Molecular evidence for the involvement of PPAR-δ and PPAR-γ in anti-inflammatory and neuroprotective activities of palmitoylethanolamide after spinal cord trauma

Irene Paterniti,Rosalia Crupi,Daniela Impellizzeri,Salvatore Cuzzocrea,Michela Campolo,Rossana Morabito,Emanuela Esposito

doi:10.1186/1742-2094-10-20

Irene Paterniti, Rosalia Crupi + Show 5 more

Open Access

https://doi.org/10.1186/1742-2094-10-20

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Abstract

BackgroundPalmitoylethanolamide (PEA) is an endogenous fatty acid amide displaying anti-inflammatory and analgesic actions. Moreover, several data have suggested that PEA reduced inflammation and tissue injury associated with spinal cord trauma and showed a regulatory role for peroxisome proliferator-activated receptor (PPAR)-α signaling in the neuroprotective effect of PEA. However, several other mechanisms could explain the anti-inflammatory and anti-hyperalgesic effects of PEA, including the activation of PPAR-δ and PPAR-γ. The aim of the present study was to carefully investigate the exact contribution of PPAR-δ and PPAR-γ in addition to PPAR-α, in the protective effect of PEA on secondary inflammatory damage associated with an experimental model of spinal cord injury (SCI).MethodsSCI was induced in mice through a spinal cord compression by the application of vascular clips (force of 24 g) to the dura via a four-level T5 to T8 laminectomy, and PEA (10 mg/kg, intraperitoneally, 1 and 6 hours after SCI) was injected into wildtype mice and into mice lacking PPAR-α (PPAR-αKO). To deepen the ability of specific PPAR-δ and PPAR-γ antagonists to reverse the effect of PEA, mice were administered GSK0660 or GW9662, 30 minutes before PEA injection.ResultsGenetic ablation of PPAR-α in mice exacerbated spinal cord damage, while PEA-induced neuroprotection seemed be abolished in PPARαKO mice. Twenty-four hours after spinal cord damage, immunohistological and biochemical studies were performed on spinal cord tissue. Our results indicate that PPAR-δ and PPAR-γ also mediated the protection induced by PEA. In particular, PEA was less effective in PPAR-αKO, GSK0660-treated or GW9662-pretreated mice, as evaluated by the degree of spinal cord inflammation and tissue injury, neutrophil infiltration, proinflammmatory cytokine, inducible nitric oxide synthase expression and motor function. PEA is also able to restore PPAR-δ and PPAR-γ expression in spinal cord tissue.ConclusionThis study indicates that PPAR-δ and PPAR-γ can also contribute to the anti-inflammatory activity of PEA in SCI.

Highlights

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide displaying anti-inflammatory and analgesic actions
We have recently demonstrated using peroxisome proliferator-activated receptor (PPAR)-α knockout (PPAR-αKO) mice that endogenous PPAR-α activity reduces the degree of development of inflammation and tissue injury events associated with spinal cord trauma in mice, suggesting the existence of an intrinsic anti-inflammatory mechanism mediated by PPAR-α [22]
Role of functional PPAR-α gene in the protective and antiinflammatory properties of PEA on the degree of spinal cord trauma As PPAR-α is constitutively expressed in astrocytes and neurons, it has been proposed that PPAR-α regulates brain and spinal cord lipid homeostasis during physiological conditions

Summary

Introduction

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide displaying anti-inflammatory and analgesic actions. Several data have suggested that PEA reduced inflammation and tissue injury associated with spinal cord trauma and showed a regulatory role for peroxisome proliferator-activated receptor (PPAR)-α signaling in the neuroprotective effect of PEA. The aim of the present study was to carefully investigate the exact contribution of PPAR-δ and PPAR-γ in addition to PPAR-α, in the protective effect of PEA on secondary inflammatory damage associated with an experimental model of spinal cord injury (SCI). Spinal cord injury (SCI) is the result of an initial physical trauma followed by a secondary degenerative process. SCI leads to the destruction of ascending and descending axonal tracts that control motor, sensory and autonomic functions. Post-traumatic inflammatory reaction may play an important role in the secondary injury processes after SCI [1,2]. The secondary damage is sustained by a large number of cellular, molecular, and biochemical cascades and a large body of data suggests the presence of a local inflammatory response, which amplifies the secondary damage [3]

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