Not co-ultramicronized composite including palmitoylethanolamide and luteolin reduces cell damage but palmitoylethanolamide alone

In a critical letter to the editor the conclusion of a recent paper supporting the pharmacology of Pealut (Glialia) was discussed and rejected.

In the studies of the pharmacologists Irene PaternitiDaniela ImpellizzeriRosanna Di PaolaMichele NavarraSalvatore Cuzzocrea and Emanuela Esposito co-ultramicronized PEA and luteolin were tested in several models. However, the results were wrongly interpreted in support of this combination. In the critical letter we can read:

The results presented by Paterniti et al are interesting and should be interpreted in quite a different way as the authors did.

In figure 2 the core results of the study are summarized. This figure clearly demonstrates that increasing doses of palmitoylethanolamide ( 1 uM, 2.7 uM and 27 uM ) are increasingly  effective in reducing cell death. As there are no controls added in the experiments of pure palmitoylethanolamide in the higher dose range (2.7-27 uM), it is not possible to draw the conclusion as the authors do that co-ultramicronization of palmitoylethanolamide and luteolin are the neuroprotective factor. Furthermore, in many of the other figures (3, 4a, 4b and 5) no control values are depicted, and only dose-ranges of 0,27, 2,7 and 27 uM co-ultramicronized palmitoylethanolamide and luteolin are presented.

Therefore one should conclude these experiments by stating that palmitoylethanolamide (with or without luteolin) protects neurons in a dose-dependent way.

The same group published a different set of data one year ago, using PEA 10 mg/kg BW, not ultramicroinzed, and in that paper the protective effect of PEA was exactly identical as high dose ultra-micronized PEA+ luteolin:

Schermafbeelding 2014-04-24 om 21.47.10

Schermafbeelding 2014-04-24 om 21.47.18The paper critizised ended with a remarkable statement for a pharmacological paper:

Of note, a dietary food for special medical purposes by Epitech Group, Saccolongo, Italy, whose active ingredient is a co- ultramicronized PEALut, has recently become available in some European countries for neuroinflammatory conditions.

1. One does not add a clear marketing statement to a pharmacological paper, the more so as there are no human data available on PeaLut, and

2. PeaLut has only become available in Italy under the brandname Glialia, there are no data available to support the notification of this combi-PEA drug as food for medical purposes in other countries.

The final conclusion of the authors in the PeaLut paper was:

These data show new and important neuroprotective effects of the co-ultraPEALut compound, due to a combination of anti-inflammatory properties of PEA and the antioxidant capacity of Lut.

In the light of their previous dataset this is indeed a strange conclusion, without proper controls.

The same conclusion in the absence of a control PEA group we find in a 2013 paper of Esposito et al: The association of palmitoylethanolamide with luteolin reduces neurotoxicity and apoptosis in amyloidbeta stressed hippocampal organotypic slice cultures. Here PeaLut was tested, without proper PEA controls and the conclusion was again supporting the combination of PEA and luteolin:

Our data indicate that PEALut compound was able to blunt a Aβ1-42 -induced neurotoxicity and to control glial activation. These results suggest that this association may provide an effective strategy for AD.

One should however discuss the results as dependent solely on the presence of PEA, without giving the credits to a new marketed PEA formulation as PeaLut.

Source: A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury by Irene Paterniti, Daniela Impellizzeri, Rosanna Di Paola, Michele Navarra, Salvatore Cuzzocrea and Emanuela Esposito. Journal of Neuroinflammation 2013, 10:91 doi:10.1186/1742-2094-10-91

Neuroprotection with palmitoylethanolamide depends on concentration, not on co-ultramicronization by Jan Keppel Hesselink (2014-04-24 17:39) institute neuropathic pain; comment to Journal of Neuroinflammation 2013, 10:91 doi:10.1186/1742-2094-10-91

Irene Paterniti, Daniela Impellizzeri, Rosalia Crupi, Rossana Morabito, Michela Campolo, Emanuela Esposito, Salvatore Cuzzocrea Molecular evidence for the involvement of PPAR-δ and PPAR-γ in anti-inflammatory and neuroprotective activities of palmitoylethanolamide after spinal cord trauma. Journal of Neuroinflammation 2013, 10:20 (1 February 2013)

E. Esposito, I. Paterniti, M. Campolo, M. Cordaro, S. Cuzzocrea. The association of palmitoylethanolamide with luteolin reduces neurotoxicity and apoptosis in amyloid-beta stressed hippocampal organotypic slice cultures.  2013-Esposito-PeaLut-Alzheimer: presented at the 36° CONGRESSO NAZIONALE DELLA SOCIETÀ ITALIANA DI FARMACOLOGIA, Il ruolo della RICERCA farmacologica per la CRESCITA e la SALUTE in Italia Torino, 23-26 ottobre 2013

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