLA 2 ), a lipase that mediates inflammation and cell death, using an in vitro neuronal death model and an in vivo contusive spinal cord injury model performed at the 10 th thoracic (T10) vertebral level. We found that coadministration of TNF-α and glutamate induced spinal neuron death, and activation of RhoA, Rho kinase and cPLA 2 . Inhibition of RhoA, Rho kinase and cPLA 2 significantly reduced TNF-α/glutamate-induced cell death by 33%, 52% and 43%, respectively (p < 0.001). Inhibition of RhoA and Rho kinase also significantly down-regulated cPLA 2 activation by 66% and 60%, respectively (p < 0.01). Furthermore, inhibition of RhoA and Rho kinase reduced the release of arachidonic acid, a downstream substrate of cPLA 2 . The immunofluorescence staining showed that ROCK 1 or ROCK 2, two isoforms of Rho kinase, was co-localized with cPLA 2 in neuronal cytoplasm. Interestingly, co-immunoprecipitation (Co-IP) assay showed that ROCK 1 or ROCK 2 , bonded directly with cPLA 2 and phospho-cPLA 2 . When the Rho kinase inhibitor Y27632 was applied in mice with T10 contusion injury, it significantly decreased cPLA 2 activation and expression, and reduced injury-induced apoptosis in the lesion area. Taken together, our results reveal a novel mechanism of RhoA/Rho kinase-mediated neuronal death through regulating cPLA 2 activation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Walker

et al. 2016

Mol Neurobiol

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“…Injection of phospholipase A 2 has also been shown to initiate inflammation and cell tissue damage that are characteristic of traumatic SCI. 47 Chemical models of demyelination are useful for evaluation of therapies directed to enhance remyelination. These models include injection of ethidium bromide, lysolethicin, murine hepatitis virus, or a cocktail of myelin-specific antibodies and complement.…”

Section: Chemical Modelsmentioning

confidence: 99%

Spinal cord injury models: a review

et al. 2014

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Background: Animal spinal cord injury (SCI) models have proved invaluable in better understanding the mechanisms involved in traumatic SCI and evaluating the effectiveness of experimental therapeutic interventions. Over the past 25 years, substantial gains have been made in developing consistent, reproducible and reliable animal SCI models. Study design: Review. Objective: The objective of this review was to consolidate current knowledge on SCI models and introduce newer paradigms that are currently being developed. Results: SCI models are categorized based on the mechanism of injury into contusion, compression, distraction, dislocation, transection or chemical models. Contusion devices inflict a transient, acute injury to the spinal cord using a weight-drop technique, electromagnetic impactor or air pressure. Compression devices compress the cord at specific force and duration to cause SCI. Distraction SCI devices inflict graded injury by controlled stretching of the cord. Mechanical displacement of the vertebrae is utilized to produce dislocation-type SCI. Surgical transection of the cord, partial or complete, is particularly useful in regenerative medicine. Finally, chemically induced SCI replicates select components of the secondary injury cascade. Although rodents remain the most commonly used species and are best suited for preliminary SCI studies, large animal and nonhuman primate experiments better approximate human SCI. Conclusion: All SCI models aim to replicate SCI in humans as closely as possible. Given the recent improvements in commonly used models and development of newer paradigms, much progress is anticipated in the coming years. Spinal Cord (2014) 52, 588-595; doi:10.1038/sc.2014.91; published online 10 June 2014 INTRODUCTIONSpinal cord injury (SCI) models have proved indispensible not only for investigating the efficacy of therapeutic interventions but also for better understanding the molecular pathways involved. SCI models have evolved significantly over the past century since Allen developed the first weight-drop contusion model in 1911. 1 SCI models aim to recreate features of human SCI as closely as possible. These models vary in terms of the animal utilized, site of injury infliction and injury mechanism.Rats are used most commonly in preliminary studies as they are relatively inexpensive, readily available and have demonstrated similar functional, electrophysiological, and morphological outcomes to humans following SCI. 2 Mice are particularly useful for genetic studies. 3 Nonhuman primate SCI models-including marmosets, macaques and squirrel monkeys-better approximate human SCI than rodent models, and they accommodate assessment of multiple recovery variables and rehabilitative therapy. 4 New world primates like marmosets confer advantages over old world primates as they are smaller, easier to handle, have a higher breeding efficiency and can be bred in experimental colonies. SCI models that incorporate large animals-such as pigs or dogs-can also be used when it is important for furth...

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“…5,6 All those techniques can be used to observe morphology changes of various types of cells or structures in the WM at the cellular level. However, the requirement of the staining procedure may cause false outcomes 7,8 .…”

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confidence: 99%

Assessment of White Matter Loss Using Bond-Selective Photoacoustic Imaging in a Rat Model of Contusive Spinal Cord Injury

Wang

Cheng

et al. 2014

Journal of Neurotrauma

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White matter (WM) loss is a critical event after spinal cord injury (SCI). Conventionally, such loss has been measured with histological and histochemical approaches, although the procedures are complex and may cause artifact. Recently, coherent Raman microscopy has been proven to be an emerging technology to study de-and remyelination of the injured spinal cord; however, limited penetration depth and small imaging field prevent it from comprehensive assessments of large areas of damaged tissues. Here, we report the use of bond-selective photoacoustic (PA) imaging with 1730-nm excitation, where the first overtone vibration of CH 2 bond is located, to assess WM loss after a contusive SCI in adult rats. By employing the first overtone vibration of CH 2 bond as the contrast, the mapping of the WM in an intact spinal cord was achieved in a label-free three-dimensional manner, and the physiological change of the spinal cord before and after injury was observed. Moreover, the recovery of the spinal cord from contusive injury with the treatment of a neuroprotective nanomedicine ferulic-acid-conjugated glycol chitosan (FA-GC) was also observed. Our study suggests that bond-selective PA imaging is a valuable tool to assess the progression of WM pathology after SCI as well as neuroprotective therapeutics in a label-free manner.

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A novel role of phospholipase A₂ in mediating spinal cord secondary injury

Abstract: PLA2, increased significantly after SCI, may play a key role in mediating neuronal death and oligodendrocyte demyelination following SCI. Blocking PLA2 action may represent a novel repair strategy to reduce tissue damage and increase function after SCI.

Cited by 143 publications

References 42 publications

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Spinal cord injury models: a review

Assessment of White Matter Loss Using Bond-Selective Photoacoustic Imaging in a Rat Model of Contusive Spinal Cord Injury

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A novel role of phospholipase A2 in mediating spinal cord secondary injury

Abstract: PLA2, increased significantly after SCI, may play a key role in mediating neuronal death and oligodendrocyte demyelination following SCI. Blocking PLA2 action may represent a novel repair strategy to reduce tissue damage and increase function after SCI.

Cited by 143 publications

References 42 publications

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Spinal cord injury models: a review

Assessment of White Matter Loss Using Bond-Selective Photoacoustic Imaging in a Rat Model of Contusive Spinal Cord Injury

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A novel role of phospholipase A₂ in mediating spinal cord secondary injury