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. 2018 Sep 14;15(1):264.
doi: 10.1186/s12974-018-1303-5.

Effect of PEA-OXA on Neuropathic Pain and Functional Recovery After Sciatic Nerve Crush

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Free PMC article

Effect of PEA-OXA on Neuropathic Pain and Functional Recovery After Sciatic Nerve Crush

Enrico Gugliandolo et al. J Neuroinflammation. .
Free PMC article

Abstract

Background: Animal models of sciatic nerve injury are commonly used to study neuropathic pain as well as axon regeneration. Inflammation/immune response at the site of nerve lesion is known to be an essential trigger of the pathological changes that have a critical impact on nerve repair and regeneration; moreover, the damage to peripheral nerve can cause a loss of sensory function and produces a persistent neuropathic pain. N-Acylethanolamines (NAEs) involve a family of lipid molecules existent in animal and plant, of which is N-palmitoylethanolamide (PEA) that arouses great attention owing to its anti-inflammatory, analgesic, and neuroprotective activities. The modulation of specific amidases for NAEs (and in particular NAE-hydrolyzing acid amidase NAAA, which is more selective for PEA) could be a condition to preserve its levels. Here, we investigated, in a mice model of sciatic nerve crush, the effect of 2-pentadecyl-2-oxazoline (PEA-OXA) the oxazoline of PEA that reportedly modulates activity of NAAA.

Methods: In this experimental model, the mice, following the sciatic nerve crush, were treated daily with PEA-OXA at a dose of 10 mg\kg for 14 days. Therefore, we evaluated the effects of PEA-OXA on the degree of injury, on the inhibition of neuropathic pain, and on the inflammatory process, as in the improvement of reparative processes and therefore in the restoration of locomotor function.

Results: Our results showed that PEA-OXA (10 mg/kg) treatment, daily, for 14 days after sciatic nerve crush, have an anti-inflammatory and neuroprotective effect and moreover have an analgesic protective effect on hypersensitivity, and improve the functional recovery after nerve crush.

Conclusions: Therefore, treatment with PEA-OXA as a whole has shown a protective effect, which makes it a powerful candidate for the treatment of peripheral nerve injury and neuropathic pain.

Keywords: Neuroinflammation; PEA-OXA; Sciatic nerve.

Conflict of interest statement

Ethics approval and consent to participate

The University of Messina Review Board for the care of animals approved the research. All animal experiments observe the regulations in Italy (D.M. 116192) as well as the EU regulations (O.J. of E.C. L 358/1 12/18/1986).

Consent for publication

“Not applicable” in this section.

Competing interests

Dr. Salvatore Cuzzocrea is a co-inventor on patent WO2013121449A8 (Epitech Group SpA) which deals with compositions and methods for the modulation of amidases capable of hydrolysing N-acylethanolamines applied in the therapy of inflammatory diseases. Moreover, Dr. Cuzzocrea is also a co-inventor with Epitech group on the following patents:

1. EP2821,083

2. MI2014A001495

3. 102015000067344

None of the other authors have any conflicts of interest to declare.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Effect of PEA-OXA on histological changes and mast cell density in sciatic nerve. a Sciatic nerve structure from sham mice. b Nerve from the vehicle group exhibited, 14 days after sciatic nerve crush, the several areas of edema with an abundant presence of infiltrate and degraded myelin sheets. c PEA-OXA treatment significantly reduces the presence of edema and infiltrate, as indicated by nerve histological score in d. e Immunofluorescent staining for β-III-tubulin on longitudinal sections of the sciatic nerve. Following crushing of the sciatic nerve and treatment with PEA-OXA, there is a significant increase in expression of β-III-tubulin, compared to the vehicle group. f, f1 Western blot analysis of the lumbar portion of the spinal cord showed the expression and relative densitometric analysis for β-III-tubulin. The PEA-OXA treatment was able to significantly increase the β-III-tubulin compared with vehicle group. Each data are expressed as mean ± SEM from N  =  10 mice for each group. ***p < 0.001 vs corresponding sham group. ##p < 0.01 vs vehicle group. ###p < 0.001 vs. vehicle group
Fig. 2
Fig. 2
Effect of PEA-OXA on mast cells density and pain behavior. The blue toluidine staining for highlight the mast cells, a for sham group. b 14 days after sciatic nerve crush, there is a significant increase in mast cell number in sciatic nerve from vehicle group. c How daily treatment with PEA-OXA significantly reduces the presence of mast cell compared to vehicle group as shown by d. e, f The analgesic effect of daily treatment of PEA-OXA 10 mg\kg, on thermal hyperalgesia (Plantar test) and mechanical allodynia. g, g1 The c-fos expressions by western blot analysis in the lumbar portion of the spinal cord. h, h1 Western blot analysis on the lumbar portion of the spinal cord for NAAA expressions. Each data are expressed as mean ± SEM from N  =  10 mice for each group. ***p < 0.001 vs corresponding sham group. #p < 0.05 vs. vehicle group, ##p < 0.01 vs vehicle group, ###p < 0.001 vs. vehicle group
Fig. 3
Fig. 3
Effect of PEA-OXA on inflammatory response after sciatic nerve crush. Western blot analysis of the lumbar portion of the spinal cord showed the expression and relative densitometric analysis for: Ikb-α (a, a1); for Nf-κb (b, b1); for TNF-α (c, c1); and for IL-1β (d, d1). Each data are expressed as mean ± SEM from N  =  10 mice for each group. ***p < 0.001 vs corresponding sham. ##p < 0.01 vs vehicle group, ###p < 0.001 vs. vehicle group
Fig. 4
Fig. 4
Effect of PEA-OXA on astrocytes and microglia activation after sciatic nerve crush. The immunofluorescent staining on longitudinal sections of the sciatic nerve for GFAP and Iba-1, showed a significant increase in GFAP and Iba-1 expression in the vehicle group (b, f, respectively) compared to sham mice (a, e, respectively). PEA-OXA treatment significantly reduces the expression for GFAP and Iba-1 compared to the vehicle group, c, g, respectively. The western blot analysis of the lumbar portion of the spinal cord showed the expression and relative densitometric analysis for GFAP and Iba-1 (d, d and h, h1, respectively). Each data are expressed as mean ± SEM from N  =  10 mice for each group. ***p < 0.001 vs corresponding sham. ###p < 0.001 vs. vehicle group
Fig. 5
Fig. 5
Effect of PEA-OXA on apoptotic pathway after sciatic nerve crush. Western blot analysis of the lumbar portion of the spinal cord showed the expression and relative densitometric analysis for caspase-3 (a, a1); Bax (b, b1); Bcl-2 (c, c1). d The TUNEL staining on longitudinal section of sciatic nerve tissue. Each data are expressed as mean ± SEM from N  =  10 mice for each group. ***p < 0.001 vs corresponding sham group. ##p < 0.01 vs vehicle group. ###p < 0.001 vs. vehicle group
Fig. 6
Fig. 6
Effect of PEA-OXA on neural regeneration and functional recovery after sciatic nerve crush. a The western blot analysis of the lumbar portion of the spinal cord showed the expression and relative densitometric analysis for NGF; the PEA-OXA treatment was able to significantly increase the NGF compared with vehicle group. As an index of functional nerve recovery, we evaluated the sciatic functional index SFI (b), the SFI value varies from 0 to − 100, with 0 corresponding to normal function and − 100 corresponding to complete dysfunction. For beam walk test to assess motor coordination improvement after sciatic nerve crush, the test consists of evaluating the ability of mice to cross a wooden beam, the PEA-OXA treatment significantly improves the motor coordination when compared with the vehicle group. In fact, the mice of the vehicle group showed a greater number of sliding of the paw (c), a greater time of crossing of the beam (d), and a greater freeze time spent during the crossing (e). Each data are expressed as mean ± SEM from N  =  10 mice for each group. ***p < 0.001 vs corresponding sham group. ##p < 0.01 vs. vehicle group. ###p < 0.001 vs. vehicle group

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